Mitochondrial dynamics in health and disease: 2023년 Nature reveiw

[문형철]

• Review Article
• Open access
• Published: 06 September 2023

Mitochondrial dynamics in health and disease: mechanisms and potential targets

• Wen Chen, 
• Huakan Zhao & 
• Yongsheng Li 

Signal Transduction and Targeted Therapy volume 8, Article number: 333 (2023) Cite this article

Abstract

Mitochondria are organelles that are able to adjust and respond to different stressors and metabolic needs within a cell, showcasing their plasticity and dynamic nature. These abilities allow them to effectively coordinate various cellular functions. Mitochondrial dynamics refers to the changing process of fission, fusion, mitophagy and transport, which is crucial for optimal function in signal transduction and metabolism.

An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular fate, and a range of diseases, including neurodegenerative disorders, metabolic diseases, cardiovascular diseases and cancers. Herein, we review the mechanism of mitochondrial dynamics, and its impacts on cellular function. We also delve into the changes that occur in mitochondrial dynamics during health and disease, and offer novel perspectives on how to target the modulation of mitochondrial dynamics.

미토콘드리아는 세포 내에서 다양한 스트레스 요인과 신진대사 요구에 따라 조절하고 반응할 수 있는 세포 소기관으로, 가소성과 역동적인 특성을 보여줍니다. 이러한 능력 덕분에 다양한 세포 기능을 효과적으로 조정할 수 있습니다. 미토콘드리아 역학은 분열, 융합, 미토파지 및 수송의 변화 과정을 의미하며, 이는 신호 전달과 신진대사의 최적 기능에 매우 중요합니다.

미토콘드리아 역학의 불균형은

미토콘드리아 기능을 방해하여

비정상적인 세포 운명을 초래하고

신경 퇴행성 질환,

대사 질환,

심혈관 질환 및

암을 포함한 다양한 질병을 일으킬 수 있습니다.

이 글에서는 미토콘드리아 역학의 메커니즘과 세포 기능에 미치는 영향에 대해 살펴봅니다. 또한 건강과 질병 중에 미토콘드리아 역학에서 일어나는 변화를 탐구하고, 미토콘드리아 역학 조절을 표적으로 삼는 방법에 대한 새로운 관점을 제시합니다.

Article 17 March 2022

Introduction

Mitochondria (mt) are highly plastic and dynamic organelles that critical for cellular metabolism, stress responses and homeostasis maintenance. As the sites for biochemical processes such as adenosine triphosphate (ATP) production, fatty acid synthesis, intracellular reactive oxygen species (ROS) generation, oxidative phosphorylation (OXPHOS), thermogenesis and calcium (Ca2+) homeostasis, mitochondria are considered as the hub of cellular metabolism.1,2 Furthermore, signal intermediates generated in mitochondria during metabolism are important for regulating cellular function and phenotype.3 

For example, mt-ROS are implicated in the signal transduction of inflammatory responses. Once the toll-like receptor (TLR) signaling is activated by lipopolysaccharide (LPS), mitochondria will be recruited to the phagosome and augmented the production of mt-ROS to enhance the antibacterial activity of macrophages.4 In addition, dysfunctional mitochondrial are closely interrelated to a range of disease and pathology including metabolic diseases, neurodegenerative disorders and cancers, which are broadly characterized by impaired mitochondrial function.5,6

미토콘드리아(mt)는 세포 대사, 스트레스 반응, 항상성 유지에 중요한 역할을 하는 매우 가소성 있고 역동적인 세포 소기관입니다. 

미토콘드리아는 

아데노신 삼인산(ATP) 생성, 

지방산 합성, 

세포 내 활성 산소종(ROS) 생성, 

산화적 인산화(OXPHOS), 

열 발생 및 

칼슘(Ca2+) 항상성 유지와 같은 생화학 과정의 부위로서 세포 대사의 허브로 간주됩니다.1,2 또한 대사 과정에서 미토콘드리아에서 생성되는 신호 중간체는 세포 기능과 표현형을 조절하는 데 중요합니다.3 

예를 들어, 

mt-ROS는 염증 반응의 신호 전달에 관여합니다. 

지질다당류(LPS)에 의해 톨유사수용체(TLR) 신호가 활성화되면 

미토콘드리아가 파고솜으로 모집되어 

대식세포의 항균 활동을 강화하기 위해 mt-ROS의 생성을 증가시킵니다.4 

또한 미토콘드리아의 기능 장애는 대사 질환, 신경 퇴행성 질환 및 암을 포함한 다양한 질병 및 병리와 밀접한 관련이 있으며, 이는 광범위하게 미토콘드리아의 기능 장애를 특징으로 합니다.5,6

The process of changes in the morphology, quantity and position of mitochondria within eukaryotic cells are defined as mitochondrial dynamics, which are indispensable for proper functions of the cells, e.g., energy production and other pivotal cellular processes including movement, differentiation, cell cycle, senescence and apoptosis.7 Dysregulation of mitochondrial dynamics is one key pathogenic mechanisms of a diverse of diseases and pathologies that are characterized by dysfunctional mitochondrial.8,9 

For example, ischemia cause excessive mitochondrial fission and fragmentation, resulting in cardiomyocyte death.10,11 On the contrary, emerging evidence indicates that enhancing mitochondrial fitness by regulating mitochondrial dynamics could prolong life-span and bring beneficial for health.12,13,14 

For instance, mitochondrial fission mediated by dynamin-related protein (Drp1) may be a key determinant of insulin resistance; and aerobic exercise intervention restrains the activation of Drp1 and mitochondrial fission, which improves fat acid oxidation (FAO) and insulin sensitivity.15

진핵세포 내 미토콘드리아의 형태, 양, 위치가 변화하는 과정을 미토콘드리아 역학으로 정의하며, 이는 

에너지 생산과 같은 세포의 적절한 기능과

 운동, 

분화, 

세포 주기, 

노화 및 세포 사멸을 포함한 기타 중추적인 세포 과정에 필수적입니다.7

미토콘드리아 역학의 조절 장애는 미토콘드리아 기능 장애를 특징으로 하는 다양한 질병 및 병리의 주요 병인 기전 중 하나입니다.8,9

예를 들어, 허혈은 과도한 미토콘드리아 분열과 단편화를 유발하여 심근세포 사멸을 초래합니다.10,11

반대로, 미토콘드리아 역학을 조절하여 미토콘드리아 적합성을 향상하면 수명을 연장하고 건강에 유익할 수 있다는 새로운 증거가 있습니다.12,13,14 예를 들어, 다이나민 관련 단백질(Drp1)에 의해 매개되는 미토콘드리아 분열은 인슐린 저항성의 주요 결정 요인이 될 수 있으며, 유산소 운동 중재는 Drp1과 미토콘드리아 분열의 활성화를 억제하여 지방산 산화(FAO)와 인슐린 감수성을 개선합니다.15

 

As such, comprehensive understanding of mitochondrial dynamics will conduce to develop more precise strategies for targeted regulation of mitochondrial function. Herein, we introduce the regulation mechanism of mitochondrial dynamics, its role in mediating cellular function, its alterations in health and diseases, and provide new insights for targeted modulation of mitochondrial dynamics.

따라서 미토콘드리아 역학에 대한 포괄적인 이해는 미토콘드리아 기능의 표적 조절을 위한 보다 정밀한 전략 개발로 이어질 것입니다. 이 글에서는 미토콘드리아 역학의 조절 메커니즘, 세포 기능을 매개하는 미토콘드리아의 역할, 건강과 질병의 변화를 소개하고 미토콘드리아 역학의 표적 조절을 위한 새로운 통찰 제공합니다.

Overview of mitochondrial dynamics

Mitochondria undergo the continuous processes of fission, fusion, mitophagy and transport cycles, which determine the morphology, quality, quantity and distribution of mitochondria within cells, as well as the mitochondrial function (Fig. 1). Mitochondria have their own DNA and need to constantly repair and replace their components to function properly. Through mitochondrial dynamics, damaged components can be removed from a mitochondrion, or impaired mitochondria can be entirely eliminated by mitophagy, to prevent further cellular damage.16 Maintaining a balance of mitochondrial dynamics is pivotal for optimal function of mitochondria and cell fate.17 

미토콘드리아는 분열, 융합, 미토파지 및 수송 주기의 지속적인 과정을 거쳐 세포 내 미토콘드리아의 형태, 품질, 양 및 분포와 미토콘드리아 기능을 결정합니다(그림 1).

미토콘드리아는 자체 DNA를 가지고 있으며,

제대로 기능하기 위해 지속적으로 구성 요소를 수리하고 교체해야 합니다.

미토콘드리아 역학을 통해

손상된 구성 요소를 미토콘드리아에서 제거하거나

손상된 미토콘드리아를 미토파지에 의해 완전히 제거하여 더 이상의 세포 손상을 방지할 수 있습니다.16

미토콘드리아 역학의 균형을 유지하는 것은 미토콘드리아의 최적 기능과 세포의 운명을 결정짓는 중요한 요소입니다.17 

Schematic illustration of the mitochondrial dynamics. a mitochondrial fission and fusion. The primary fusion factors involved are Opa1, MFN1, and MFN2, which bind to the inner and outer membranes of mitochondria (IMM and OMM). Fission is mainly mediated by Drp1, which binds to the OMM and forms a ring-like structure around the organelle, resulting in its division into two separate ones. b Mitophagy: the PINK/parkin target damaged mitochondria to the lysosome for degradation. c Mitochondrial transport along microtubules is facilitated by TRAK/Miro motor adapter complex. Drp1: dynamin-related protein 1; MFN1/2: mitogenic protein 1/2; Opa1: optic atrophy protein 1; Fis1: protein fission 1; Mff: mitochondrial fission factor, PINK: PTEN-induced kinase 1, Miro: mitochondrial rho GTPase

In brief, fission contributes to mitochondrial quality control by elimination of impaired or dysfunctional mitochondria, and promotes apoptosis facing the severe cellular stress, while fusion is conducive to mix and exchange the intramitochondrial contents between mitochondria, these help to maintain mitochondrial function.16 Besides, mitophagy is indispensable for quality control of mitochondrial and inhibiting pro-apoptotic proteins release by selective clearance of damaged mitochondria.18 

간단히 말해, 분열은 손상되거나 기능 장애가 있는 미토콘드리아를 제거하여 미토콘드리아의 품질 관리에 기여하고 심각한 세포 스트레스에 직면한 세포 사멸을 촉진하며, 융합은 미토콘드리아 간 미토콘드리아 내 내용물을 혼합하고 교환하여 미토콘드리아 기능을 유지하는 데 도움이 됩니다.16

또한, 미토파지는

손상된 미토콘드리아를 선택적으로 제거하여

미토콘드리아의 품질을 조절하고

세포사멸 단백질 방출을 억제하는 데 필수적입니다.18

Mitochondrial transport is also important for ensuring that mitochondria are located in the proper cellular regions where their energy-generating functions are needed.19 At present, it has been established that each step of mitochondrial dynamics is precisely regulated by upstream signaling cascades. We also summarize the key proteins and its upstream signals that orchestrate the process of mitochondrial fission and fusion (Fig. 2).

미토콘드리아 수송은

미토콘드리아가 에너지 생성 기능이 필요한 적절한 세포 영역에 위치하도록 하는 데에도 중요합니다.19

현재 미토콘드리아 역학의 각 단계는 상류 신호 캐스케이드에 의해 정밀하게 조절된다는 것이 확립되어 있습니다. 또한 미토콘드리아의 분열과 융합 과정을 조율하는 주요 단백질과 그 업스트림 신호를 요약했습니다(그림 2).

Fig. 2

Key proteins and signaling pathways orchestrate mitochondrial fusion and fission. Representative signaling pathways involved in mitochondrial fusion and fission. Green arrows represent stimulation or activation of pathway; red lines represent repression or inactivation of pathway

Structure of mitochondria

Mitochondria are organelles that enclosed by a double membrane consisting of outer membrane, inner membrane, the inter-membrane space (IMS) and the matrix.20 The outer mitochondrial membrane (OMM) is a lipid bilayer that encloses the entire mitochondrion. It is composed of various lipids and proteins that are crucial for its structure and function. The main lipid components of the OMM are phospholipids, which make up approximately two-thirds of the membrane’s total lipid content.21 One of the primary functions of the OMM is acting as a barrier between the mitochondria and the cytoplasm. Another important function of OMM is mediating the transport of metabolites and ions in or out of mitochondria. Especially, the voltage-dependent anion channels (VDAC), the major channel of the OMM, plays a pivotal role in transporting metabolic molecules such as ATP, adenosine diphosphate (ADP), and other respiratory substrates across the OMM.22 

미토콘드리아는 외막, 내막, 막간 공간(IMS), 매트릭스로 구성된 이중막으로 둘러싸인 세포 소기관입니다.20 

외미토콘드리아막(OMM)은 미토콘드리아 전체를 둘러싸고 있는 지질 이중층입니다. 미토콘드리아의 구조와 기능에 중요한 다양한 지질과 단백질로 구성되어 있습니다. OMM의 주요 지질 성분은 인지질로, 막 전체 지질 함량의 약 3분의 2를 차지합니다.21 OMM의 주요 기능 중 하나는 미토콘드리아와 세포질 사이의 장벽 역할을 하는 것입니다. OMM의 또 다른 중요한 기능은 미토콘드리아 안팎으로 대사산물과 이온의 수송을 매개하는 것입니다. 특히, OMM의 주요 채널인 전압 의존성 음이온 채널(VDAC)은 ATP, 아데노신 디포스페이트(ADP) 및 기타 호흡기 기질과 같은 대사 분자를 OMM을 통해 운반하는 데 중추적인 역할을 합니다.22

In addition to its structural and transport functions, the OMM is also involved in a variety of intracellular signaling pathways. For example, intrinsic apoptosis pathway activates the pro-apoptotic BCL-2 family proteins Bax/Bak activity, promoting pore formation in OMM allowing cytochrome c (Cyt C) to release from the mitochondria into the cytosol, then activates caspases and initiates apoptosis.23 Finally, the OMM carries all the proteins and molecules involved in mitochondrial dynamics.24

OMM은 구조 및 수송 기능 외에도 다양한 세포 내 신호 전달 경로에 관여합니다. 예를 들어, 내재적 세포 사멸 경로는 세포 사멸을 촉진하는 BCL-2 계열 단백질인 Bax/Bak 활성을 활성화하여 OMM의 기공 형성을 촉진함으로써 미토콘드리아에서 세포질로 사이토크롬 C(Cyt C)가 방출되도록 한 다음 카스파제를 활성화하고 세포 사멸을 개시합니다.23 마지막으로, OMM은 미토콘드리아 역학에 관여하는 모든 단백질과 분자를 운반합니다.24

The inner mitochondrial membrane (IMM) is a highly convoluted membrane that forms invaginations that extend deeply into the matrix called cristae. These cristae provide more surface area and room for matrix, allowing for more efficient OXPHOS.20 The most important of these functions is the production of ATP. The electron transport chain (ETC) complexes I-IV integrated into the IMM, transfer electrons from reduced substrates, such as icotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FADH2) and Cyt C, to molecular oxygen.20 Besides, the IMM is also critical for Ca2+ homeostasis. The IMM contains several Ca2+ transporters, including mitochondrial calcium uniporter (MCU) and mitochondrial Na+/Ca2+ exchanger (NCX).25 These transporters regulate the flux of calcium ions into and out of the mitochondria, maintaining appropriate calcium levels within the organelle. Generation of ROS is another important function of the IMM.26 The IMM carries several enzymes that control ROS production, including superoxide dismutase (SOD), which catalyze the dismutation of superoxide radicals (O2-) into molecular oxygen and hydrogen peroxide, and glutathione peroxidase (GPX), which catalyzes the reduction of hydrogen peroxide to water and oxygen. Finally, the IMM also plays an important role in the regulation of apoptosis.27 The mitochondrial permeability transition pore (mPTP), non-specific channel assembled by a large protein complex that located in the IMM, is involved in the regulation of apoptosis. Opening the mPTP leads to the release of Cyt C and other apoptotic molecules from the mitochondria into cytoplasm, triggering the apoptotic cascades.

미토콘드리아 내막(IMM)은 매우 복잡한 막으로, 크리스테라고 불리는 매트릭스 깊숙이 확장된 침윤을 형성합니다. 이러한 크리스테는 더 많은 표면적과 매트릭스를 위한 공간을 제공하여 보다 효율적인 옥시포스를 가능하게 합니다.20 이러한 기능 중 가장 중요한 것은 ATP의 생산입니다. 

IMM에 통합된 전자 수송 사슬(ETC) 복합체 I-IV는 

이코틴아미드 아데닌 디뉴클레오티드(NADH), 

플라빈 아데닌 디뉴클레오티드(FADH2), 

Cyt C와 같은 환원 기질에서 분자 산소로 전자를 전달합니다.20 

시토크롬c는 아포토시스(apoptosis)의 조정자이기도 하다. 아포토시스는 통제된 세포자살사로 발생과정이나 DNA손상에 의한 반응으로 일어난다. 시토크롬c는 아포토시스를 이끄는 자극에 반응하여 미토콘드리아 내막에서 방출된다. 아포토시스를 야기하는 자극은 여러가지인데, 산소 결핍이나 칼슘농축등이 있다. 시토크롬c의 방출은 카스페이스(caspase)9를 불활성화시키고 연쇄적으로 카스페이스 3과 4를 활성화하여 세포자살에 이르게 한다.

또한 IMM은 Ca2+ 항상성에도 매우 중요합니다. IMM에는 미토콘드리아 칼슘 유니포터(MCU)와 미토콘드리아 Na+/Ca2+ 교환기(NCX)를 포함한 여러 Ca2+ 수송체가 포함되어 있습니다.25 이러한 수송체는 미토콘드리아 안팎으로 칼슘 이온의 흐름을 조절하여 세포 내 적절한 칼슘 수치를 유지합니다. 

ROS 생성은 IMM의 또 다른 중요한 기능입니다.26 

IMM에는 

과산화수소 라디칼(O2-)이 분자 산소와 과산화수소로 변이되는 것을 촉매하는 슈퍼옥사이드 디스뮤타제(SOD)와 

과산화수소가 물과 산소로 환원되는 것을 촉매하는 글루타치온 퍼옥시다제(GPX) 등 ROS 생산을 제어하는 여러 효소가 존재합니다. 

마지막으로, IMM은 세포 사멸 조절에도 중요한 역할을 합니다.27 IMM에 위치한 대형 단백질 복합체에 의해 조립된 비특이적 채널인 미토콘드리아 투과성 전이 기공(mPTP)이 세포 사멸 조절에 관여합니다. mPTP가 열리면 미토콘드리아에서 세포질로 Cyt C 및 기타 세포 사멸 분자가 방출되어 세포 사멸 캐스케이드가 촉발됩니다.

The IMS is the smallest and most constricted part of the mitochondria.20,28 IMS serves various functions, making it one of the most important sub-compartments in the mitochondria. IMS possesses a wide variety of protein import pathways, which allows the importation of diverse proteins essential in mitochondrial DNA (mtDNA) maintenance, apoptosis, and protein folding.28 

The OMM sorts and translocates proteins and assembly machinery complex. Once interacted with the protein, mitochondrial IMS imports, and assembly machinery system assists in the insertion of conserved cysteine motifs-containing proteins into IMS.28 Additionally, enzymes present in the space are responsible for catalyzing the formation of disulfide bonds, which are pivotal for correct folding and stability of many mitochondrial and secretory proteins.28 Furthermore, the IMS regulates cell signaling by controlling calcium signaling and ROS production,29 and also plays an important role in the intrinsic apoptosis process, resulting in programmed cell death.30 Overall, the IMS is a crucial and multifaceted sub-compartment that contributes to various cellular processes. Any disruption to the IMS homeostasis can lead to mitochondrial dysfunction, which can cause severe health complications such as metabolic disorders, immune system dysfunction, and neurodegenerative diseases.31

IMS는 미토콘드리아에서 가장 작고 수축된 부분입니다.20,28 IMS는 다양한 기능을 수행하여 미토콘드리아에서 가장 중요한 하위 구획 중 하나입니다. 

IMS는 

다양한 단백질 유입 경로를 가지고 있어 

미토콘드리아 DNA(mtDNA) 유지, 

세포 사멸 및 단백질 폴딩에 필수적인 다양한 단백질을 유입할 수 있습니다.28 

OMM은 단백질과 조립 기계 복합체를 분류하고 위치를 이동시킵니다. 단백질과 상호 작용하면 미토콘드리아 IMS가 수입되고 조립 기계 시스템은 보존된 시스테인 모티프 함유 단백질을 IMS에 삽입하는 것을 지원합니다.28 

또한 공간에 존재하는 효소는 많은 미토콘드리아 및 분비 단백질의 올바른 폴딩과 안정성에 중요한 이황화 결합의 형성을 촉매합니다.28 

또한 IMS는 

칼슘 신호 전달과 ROS 생성을 조절하여 

세포 신호를 조절하고,29 

내재적 세포 사멸 과정에서도 중요한 역할을 수행하여 

프로그램된 세포 사멸을 초래합니다.30 

전반적으로 IMS는 다양한 세포 과정에 기여하는 중요하고 다면적인 하위 구획입니다. IMS 항상성이 깨지면 미토콘드리아 기능 장애가 발생하여 대사 장애, 면역계 기능 장애, 신경 퇴행성 질환과 같은 심각한 건강상의 합병증을 유발할 수 있습니다.31

The space enclosed by the IMM is named as the mitochondrial matrix, which are filled with a fluid containing various metabolic products, enzymes, ribosomes, proteins, as well as mtDNA. Its peculiar structure and composition provide an excellent site for virous biochemical reactions, such as protein biosynthesis, lipid biosynthesis, Krebs cycle, OXPHOS, and mtDNA replication. The main function of the matrix is to produce ATP through OXPHOS by forming a proton motive force across the IMM.20 

미토콘드리아를 둘러싸고 있는 공간을 미토콘드리아 매트릭스라고 하며, 

이 공간은 다양한 대사 산물, 효소, 리보솜, 단백질 및 mtDNA를 포함하는 액체로 채워져 있습니다. 

그 독특한 구조와 구성은 

단백질 생합성, 

지질 생합성, 

크렙스 주기, 

옥스포스, 

mtDNA 복제와 같은 바이러스성 생화학 반응에 탁월한 장소를 제공합니다. 

매트릭스의 주요 기능은 

IMM을 가로질러 양성자 원동력을 형성하여 

OXPHOS를 통해 ATP를 생성하는 것입니다.20

In the matrix, the catabolism of carbohydrates, lipids, and proteins occurs via the tricarboxylic acid (TCA) cycle and subsequent OXPHOS, resulting in ATP production.32 Apart from energy production, the matrix regulates metabolic processes, e.g., transporting proteins to the mitochondria, maintaining ion balance, and removing ROS. The matrix contains specific transporters, such as the mitochondrial pyruvate carriers33 and the ATP/ADP translocases,34 that enable molecules to mobilize in and out of the mitochondria. Additionally, the matrix houses chaperones and proteases that monitor protein folding, assembly, quality control, and degradation.35 The matrix’s unique composition enables its efficient function in the production of cellular energy, metabolic regulation, and other essential cellular functions.

매트릭스에서 

탄수화물, 지질, 단백질의 이화 작용은 

트리카르복실산(TCA) 순환과 후속 옥스포스를 통해 일어나며, 

그 결과 ATP가 생성됩니다.32 

매트릭스는 

에너지 생산 외에도 

단백질을 미토콘드리아로 운반하고 

이온 균형을 유지하며 

ROS를 제거하는 등의 대사 과정을 조절합니다. 

매트릭스에는 미토콘드리아 피루브산 운반체33 및 ATP/ADP 전위체34와 같은 특정 수송체가 포함되어 있어 분자가 미토콘드리아 안팎으로 이동할 수 있도록 합니다. 

또한 매트릭스에는 

단백질 접힘, 조립, 품질 관리 및 분해를 모니터링하는 샤프론과 프로테아제가 있습니다.35 

매트릭스의 독특한 구성은 

세포 에너지 생산, 

대사 조절 및 기타 필수 세포 기능의 효율적인 기능을 가능하게 합니다.

Mitochondrial fission

Mitochondrial fission is a multi-step procedure that giving rise to the splitting of one mitochondrion into two.36 The process of division primarily occurs at sites where the OMM constricts due to the polymerization of actin or interaction with the endoplasmic reticulum (ER). This process involves the recruitment of the GTPase enzyme Drp1 by various OMM adapter proteins, including mitochondrial fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics protein (MiD)-49, and MiD51.37,38 Then, highly oligomerized of Drp1 is activated by mitochondrial specific lipid cardiolipin to form large helical structures and augments GTPase activity at the mitochondrial fission foci.37 Nucleotide-driven allostery of Drp1 facilitates its self-assembly, conformational transformation and disassembly to encircle mitochondria and induces mitochondrial fission.

Drp1 exists in the cytoplasm when inactivated, and its activation is regulated by phosphorylation, SUMOylation, ubiquitination and S-nitrosylation modification.39,40 

미토콘드리아 분열은 하나의 미토콘드리아가 두 개로 분리되는 다단계 과정입니다.36 분열 과정은 주로 액틴의 중합 또는 소포체(ER)와의 상호 작용으로 인해 OMM이 수축되는 부위에서 발생합니다.

이 과정에는

미토콘드리아 분열 1(Fis1),

미토콘드리아 분열 인자(Mff),

미토콘드리아 역학 단백질(MiD)-49 및 MiD51을 포함한

다양한 OMM 어댑터 단백질에 의한 GTPase 효소 Drp1의 영입이 포함됩니다.37,38

그런 다음

고도로 올리고머화된 Drp1은

미토콘드리아 특이 지질 카디오리핀에 의해 활성화되어 큰 나선 구조를 형성하고

미토콘드리아 분열 부위에서 GTPase 활동을 증강시킵니다.37

https://www.youtube.com/watch?v=ZTyLLOjfi_4

뉴클레오타이드에 의한 Drp1의 알로스테리는

미토콘드리아를 둘러싸기 위한

자기 조립,

형태 변형 및 분해를 촉진하고

미토콘드리아 분열을 유도합니다.

Drp1은 비활성화되었을 때 세포질에 존재하며, 활성화는 인산화, 수모일화, 유비퀴틴화 및 S-니트로실화 변형에 의해 조절됩니다.39,40

Phosphorylation and SUMOylation also regulate mitochondrial recruitment of cytosolic Drp1.41,42 During cell mitosis, activation of Drp1 through phosphorylation at S616 by cyclin dependent kinase (Cdk)-1 and protein kinase C isoform delta (PKCδ) facilitates mitochondrial division.43 Other kinases, such as activation of mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), Cdk5 and Ca2+/calmodulin dependent protein kinase II (CAMKII), have also been reported to phosphorylate Drp1-S616 to facilitate mitochondrial fission.39 Additionally, the activity of Drp1 is restrained when protein kinase A (PKA)-mediated phosphorylation of Drp1 at S637, while dephosphorylation at S637 by calcineurin-mediated pathways facilitate mitochondrial cleavage by recruiting Drp1 to the OMM.44 On the other hand, phosphorylation of Drp1-S637 by CaMK1α and Rho-associated coiled-coil containing protein kinase 1 (ROCK1) increases the division activity of Drp1, suggesting that except from the phosphorylated site, the cellular context also perform a profound influence on the activity of Drp1.45

인산화 및 수모일화는 또한 세포질 Drp1의 미토콘드리아 영입을 조절합니다.41,42 세포 유사 분열 중에 사이클린 의존성 키나아제(Cdk)-1 및 단백질 키나아제 C 이소형 델타(PKCδ)에 의한 S616에서의 인산화를 통한 Drp1의 활성화는 미토콘드리아 분열을 촉진합니다.43 

미토겐 활성화 단백질 키나아제(MAPK), 

세포 외 신호 조절 키나아제(ERK), 

Cdk5 및 Ca2+/칼모둘린 의존성 단백질 키나아제 II(CAMKII)의 활성화와 같은 다른 키나아제들도 

Drp1-S616을 인산화하여 미토콘드리아 분열을 촉진하는 것으로 보고되었습니다.39 또한, 

단백질 키나아제 A(PKA)에 의해 S637에서 Drp1이 인산화되면 Drp1의 활성이 억제되는 반면, 

칼시뉴린 매개 경로에 의한 S637에서의 탈인산화는 Drp1을 OMM으로 유인하여 미토콘드리아 분열을 촉진합니다.44 

한편, CaMK1α 및 Rho 관련 코일 함유 단백질 키나아제 1 (ROCK1)에 의한 Drp1-S637의 인산화는 Drp1의 분열 활성을 증가시켜 인산화 된 부위 외에도 세포 맥락이 Drp1의 활성에 깊은 영향을 미친다는 것을 시사합니다.45

The activity of Drp1 is also affected by its SUMOylation status. The SUMOylation of Drp1 by SUMO-1 intercepts the lysosomal degradation of Drp1, further promoting mitochondrial division. Conversely, DeSUMOylation of SUMO-2/3 from Drp1 by the enzyme SUMO specific peptidase 3 (SENP3) reinforces mitochondrial fission via facilitating interaction of Drp1 with the OMM resident adapter protein Mff.46 In addition, AMP-activated protein kinase (AMPK) phosphorylates Mff, then promote the binding of Drp1 with Mff, which facilitates recruitment of Drp1 from the cytosol to mitochondria under energetic stress.47 

Drp1의 활성은 또한 수모일화 상태에 의해 영향을 받습니다. SUMO-1에 의한 Drp1의 SUMO일화는 Drp1의 리소좀 분해를 차단하여 미토콘드리아 분열을 더욱 촉진합니다. 반대로, 효소 수모 특이적 펩티다제 3(SENP3)에 의한 Drp1의 SUMO-2/3의 탈수모화는 Drp1과 OMM 상주 어댑터 단백질 Mff의 상호작용을 촉진하여 미토콘드리아 분열을 강화합니다.46 또한 AMP 활성화 단백질 키나아제(AMPK)는 Mff를 인산화한 다음 Drp1과 Mff의 결합을 촉진하여 에너지 스트레스 하에서 Drp1이 사이토졸에서 미토콘드리아로 이동하는 것을 용이하게 합니다.47

Moreover, E3 ubiquitin ligase MARCH5 mediated-ubiquitination of Drp1 protein and its receptor MiD49 facilitates the degradation of these two protein, therefore suppressing mitochondrial fission.48 Finally, S-nitrosylation of Drp1 at C-terminal GTPase effector domain caused by β-amyloid protein facilitates Drp1 assembly and GTPase capability, which triggering mitochondrial fission in Alzheimer’s disease.49 Besides, Post-translational modification of Drp1 receptors also affects their stability and activity. For example, AMPK-mediated phosphorylation of Mff promotes Drp1 recruitment to OMM;47,50 MiD49 can be ubiquitinated by MARCH5/MITOL and subsequently degraded by proteasome, which restraining mitochondrial fission.48 Hence, multiple signaling pathways integrate different post-translational modifications of Drp1 and its receptors to orchestrate the process of mitochondrial fission.

또한, E3 유비퀴틴 리가제 MARCH5가 Drp1 단백질과 그 수용체 MiD49를 매개로 유비퀴틴화하면 이 두 단백질의 분해를 촉진하여 미토콘드리아 분열을 억제합니다.48

마지막으로, β-아밀로이드 단백질에 의한 C-말단 GTPase 이펙터 도메인에서 Drp1의 S-니트로실화는 알츠하이머병에서 미토콘드리아 분열을 유발하는 Drp1 조립 및 GTPase 기능을 촉진합니다.49

또한, Drp1 수용체의 번역 후 변형은 수용체의 안정성과 활성에도 영향을 미칩니다. 예를 들어, AMPK를 매개로 한 Mff의 인산화는 Drp1이 OMM으로 이동하는 것을 촉진하고,47,50 MiD49는 MARCH5/MITOL에 의해 유비퀴틴화되고 이후 프로테아좀에 의해 분해되어 미토콘드리아 분열을 억제합니다.48 따라서 여러 신호 경로가 Drp1과 그 수용체의 다양한 번역 후 변형을 통합하여 미토콘드리아 분열 과정을 조율합니다.

Inhibition of Drp1 activity by dominant-inactivation mutations results in the formation of elongated tangles and collapses of mitochondria.38 The knockout of mouse Drp1 through genetic engineering results in embryonic lethality, indicating the crucial role of Drp1-dependent mitochondrial division in embryogenesis.51,52,53 Beyond affecting mitochondrial function and morphology, mitochondrial fission possess other functions, such as promoting mitochondrial transport, mitophagy, cell division as well as apoptosis.51,52,53

우성 비활성화 돌연변이에 의한 Drp1 활성 억제는 미토콘드리아의 길쭉한 엉킴과 붕괴를 초래합니다.38 유전 공학을 통한 마우스 Drp1의 녹아웃은 배아 치사를 초래하여 배아 발생에서 Drp1 의존 미토콘드리아 분열이 중요한 역할을 한다는 것을 나타냅니다.51,52,53 

미토콘드리아 분열은 

미토콘드리아의 기능과 형태에 영향을 미치는 것 외에도 

미토콘드리아 수송, 

미토파지, 

세포 분열 및 세포 사멸을 촉진하는 등의 다른 기능을 가지고 있습니다.51,52,53

Mitochondrial fusion

Mitochondrial fusion includes several steps, starting with the activation of dynein-associated GTPases, including mitofusin (MFN) 1/2 on OMM, FAM73a/FAM73b and optic atrophy protein 1 (Opa1) on IMM,54,55,56 followed by OMM fusion induced by GTP hydrolysis, subsequently IMM fusion and finally the mixing of intra-mitochondrial components.54 Mitochondrial fusion dilutes dysfunctional proteins and mutated mtDNA by mixing mitochondrial proteins, mtDNA and other matrix components to maintain mitochondrial homogeneity and functional stability.55 Genetic knockout of MFN1 and/or MFN2, destroys the mitochondrial structure and induces serious cellular defects, including smaller and more fragmented mitochondria, lower mitochondrial membrane potential, attenuated respiration activity and ATP production, which in turn suppresses cell proliferation.57

미토콘드리아 융합은 여러 단계를 거치는데, 

먼저 OMM의 미토퓨신(MFN) 1/2, 

IMM의 FAM73a/FAM73b 및 시신경 위축 단백질 1(Opa1)을 포함한 다이닌 관련 GTPase의 활성화로 시작하여,54,55,56 

GTP 가수분해로 유도된 OMM 융합, 

이어서 IMM 융합 및 마지막으로 미토콘드리아 내 구성 요소의 혼합이 이루어집니다.54 

미토콘드리아 융합은 

미토콘드리아 단백질, 

mtDNA 및 기타 매트릭스 성분을 혼합하여 

기능 장애 단백질과 돌연변이 mtDNA를 희석하여 

미토콘드리아의 균질성과 기능적 안정성을 유지합니다.55 

MFN1 및/또는 MFN2의 유전자 녹아웃은 미토콘드리아 구조를 파괴하고 더 작고 조각난 미토콘드리아, 낮은 미토콘드리아 막 전위, 약화된 호흡 활동 및 ATP 생산을 포함한 심각한 세포 결함을 유발하여 세포 증식을 억제합니다.57

The most efficient process of mitochondrial fusion is observed when both MFN proteins are present simultaneously. Additionally, a deficiency in MFN1 leads to a significantly fragmented mitochondrial morphology, while cells lacking MFN2 display a high percentage (85%) of mitochondria appearing as spheres or ovals, indicating that the functions of MFN1 and MFN2 are distinct.58 Importantly, the turnover and activity of MFNs are also precisely orchestrated by post-translational modifications. For example, the acetylation of MFN1 at K222 or K491 inhibits the MFN1 GTPase activity.59 In addition, the pro-fusion activity of MFN1 is affected by phosphorylation at multiple sites. For instance, phosphorylation of MFN1 at T562 regulated by MEK/ERK cascade restricts MFN1 assembly and pro-fusion capability, and facilitates its interaction with the proapoptotic protein Bak, leading to impaired mitochondrial fusion and apoptosis.57 Under glucose deprivation, histone deacetylase 6 (HDAC6)-mediated deacetylation of MFN1 at K222 or K491 causes increased MFN1 activity and hyperfused mitochondrial networks.59 

미토콘드리아 융합의 가장 효율적인 과정은 

두 가지 MFN 단백질이 동시에 존재할 때 관찰됩니다. 

또한, 

MFN1이 결핍되면 미토콘드리아 형태가 현저히 파편화되는 반면, 

MFN2가 결핍된 세포는 미토콘드리아의 높은 비율(85%)이 구형 또는 타원형으로 나타나 

MFN1과 MFN2의 기능이 서로 다르다는 것을 나타냅니다.58 

중요한 것은 MFN의 회전율과 활성도 번역 후 변형에 의해 정밀하게 조율된다는 점입니다. 

예를 들어, K222 또는 K491에서 MFN1의 아세틸화는 MFN1 GTPase 활성을 억제합니다.59 또한 MFN1의 친융합 활성은 여러 부위에서의 인산화에 의해 영향을 받습니다. 예를 들어, MEK/ERK 캐스케이드에 의해 조절되는 T562에서 MFN1의 인산화는 MFN1 조립 및 융합 능력을 제한하고, 세포사멸 단백질 Bak과의 상호작용을 촉진하여 미토콘드리아 융합 및 세포사멸을 손상시킵니다.57 포도당 결핍 상태에서 히스톤 탈아세틸화 효소 6(HDAC6)에 의한 K222 또는 K491의 MFN1 탈아세틸화는 MFN1 활성 증가 및 과융합 미토콘드리아 네트워크를 유발합니다.59

Furthermore, PRKN-dependent ubiquitination and proteasomal degradation of MFN2 is involved in OMM-ER contact site remodeling and the enhanced mitophagy.60 Under cellular stress, MFN2 is phosphorylated at Ser27 by Jun N-terminal kinase (JNK), and subsequently degradated by the proteasome, which is mediated by E3-ubiqutin ligase HUWE1.61 Intercepting the phosphorylation at Ser27 reduces MFN2 degradation, facilitates mitochondrial elongation, and prevent apoptosis. Hence, mitochondrial dynamics are integrated into various physiological activities and signaling cascades through regulating the post-translational modifications of MFNs.

또한, PRKN 의존적 유비퀴틴화 및 프로테아좀에 의한 MFN2의 분해는 OMM-ER 접촉 부위 리모델링 및 미토파지 강화에 관여합니다.60 세포 스트레스 하에서 MFN2는 준 N-말단 키나아제(JNK)에 의해 Ser27에서 인산화되고, 이후 프로테아좀에 의해 분해되며, 이는 E3-우비쿠틴 리가제 HUWE1에 의해 매개됩니다.61 Ser27에서 인산화를 차단하면 MFN2 분해를 줄이고 미토콘드리아 신장을 촉진하며 세포 사멸을 방지할 수 있습니다. 따라서 미토콘드리아의 역학은 MFN의 번역 후 변형을 조절함으로써 다양한 생리적 활동과 신호 캐스케이드에 통합됩니다.

On the other hand, transcriptional regulation of MFNs also affects mitochondrial fusion in response to stress conditions. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1)-β upregulates MFN2 expression‎ through transcriptional activation, thereby promoting mitochondrial fusion and OXPHOS.62 Besides, MFN1 is identified as a target for miR-140, and miR-140 negatively regulates the transcriptional expression‎ of MFN1, thereby promoting mitochondrial fission and apoptosis.63

한편, MFN의 전사 조절은 스트레스 조건에 대한 미토콘드리아 융합에도 영향을 미칩니다. 전사 활성제인 퍼옥시좀 증식인자 활성화 수용체 감마 활성제 1(PGC1)-β는 전사 활성화를 통해 MFN2 발현을 상향 조절하여 미토콘드리아 융합과 옥시포스를 촉진합니다.62 또한, MFN1은 miR-140의 표적으로 확인되었으며, miR-140은 MFN1의 전사 발현을 음성적으로 조절하여 미토콘드리아 분열과 아포토시스(세포 사멸)을 촉진합니다.63

Fusion of IMM is mainly regulated by the optic atrophy 1 (Opa1), which is a dynamin-like GTPase inserted into the IMM by its N-terminal.64 There are two splicing forms of Opa1: IMM-anchored long form-Opa1 (L-Opa1) and soluble short form-Opa1 (S-Opa1). L-Opa1 is proteolytically hydrolyzed to S-Opa1 by OMA1 and YME1 Like 1 ATPase (YME1Ll), and the relative levels of L-Opa1 and S-Opa1 are a key factor in determining the viability of mitochondrial fusion.65 In addition to controlling the IMM fusion, Opa1 also orchestrates cristae integrity, mtDNA maintenance, bioenergetics, as well as respiratory chain super complex assembly, so that Opa1 directly affects mitochondrial cytochrome release and oxidative respiration efficiency.51,66 Early embryonic lethality are observed in double knockout or OPA1 mutant mice.67 Furthermore, mutations in Opa1 gene are detected in 60–70% of autosomal dominant optic atrophy (ADOA) patients, characterized by retinal ganglion cells lost along with impaired visual acuity at early age.68

IMM의 융합은 주로 N-말단에 의해 IMM에 삽입된 다이나민 유사 GTPase인 옵틱 위축 1(Opa1)에 의해 조절됩니다.64 Opa1의 스플라이싱 형태는 IMM 고정형 긴 형태-Opa1(L-Opa1)과 용해성 짧은 형태-Opa1(S-Opa1)의 두 가지가 있습니다. L-Opa1은 OMA1 및 YME1 유사 1 ATPase(YME1Ll)에 의해 단백질 가수분해되어 S-Opa1로 전환되며, L-Opa1과 S-Opa1의 상대적 수준은 미토콘드리아 융합의 생존력을 결정하는 핵심 요소입니다.65 Opa1은 IMM 융합을 제어하는 것 외에도 크리스테 무결성, mtDNA 유지, 생체 에너지학, 호흡 사슬 초복합체 조립을 조율하여 Opa1이 미토콘드리아 시토크롬 방출 및 산화 호흡 효율에 직접 영향을 미칩니다.51,66 이중 녹아웃 또는 오파1 돌연변이 생쥐에서 초기 배아 치사율이 관찰됩니다.67 또한, 오파1 유전자의 돌연변이는 상염색체 우성 시신경 위축증(ADOA) 환자의 60-70%에서 발견되며, 이는 어린 나이에 시력 손상과 함께 망막 신경절 세포가 소실되는 것이 특징입니다.68

Mitophagy

Mitophagy, an evolutionarily conserved process that selectively removes dysfunctional or superfluous mitochondria by autophagy, is pivotal for both mitochondrial quantity and quality control.18 Mitophagy is a complex and dynamic process that involves two steps. Firstly, dysfunctional or damaged areas of mitochondria are identified and selectively enclosed by double-membraned autophagosomes. Secondly, the autophagosomes fuse with lysosomes to form autolysosomes where damaged mitochondria are degraded by hydrolases. At present, the pathway comprised of PTEN-induced kinase 1 (PINK1) and Parkin, an E3 ubiquitin ligase, is identified as a key player of mitophagy in mammals.69 

미토파지는 

오토파지에 의해 기능 장애가 있거나 

불필요한 미토콘드리아를  선택적으로 제거하는 진화적으로 보존된 과정으로, 

미토콘드리아의 양과 질을 조절하는 데 중추적인 역할을 합니다.18 

미토파지는 두 단계로 이루어지는 복잡하고 역동적인 과정입니다.

 먼저, 미토콘드리아의 기능 장애 또는 손상된 부위가 식별되어 

이중막 오토파지로 선택적으로 둘러싸입니다. 

둘째, 오토파지솜이 리소좀과 융합하여 오토리소좀을 형성하고, 

여기서 손상된 미토콘드리아가 가수분해효소에 의해 분해됩니다. 

현재 포유류에서 미토파지의 핵심적인 역할을 하는 것으로 밝혀진 것은 PTEN 유도 키나아제 1(PINK1)과 E3 유비퀴틴 리가제인 파킨(Parkin)으로 구성된 경로입니다.69 

In healthy mitochondrial, PINK1 is rapidly cleaved, and subsequently degraded in a proteasome-dependent manner in IMM. In damaged mitochondria, IMM depolarization prevents the degradation of PINK1, causing accumulation of full-length PINK1 with kinase activity in the OMM. Then, PINK1 recruits parkin to the OMM and stimulates its ubiquitin ligase activity via phosphorylating ubiquitin at Ser65. Parkin-mediated ubiquitination facilitates the degradation of multiple OMM proteins, such as MFN1, MFN2, and VDAC1, while also attracting autophagy receptors such as p62 and optineurin. Consequently, the ubiquitinated mitochondria are combined with LC3-positive autophagosomes by these receptors, leading to the formation of autophagosomes that eliminate damaged mitochondria.69,70 

건강한 미토콘드리아에서 

PINK1은 빠르게 절단된 후 

IMM에서 프로테아좀에 의존하는 방식으로 분해됩니다. 

손상된 미토콘드리아에서는 

IMM 탈분극이 PINK1의 분해를 방지하여 

OMM에 키나아제 활성을 가진 전체 길이의 PINK1이 축적됩니다. 

그런 다음 PINK1은 파킨을 OMM으로 모집하고 Ser65에서 유비퀴틴을 인산화하여 유비퀴틴 리가제 활성을 자극합니다. 파킨 매개 유비퀴틴화는 MFN1, MFN2, VDAC1과 같은 여러 OMM 단백질의 분해를 촉진하는 동시에 p62 및 옵티뉴린과 같은 자가포식 수용체를 끌어들입니다. 결과적으로 유비퀴틴화된 미토콘드리아는 이러한 수용체에 의해 LC3 양성 오토파지와 결합하여 손상된 미토콘드리아를 제거하는 오토파지를 형성하게 됩니다.69,70 

Impaired mitophagy refers to the inability of cells to effectively eliminate dysfunctional mitochondria, leading to their accumulation and disruption of mitochondrial function and cellular homeostasis. This phenomenon is closely associated with a variety of diseases, including neurodegenerative and cardiovascular diseases.70

손상된 미토파지는 

세포가 기능 장애 미토콘드리아를 효과적으로 제거하지 못하여 

미토콘드리아가 축적되고 

미토콘드리아 기능과 세포 항상성을 방해하는 것을 말합니다. 

이 현상은 신경 퇴행성 및 심혈관 질환을 포함한 다양한 질병과 밀접한 관련이 있습니다.70

Mitochondrial transport

Spatial distribution of mitochondria regulated by mitochondrial transport has been proved to be critical for highly polarized cells including neurons.71 Neurons are consisted of three distinct regions: soma, long axon and thick dendrites. Axonal transport, mitochondrial movement from soma to distal axonal, is driven by microtubule-anchored kinesin1 (also called KIF5) and dynein motors, while etrograde movement (toward soma) of mitochondria is orchestrated by cytoplasmic dynein‐dynactin complex.72 Furthermore, these opposing microtubule-based motors are linked to mitochondria through interaction with TRAK family adapter proteins including TRAK1 and TRAK2, and mitochondrial rho (MIRO).73 The direction of mitochondrial movement within the cell is determined by the balance of forces between motor and anchor proteins, both simultaneously present on the OMM of one specific mitochondria.74 Mitochondrial dysfunction triggered by aberrant mitochondrial transport is identified as one of the important pathogenic factors of neurodegenerative disorders and cancers.72,74

미토콘드리아 수송에 의해 조절되는 미토콘드리아의 공간적 분포는 

뉴런을 포함한 고도로 분극화된 세포에 매우 중요하다는 것이 입증되었습니다.71 

뉴런은 세포질, 긴 축삭, 두꺼운 수상돌기의 세 가지 영역으로 구성됩니다. 

축삭 수송, 

즉 cell body에서 원위 축삭으로의 미토콘드리아 이동은 

미세소관 고정 키네신1(KIF5라고도 함)과 다이네인 모터에 의해 주도되는 반면, 

미토콘드리아의 역행성 이동(소체 방향)은 세포질 다이네인-다이낙틴 복합체에 의해 조율됩니다.72 

또한, 이러한 상반된 미세소관 기반 모터는 TRAK1 및 TRAK2를 포함한 TRAK 계열 어댑터 단백질 및 미토콘드리아 로(MIRO)와의 상호작용을 통해 미토콘드리아와 연결됩니다.73 

세포 내 미토콘드리아 이동 방향은 

특정 미토콘드리아의 OMM에 동시에 존재하는 모터와 

앵커 단백질 간의 힘의 균형에 의해 결정됩니다.74 

비정상적인 미토콘드리아 수송에 의해 유발되는 미토콘드리아 기능 장애는 

신경 퇴행성 질환 및 암의 중요한 병원성 요인 중 하나로 확인되었습니다.72,74

Mitochondrial dynamics and cellular function

As important signaling organelles, mitochondria adjust a series of functions in cell including cellular metabolism, energy production and ion homeostasis, senescence and apoptosis, which dictate the fate of cells. Many mechanisms aid to the transmission of mitochondrial fitness to cells. Emerging studies shows that mitochondrial dynamics are important contributors to diverse cellular function (Fig. 3).

미토콘드리아는 중요한 신호 전달 기관으로서 

세포 대사, 

에너지 생산, 

이온 항상성, 

노화 및 세포 사멸 등 세포의 운명을 좌우하는 일련의 기능을 조절합니다. 

많은 메커니즘이 미토콘드리아의 건강 상태를 세포에 전달하는 데 도움을 줍니다. 최근 연구에 따르면 미토콘드리아 역학은 다양한 세포 기능에 중요한 기여를 하는 것으로 나타났습니다(그림 3).

Fig. 3

Mitochondrial dynamics and cellular function. a Mitochondrial dynamics and cell metabolism under different nutrient supplies. b Mitochondrial dynamics in the movement of mature circulating T cells. c Mitochondrial dynamics in cell differentiation. d Mitochondrial dynamics in cell cycle. e Mitochondrial dynamics in cellular senescence. f Mitochondrial dynamics in cellular apoptosis

미토콘드리아 역학과 세포 기능. 

a 미토콘드리아 역학과 다양한 영양소 공급에 따른 세포 대사. 

b 성숙한 순환 T 세포의 이동에 있어서 미토콘드리아 역학. 

c 세포 분화에서 미토콘드리아 역학. 

d 세포 주기에서 미토콘드리아 역학. 

e 세포 노화에서 미토콘드리아 역학. 

f 세포 아포토시스에서 미토콘드리아 역학.

Cell Metabolism

Literature has revealed a fascinating correlation between the balance of energy demand and supply, and the structure of mitochondria. When cells are grown in nutrient-rich environments, they often exhibit fragmented mitochondria with impaired OXPHOS, reduced mtDNA, and increased production of ROS.

On the other hand, mitochondria in cells experiencing nutritional deficiencies tend to remain connected for longer periods, maintaining highly efficient OXPHOS and increased levels of ATP.75

Under low nutrient supplement, several metabolic sensor kinases can drive mitochondrial elongation.76 PKA, one of the kinases regulating phosphorylation at the Ser637, acts in a cAMP-dependent manner which is indirectly responsive to high and low changes in cAMP/ATP.76,77 In a similar manner, activation of AMPK or restrain of mammalian target of rapamycin (mTOR) is demonstrated to induce mitochondrial fusion during nutrient depletion in cultured cells.76 These findings suggest that bioenergetic adaptation, involving changes in bioenergetic efficiency and ATP synthesis capacity, is associated with the remodeling of mitochondrial architecture.

에너지 수요와 공급의 균형과 미토콘드리아의 구조 사이에는 흥미로운 상관관계가 있다는 사실이 여러 문헌을 통해 밝혀졌습니다. 

영양이 풍부한 환경에서 세포가 성장하면 

미토콘드리아가 파편화되어 옥시포스가 손상되고 

mtDNA가 감소하며 

활성산소(ROS)의 생성이 증가하는 경우가 많습니다. 

반면, 영양 결핍을 겪고 있는 세포의 미토콘드리아는 

더 오랜 기간 동안 연결 상태를 유지하여 

매우 효율적인 OXPHOS와 증가된 ATP 수준을 유지하는 경향이 있습니다.75

영양소 보충이 부족하면 여러 대사 센서 키나아제가 미토콘드리아 신장(융합)을 촉진할 수 있습니다.76 Ser637에서 인산화를 조절하는 키나아제 중 하나인 PKA는 cAMP 의존적으로 작용하여 cAMP/ATP의 높고 낮은 변화에 간접적으로 반응합니다.76,77 유사한 방식으로, AMPK의 활성화 또는 포유류 라파마이신 표적(mTOR)의 억제는 배양 세포에서 영양소 고갈 동안 미토콘드리아 융합을 유도하는 것으로 입증되었습니다.76 이러한 발견은 생체 에너지 효율 및 ATP 합성 능력의 변화를 포함하는 생체 에너지 적응이 미토콘드리아 구조의 리모델링과 관련이 있음을 시사합니다.

In turn, mitochondrial dynamics also orchestrates the cellular metabolism.78,79 Mitochondrial fission caused by deficiency of MFNs or decline in GTPase activities manifests as metabolic dysfunction such as suppression of OXPHOS, decreased ATP synthesis, mtDNA depletion and elevated ROS levels, which are involved in various pathological conditions. Alternatively, the fusion of mitochondria counteracts metabolic insults primarily through enhancing OXPHOS and ATP generation, as well as by preventing mitochondria against mitophagy.

OXPHOS  (oxidative phosphorylation) 

미토콘드리아 역학은 세포 대사를 조율하기도 합니다.78,79 

MFN의 결핍 또는 GTPase 활성의 감소로 인한 미토콘드리아 분열은 

다양한 병리적 상태에 관여하는 OXPHOS의 억제, 

ATP 합성 감소, 

mtDNA 고갈 및 ROS 수준 상승과 같은 대사 기능 장애로 나타납니다. 

또는 미토콘드리아의 융합은 

주로 옥시포스 및 ATP 생성을 향상시키고 

미토콘드리아의 미토파지를 방지함으로써 대사 장애에 대응합니다.

Mitochondrial dynamics also possesses the capacity to regulate cellular metabolism in immune cells, thereby influencing the activation state and function of these cells. For instance, macrophages will employ glycolysis exclusively when they are polarized to a pro-inflammatory state known as M1, whereas macrophages in M2 state, which play a pivotal role in healing wounds and repairing tissues, depend on increased OXPHOS.80 Inhibiting mitochondrial fission in LPS-activated macrophages with Mdivi-1, an antiDrp1 agonist, effectively reduces glycolytic reprogramming.81 In addition, morphological analysis also demonstrates that mitochondria exhibit distinct shapes in order to assist in the differentiation of T cells.81 

미토콘드리아 역학은 

면역 세포의 세포 대사를 조절하여 

세포의 활성화 상태와 기능에 영향을 미치는 능력도 가지고 있습니다. 

예를 들어, 

대식세포는 M1이라는 염증 유발 상태로 양극화될 때 

해당 과정만을 사용하는 반면, 

상처를 치유하고 조직을 복구하는 데 중추적인 역할을 하는 M2 상태의 대식세포는 

옥스포스 증가에 의존합니다.80 

항Drp1 작용제인 Mdivi-1로 LPS 활성화 대식세포의 미토콘드리아 분열을 억제하면 해당 과정 재프로그래밍이 효과적으로 감소합니다.81 또한 형태학적 분석에 따르면 미토콘드리아는 T 세포의 분화를 돕기 위해 뚜렷한 모양을 나타냅니다.81 

Once Drp1 is phosphorylated at Ser616, effector T cells exhibit higher mitochondrial fission frequency. As a result, the mitochondria of these cells are smaller and scattered throughout the cytoplasm, facilitating anabolism. Unlike effector T cells, memory T cells depend on catabolic metabolism for their prolonged survival, which show an increased presence of fused mitochondria. The distinction in mitochondrial morphology among memory T and effector T cells delineates their differential metabolic requirements.81 When mitochondrial fusion is inhibited through selective removal of Opa1 from T cells, it leads to decreased OXPHOS and alterations in the structure of the cristae.81 Together, the stability of the fragmentation and merging mechanisms within mitochondria determines cellular metabolism and is critical for cell function.

Drp1이 Ser616에서 인산화되면 이펙터 T 세포는 더 높은 미토콘드리아 분열 빈도를 보입니다. 결과적으로 이러한 세포의 미토콘드리아는 더 작아지고 세포질 전체에 흩어져 동화 작용을 촉진합니다. 이펙터 T 세포와 달리 기억 T 세포는 융합 미토콘드리아의 존재가 증가하는 이화 대사에 의존하여 생존을 연장합니다. 기억 T 세포와 이펙터 T 세포의 미토콘드리아 형태는 서로 다른 대사 요구 사항을 나타냅니다.81 T 세포에서 Opa1을 선택적으로 제거하여 미토콘드리아 융합을 억제하면 옥스포스가 감소하고 크리스테의 구조가 변경됩니다.81 미토콘드리아 내 분열 및 병합 메커니즘의 안정성은 세포 대사를 결정하고 세포 기능에 매우 중요한 영향을 미칩니다.

Cell movement

Cell movement is fundamental for several different facets of physiological function, including tissue growth, healing of wounds, immune defense, and for disease-related processes including malignant metastasis. Mitochondria are highly polarized towards the apical portion of migratory cells, where they provide energy for actin cytoskeleton remodeling.82 In addition, mitochondrial fission and fusion events at the leading edge are crucial for localized calcium signaling, which is necessary for directional migration.83 Moreover, variations occurring in mitochondrial dynamics may also have an influence on various types of cellular movement, including epithelial-mesenchymal transition (EMT),84 metastasis,85 and trafficking of immune cells.86,87

When epithelial cells undergo EMT, they lose their cell-cell junctions and polarization, acquiring the phenotype of mesenchyme.88 

세포 이동은 

조직 성장, 

상처 치유, 

면역 방어, 

악성 전이를 포함한 질병 관련 과정 등 

여러 가지 생리적 기능에 필수적인 요소입니다. 

미토콘드리아는 이동성 세포의 정점 부분으로 고도로 편광되어 액틴 세포 골격 리모델링에 에너지를 공급합니다.82 또한, 미토콘드리아 분열 및 융합 사건은 방향성 이동에 필요한 국소화된 칼슘 신호 전달에 중요합니다.83 또한 미토콘드리아 역학에서 발생하는 변화는 상피 중간엽 전이(EMT),84 전이,85 면역 세포의 이동을 포함한 다양한 유형의 세포 이동에도 영향을 미칠 수 있습니다.86,87

상피 세포가 EMT를 겪으면 세포 간 접합과 분극화가 사라지고 중간엽 표현형을 획득합니다.88

As a result, cancer cells are able to invade and metastasize more easily. In hepatocytes, increased mitochondrial fission caused by low expression‎ of PGC-1α promoted EMT.84 Similarly, loss of GCN5L1 facilitates ROS generation through reinforcing FAO, activating ERK and Drp1, which then initiates mitochondrial rupture, ultimately causing hepatocellular carcinoma (HCC) EMT and metastasis.89 Metastatic breast cancer cells have been found to exhibit a higher concentration of fragmented mitochondria, along with increased levels of Drp1 and fewer MFN1 molecules compared to nonmetastatic breast carcinoma cells. The overexpression‎ of MFN1 or silencing of Drp1 leads to mitochondrial elongation or aggregation, which in turn significantly reduces the metastasis of breast cancer cells.85

그 결과 암세포는 더 쉽게 침입하고 전이할 수 있습니다. 간세포에서 PGC-1α의 낮은 발현으로 인한 미토콘드리아 분열 증가는 EMT를 촉진합니다.84 마찬가지로 GCN5L1의 손실은 FAO를 강화하여 ROS 생성을 촉진하고 ERK 및 Drp1을 활성화한 다음 미토콘드리아 파열을 시작하여 궁극적으로 간세포암종(HCC)의 EMT 및 전이를 유발합니다.89 전이성 유방암 세포는 비전이성 유방암 세포에 비해 더 높은 농도의 조각난 미토콘드리아와 함께 Drp1 수치가 증가하고 MFN1 분자가 더 적은 것으로 밝혀졌습니다. MFN1의 과발현 또는 Drp1의 침묵은 미토콘드리아의 연장 또는 응집으로 이어져 결과적으로 유방암 세포의 전이를 현저히 감소시킵니다.85

Immune cell transport involves various aspects such as immune cell migration, infiltration, and homing, which is also adjusted by altered mitochondrial dynamics. For example, in T lymphocytes, mitochondrial splitting assists in the formation of so-called leading edges, which determines cell movement and migration.87 Besides, inhibiting mitochondrial fission during T cell development leads to a decrease in the population of T cells with maturity within the thymus, and impedes the migration of these cells to the next station lymphoid organ.87

면역 세포 수송은 

면역 세포의 이동, 

침윤 및 귀환과 같은 다양한 측면을 포함하며, 

이는 미토콘드리아의 역학 변화에 의해 조정됩니다. 

예를 들어, 

T 림프구에서 미토콘드리아 분열은 

세포의 움직임과 이동을 결정하는 소위 리딩 에지(leading edge)의 형성을 돕습니다.87 

또한, T 세포 발달 중 미토콘드리아 분열을 억제하면 

흉선 내에서 성숙된 T 세포의 개체수가 감소하고 

이러한 세포가 다음 역 림프 기관으로 이동하는 데 방해가 됩니다.87

Cell differentiation

Cellular differentiation is the process by which stem cells are transformed into specialized cell types with unique functional properties. Cell differentiation is regulated by multiple signal transduction pathways and transcriptional modulation mechanisms. According to new scientific findings, mitochondrial dynamics influence the process of cell differentiation.90

세포 분화는 

줄기세포가 고유한 기능적 특성을 가진 특수한 세포 유형으로 변형되는 과정입니다. 

세포 분화는 여러 신호 전달 경로와 전사 조절 메커니즘에 의해 조절됩니다. 

새로운 과학적 발견에 따르면 

미토콘드리아 역학이 세포 분화 과정에 영향을 미친다고 합니다.90

Mesenchymal stem cells (MSCs), which originate in various connective tissues, are versatile stromal cells capable of differentiating into diverse cell lineages, including osteoblasts, adipocytes, and myoblasts. Metabolic activity patterns in MSCs are different from those in their differentiated progeny, with MSCs exhibiting a greater preval‎ence of the glycolytic pathway, although differentiating cells are more likely to be reliant upon OXPHOS.91 During adipogenesis, the process of differentiation of MSCs into adipocytes, there is a switch in mitochondrial dynamics has occurred from fission to fusion.92,93 Early in the process of adipogenesis, MFN2 is highly expressed, altering the process towards mitochondrial interfusion.92 As a result of the elongated mitochondria, ATP is produced, which activates CCAAT/enhancer-binding protein (C/EBP), ultimately causing genes involved in adipogenesis to be expressed, including C/EBPα, adiponectin, and peroxisome proliferator-activated receptor gamma (PPARγ).

다양한 결합 조직에서 유래하는 중간엽 줄기세포(MSC)는 

조골세포, 

지방세포, 

근아세포 등 다양한 세포 계통으로 분화할 수 있는 다용도 간질 세포입니다. 

MSC의 대사 활동 패턴은 분화된 자손의 대사 활동 패턴과 다르며, 분화 세포는 옥스포스에 의존할 가능성이 더 높지만 MSC는 해당 경로가 더 널리 퍼져 있습니다.91 MSC가 지방 세포로 분화하는 과정인 지방 형성 과정에서 미토콘드리아 역학에 분열에서 융합으로 전환이 일어납니다.92,93 지방 형성 과정 초기에 MFN2가 많이 발현되어 미토콘드리아 융합으로 과정이 바뀝니다.92 길어진 미토콘드리아의 결과로 ATP가 생성되어 CCAAT/인핸서 결합 단백질(C/EBP)을 활성화하고 궁극적으로 C/EBPα, 아디포넥틴, 퍼옥시좀 증식인자 활성화 수용체 감마(PPARγ) 등 지방 형성에 관여하는 유전자가 발현됩니다.

In contrast, high rate of generation of small, fragmented mitochondria is observed as the MSCs differentiate into osteoblasts, which indicates more mitochondrial fission in osteogenesis.92 Additionally, a study has demonstrated that mitochondrial rupture triggered by the NF-κB ligand (RANKL)/GSK-3β/Drp1 axis contributes significantly to osteoblast differentiation.94 Downregulation of Drp1 leads to impaired osteoclast differentiation and attenuates the condition in a mouse model of postmenopausal osteoporosis.94 Based on these findings, it appears that abnormal mitochondrial dynamics may assist to the development of postmenopausal osteoporosis.

대조적으로, 

중간엽줄기세포가 조골세포로 분화할 때 

작고 파편화된 미토콘드리아의 생성 비율이 높은 것으로 관찰되는데, 

이는 골 형성에서 미토콘드리아 분열이 더 많다는 것을 나타냅니다.92 

또한, 한 연구에 따르면 NF-κB 리간드(RANKL)/GSK-3β/Drp1 축에 의해 유발된 미토콘드리아 파열이 조골세포 분화에 크게 기여한다는 것이 입증되었습니다.94 폐경 후 골다공증 마우스 모델에서 Drp1의 하향 조절은 파골세포 분화 장애를 초래하고 상태를 약화시킵니다.94 이러한 발견에 따르면 비정상적인 미토콘드리아 역학이 폐경 후 골다공증의 발병에 도움이 될 수 있는 것으로 보입니다.

Besides, mitochondrial dynamics play a crucial role in the differentiation process of immune cells. As naive T cells differentiate into effector T cells, their mitochondrial mass and ATP production increase, which is essential for the energy-intensive process of activating the immune response and producing cytokines.95 Effector T cells formation requires the activation of mitochondrial biogenesis pathways that promote the synthesis of new mitochondria essential for enhanced cellular metabolism.95 Alternatively, Tregs possess more fused mitochondria, which enhances their capacity to produce ATP.96 The unique properties of elongated mitochondria in Tregs are critical for their immunosuppressive function and maintaining tissue homeostasis.

또한 미토콘드리아 역학은 

면역 세포의 분화 과정에서도 중요한 역할을 합니다. 

naive T 세포가 이펙터 T 세포로 분화하면 미토콘드리아 질량과 ATP 생산이 증가하는데, 이는 면역 반응을 활성화하고 사이토카인을 생산하는 에너지 집약적인 과정에 필수적입니다.95 이펙터 T 세포 형성을 위해서는 세포 대사를 향상시키는 데 필수적인 새로운 미토콘드리아의 합성을 촉진하는 미토콘드리아 생물 생성 경로의 활성화가 필요합니다.95 또는 Treg는 더 많은 융합 미토콘드리아를 보유하여 ATP 생산 능력을 향상시킵니다.96 Treg에서 길쭉한 미토콘드리아의 독특한 특성은 면역 억제 기능과 조직 항상성 유지에 매우 중요합니다.

Cell cycle

During cell cycle progression, the morphology, distribution, and function of mitochondria undergo dynamic alteration.97,98 The cell is in the G1 phase of its division, mitochondria engage in the process of fusion, resulting in the creation of an extensive, interconnected network of tubules that are responsible for facilitating OXPHOS and generating ATP.98 As cells progress into the S phase, mitochondria undergo fission to create smaller, more mobile mitochondria that can be distributed to daughter cells during mitosis.99 Of note, during mitosis, fission helps to selectively remove damaged or dysfunctional mitochondria. This process ensures that only healthy mitochondria are passed on to daughter cells, reducing the risk of oxidative stress and genomic instability.

세포 주기가 진행되는 동안 

미토콘드리아의 형태, 분포 및 기능은 

역동적인 변화를 겪습니다.97,98 

세포가 분열하는 G1 단계에서는 

미토콘드리아가 융합 과정에 참여하여 

광범위하고 상호 연결된 세뇨관 네트워크가 생성되어 옥시포스를 촉진하고 

ATP를 생성하는 역할을 합니다.98 

세포가 S 단계로 진행함에 따라 

미토콘드리아는 유사 분열 중에 딸 세포에 분배할 수 있는 더 작고 이동성이 뛰어난 미토콘드리아를 만들기 위해 

분열을 겪습니다.99 

주목할 점은 유사 분열 중에 분열은 손상되거나 기능 장애가 있는 미토콘드리아를 선택적으로 제거하는 데 도움이 된다는 것입니다. 이 과정을 통해 건강한 미토콘드리아만 딸 세포로 전달되어 산화 스트레스와 게놈 불안정성의 위험을 줄일 수 있습니다.

Drp1 is involved in the cell cycle. Deficiency of Drp1 causes the abnormal mitochondrial networks distribution around the microtubule organizing center. This aberrant distribution leads to chromosomal instability, excessive centromeric replication, aberrant mitotic spindles, replication stress, and arrest during the G2/M phase.100 Furthermore, cyclins and CDKs,101 and mitotic regulators (such as the Aurora family of kinases) also regulate mitochondrial dynamics.102 In the early M phase, the phosphorylation of Ser616 by CDK1/cyclin B within human Drp1 promotes desintegration of mitochondria.101 Aurora A, an upstream of CDK1/cyclin B, targets Drp1 by phosphorylating RALA. This phosphorylated RALA is then released from the cytoplasmic membrane and accumulates on the mitochondrial surface along with its effector protein. As a result of this binding, RALBP1 binds to CDK1/cyclin B, activating its kinase activity and leading to the phosphorylation of Drp1 at Ser616.102 This means that an absence of either RALA or RALBP1 results in dysfunctional mitochondrial separation and diminished cell numbers during mitosis.

Drp1은 세포 주기에 관여합니다. Drp1이 결핍되면 미세소관 조직 센터 주변에 비정상적인 미토콘드리아 네트워크가 분포하게 됩니다. 이러한 비정상적인 분포는 염색체 불안정성, 과도한 중심 중심 복제, 비정상적인 유사 분열 스핀들, 복제 스트레스 및 G2/M 단계에서의 정지를 초래합니다.100 또한 사이클린과 CDK,101 그리고 유사 분열 조절 인자(예: 오로라 키나아제 계열)도 미토콘드리아 역학을 조절합니다.102 초기 M 단계에서 인간 Drp1 내에서 CDK1/사이클린 B에 의한 Ser616의 인산화는 미토콘드리아의 분해를 촉진합니다.101 CDK1/사이클린 B의 업스트림인 오로라 A는 RALA를 인산화하여 Drp1을 표적으로 삼습니다. 이렇게 인산화된 RALA는 세포질 막에서 방출되어 이펙터 단백질과 함께 미토콘드리아 표면에 축적됩니다. 이러한 결합의 결과로 RALBP1은 CDK1/사이클린 B에 결합하여 키나아제 활성을 활성화하고 Ser616에서 Drp1의 인산화를 유도합니다.102 즉, RALA 또는 RALBP1이 없으면 미토콘드리아 분리가 제대로 이루어지지 않고 유사 분열 중에 세포 수가 감소합니다.

Senescence

Senescence is the result of cellular stress factors such as oxidative stress, telomere shortening, and DNA damage causing permanent growth arrest.103 Senescent cells are characterized by a number of changes, including alterations in cell morphology and function. An important feature of senescent cells is the development of large, elongated mitochondria.104 A possible explanation for the observed phenomenon may be related to variations of gene expression‎ patterns of key mitochondrial fragmentation and merging regulators. According to recent research, senescent endothelial cells in humans exhibit long interconnected mitochondria in response to decreased expressions of Fis1 and Drp1.105 Deferoxamine (DFO) is an iron chelating agent that induces senescence phenotype in cultured cells,106 making it an effective tool for analyzing the phenomenon of mitochondrial prolongation during cell aging. As a result of DFO-induced senescence in Chang cells, elongated giant mitochondria are formed.107 The process of forming giant mitochondria is linked to an increased fusion process and a decrease in the expression‎ of Fis1 during DFO-induced senescence. Conversely, overexpression‎ of Fis1 can reverse both the mitochondrial lengthening and senescence phenotypes induced by DFO.107

노화는 

산화 스트레스, 

텔로미어 단축, 

DNA 손상과 같은 세포 스트레스 요인으로 인해 

영구적인 성장 정지를 초래합니다.103 

노화 세포는 세포 형태와 기능의 변화를 포함한 여러 가지 변화를 특징으로 합니다. 

노화 세포의 중요한 특징은 

크고 길쭉한 미토콘드리아의 발달입니다.104 

관찰된 현상에 대한 가능한 설명은 

주요 미토콘드리아 단편화 및 병합 조절 인자의 유전자 발현 패턴의 변화와 관련이 있을 수 있습니다. 

최근 연구에 따르면, 인간의 노화 내피 세포는 Fis1과 Drp1의 발현 감소에 반응하여 미토콘드리아가 서로 길게 연결되어 있습니다.105 데페록사민(DFO)은 배양 세포에서 노화 표현형을 유도하는 철 킬레이트제로,106 세포 노화 중 미토콘드리아 연장 현상을 분석하는 데 효과적인 도구로 사용되고 있습니다. 창 세포에서 DFO로 노화를 유도한 결과, 길쭉한 거대 미토콘드리아가 형성됩니다.107 거대 미토콘드리아가 형성되는 과정은 DFO로 노화를 유도하는 동안 융합 과정의 증가와 Fis1의 발현 감소와 관련이 있습니다. 반대로, Fis1의 과발현은 DFO에 의해 유도된 미토콘드리아 길이 연장 및 노화 표현형을 모두 역전시킬 수 있습니다.107

Senescence mediators, such as p53, affect mitochondrial dynamics by promoting highly interconnected and elongated mitochondrial formation prior to inducing cellular senescence.108 According to the mechanism involved, the expression‎ of p53 was followed by the accumulation of inhibitory Drp1 phosphorylation at the Ser637 site, which in turn inhibited Drp1’s translocation to mitochondria.108 Furthermore, the IMM serine/threonine phosphatase, phosphoglycerate mutase family member 5 (PGAM5), is a critical component of mitochondrial fission because it dephosphorylates Drp1 at Ser637, which is essential to mitochondrial fission.109 PGAM5 deletion results in more fused mitochondria, decreased turnover of mitochondrial, greater ATP and ROS production, and enhanced mTOR and interferon regulatory factor/IFN signaling, and ultimately cellular senescence.110

p53과 같은 노화 매개체는 세포 노화를 유도하기 전에 고도로 상호 연결되고 길어진 미토콘드리아 형성을 촉진하여 미토콘드리아 역학에 영향을 미칩니다.108 관련된 메커니즘에 따르면, p53의 발현에 이어 Ser637 부위에 억제성 Drp1 인산화가 축적되어 Drp1의 미토콘드리아로의 전위가 억제됩니다.108 또한 IMM 세린/트레오닌 포스파타제, 포스포글리세레이트 뮤타제 계열 5(PGAM5)는 미토콘드리아 분열에 필수적인 Ser637에서 Drp1을 탈인산화하기 때문에 미토콘드리아 분열의 중요한 구성 요소입니다.109 

PGAM5가 결실되면 

융합 미토콘드리아가 증가하고, 

미토콘드리아의 회전율이 감소하며, 

ATP 및 ROS 생산이 증가하고, 

mTOR 및 인터페론 조절 인자/IFN 신호가 강화되어 

궁극적으로 세포 노화가 촉진됩니다.110

Apoptosis

Apoptosis, a mechanism for programmed cell death that is critical for mammalian development, as well as serving as a fundamental process for cellular homeostasis and defense against infections. Apoptosis is governed primarily through two groups of proteins: family Bcl-2, containing elements that are either proapoptotic (e.g., Bak and Bax), or antiapoptotic (e.g., BCL-2) members, which initially trigger the process; and the caspase family, whose members are responsible for the execution phase.111,112 The Bcl-2 protein family plays a crucial role in regulating the release of proapoptotic molecules from the IMS to the cytoplasm and maintaining the integrity of the OMM.113 Although the exact mechanism is not fully understood, the antiapoptotic factors of the Bcl-2 family have prominent roles in stabilizing the barrier capability of the OMM. While proapoptotic proteins like Bak or Bax generally counteract this function and induce permeabilization of the OMM.

세포 사멸은 

포유류의 발달에 필수적인 프로그램된 세포 사멸 메커니즘이며, 

세포 항상성 유지와 감염에 대한 방어의 기본 과정으로 작용합니다. 

세포 사멸은 주로 두 가지 단백질 그룹, 

즉 세포 사멸을 초기에 촉발하는 전세포 사멸(예: Bak 및 Bax) 또는 항세포 사멸(예: BCL-2) 성분을 포함하는 Bcl-2 계열과 

실행 단계를 담당하는 카스파제 계열을 통해 제어됩니다.111,112 

Bcl-2 단백질 계열은 IMS에서 세포질로 전아세포사멸 분자의 방출을 조절하고 OMM의 무결성을 유지하는 데 중요한 역할을 합니다.113 정확한 메커니즘은 완전히 이해되지 않았지만, Bcl-2 계열의 항아포토시스 인자들은 OMM의 장벽 기능을 안정화시키는 데 중요한 역할을 합니다. 반면, 박이나 박스와 같은 친아포토시스 단백질은 일반적으로 이 기능을 상쇄하고 OMM의 투과성을 유도합니다.

Mitochondria play a crucial role during the initiation of the apoptotic phase by secreting proapoptotic molecules, activating caspases, and inducing chromosomal condensation and fragmentation.114 An extrinsic as well as an intrinsic pathway can trigger apoptosis. Extrinsic pathway involves no direct interaction with the mitochondria, while the initiation of intrinsic pathway requires Cyt C to be released from the IMS of mitochondria, along with cristae disruption and mitochondrial outer membrane permeabilization (MOMP). Apoptotic protease factor 1 (Apaf-1) was activated by this process, which is an essential step within the intrinsic pathway, resulting in the activation of procaspase-9.114,115

미토콘드리아는 

세포사멸 전 단계 분자를 분비하고, 

카스파제를 활성화하며, 

염색체 응축 및 단편화를 유도함으로써 

세포사멸 단계가 시작되는 동안 중요한 역할을 합니다.114 

외인성 경로뿐만 아니라 

내인성 경로도 세포사멸을 유발할 수 있습니다. 

외인성 경로는 

미토콘드리아와 직접적인 상호 작용을 하지 않는 반면, 

내인성 경로가 시작되려면 크리스태 파괴 및 미토콘드리아 외막 투과성화(MOMP)와 함께 

미토콘드리아의 IMS에서 Cyt C가 방출되어야 합니다. 

이 과정에서 세포사멸 프로테아제 인자 1(Apaf-1)이 활성화되며, 이는 내재적 경로의 필수 단계로 프로카스파제-9.114,115의 활성화를 초래합니다.

The process of apoptosis leads to a dramatic reorganization of mitochondrial networks into punctate spheres rather than long interconnected tubules.116 Given that apoptotic cells display a high fission/fusion ratio, it is believed that fission is an essential part of the apoptotic process.117 It appears that Drp1 contributes to this fracturing phenotype because previous studies have confirmed that depletion of Drp1 prevents division of mitochondria during apoptosis,118 and dominant negative Drp1 (Drp1K38A) overexpression‎ inhibits the fragmentation of mitochondria during apoptosis as well.119 During early stages of apoptosis, proapoptotic molecules such as Bax and Bak, which are able to create pores, are moved to specific mitochondrial foci. These foci are then found to be colocalized with MFN2 and Drp1, which ultimately lead to the formation of sites for mitochondrial fission. It is believed that these foci play a role in preventing the merging of mitochondria, resulting in the fragmentation of mitochondria during apoptosis.120

세포 사멸 과정에서 미토콘드리아 네트워크는 서로 연결된 긴 세관이 아닌 점상 구체로 극적으로 재구성됩니다.116

세포 사멸 세포가 높은 분열/융합 비율을 보인다는 점을 고려할 때

분열은 세포 사멸 과정의 필수적인 부분인 것으로 여겨집니다.117

이전 연구에서 Drp1의 결핍이 세포 사멸 중 미토콘드리아의 분열을 방지하고,118 우성 음성 Drp1(Drp1K38A) 과발현도 세포 사멸 중 미토콘드리아의 분열을 억제하는 것으로 확인되었기 때문에 Drp1이 이러한 분열 표현형에 기여하는 것으로 보입니다.119 세포 사멸의 초기 단계에서 기공을 만들 수 있는 Bax 및 Bak과 같은 전아포토시스 분자는 특정 미토콘드리아 병소로 이동합니다. 그런 다음 이러한 초점은 MFN2 및 Drp1과 공동 위치하는 것으로 밝혀져 궁극적으로 미토콘드리아 핵분열 부위를 형성하게 됩니다. 이러한 초점은 미토콘드리아의 병합을 방지하여 세포 사멸 중에 미토콘드리아의 분열을 초래하는 역할을 하는 것으로 여겨집니다.120

However, according to another study, mitochondrial division is not crucial for MOMP and apoptosis in mammalian cells.121 Overexpression‎ of fission proteins can induce apoptosis, and this could be minimized by Bcl-2 family antiapoptotics independently of the transition of mitochondrial morphology from tubular to punctate. This suggests that mitochondrial fragmentation and apoptosis may not always be directly associated.121 The researchers used photobleaching fluorescence recovery to assess mitochondrial fragmentation and when Bak or Bax were overexpressed, mitochondria were disconnected. While Mcl-1 or Bcl-xL inhibited the appearance of biomarkers for apoptosis such as Smac/DIABLO and Cyt C in these cells, the fragmentation of mitochondria continued, suggesting that mitochondrial fission and MOMP are separate events.121

그러나 다른 연구에 따르면 미토콘드리아 분열은 포유류 세포에서 MOMP 및 세포 사멸에 중요하지 않습니다.121

분열 단백질의 과발현은

세포 사멸을 유도할 수 있으며,

이는 미토콘드리아 형태가 관형에서 점형으로 전환되는 것과는 독립적으로

Bcl-2 계열 항 세포 사멸제에 의해 최소화될 수 있습니다.

이는 미토콘드리아 단편화와 세포 사멸이 항상 직접적으로 연관되어 있는 것은 아닐 수 있음을 시사합니다.121 연구진은 광표백 형광 회복법을 사용하여 미토콘드리아 단편화를 평가했으며, 박 또는 Bax가 과발현되면 미토콘드리아의 연결이 끊어지는 것을 확인했습니다. Mcl-1 또는 Bcl-xL은 이러한 세포에서 Smac/DIABLO 및 Cyt C와 같은 세포사멸 바이오마커의 출현을 억제했지만 미토콘드리아의 단편화는 계속되어 미토콘드리아 분열과 MOMP는 별개의 사건임을 시사합니다.121

Opa1-dependent cristae remodeling, characterized by the widening of the neck of the cristae, is another feature of changes in mitochondrial morphology related to apoptosis that facilitates Cyt C release.122 Knockdown of Opa1 induces mitochondrial division and impaired cristae structure, and increases the vulnerability to apoptosis.123 Furthermore, introducing a disassembler-resistant Opa1 Q297V mutant inhibits the release of Cyt C and the onset of apoptosis, whereas it has no influence on Bax activation.123 Although mitochondrial fission’s function in caspase activation during apoptosis remains controversial, abundant literature indicates the significance of mitochondrial dynamics, including both division and merging, as core mechanisms of cell death.

오파1 의존적 크리스테 리모델링은 크리스테의 목이 넓어지는 것을 특징으로 하며, 세포 사멸과 관련된 미토콘드리아 형태 변화의 또 다른 특징으로 세포 C 방출을 촉진합니다.122 오파1을 녹다운하면 미토콘드리아 분열과 크리스테 구조 손상을 유도하고 세포 사멸에 대한 취약성을 증가시킵니다.123 또한, 분해기 저항성 Opa1 Q297V 돌연변이를 도입하면 Cyt C의 방출과 세포 사멸의 시작을 억제하는 반면, Bax 활성화에는 영향을 미치지 않습니다.123 세포 사멸 중 카스파제 활성화에서 미토콘드리아 분열의 기능은 여전히 논란의 여지가 있지만, 풍부한 문헌은 분열과 병합을 포함한 미토콘드리아 역학이 세포 사멸의 핵심 메커니즘으로서 중요하다는 것을 나타냅니다.

Overall, mitochondrial dynamics play a crucial role in maintaining optimal mitochondrial function, which is essential for energy production and other vital cellular processes.

전반적으로 미토콘드리아 역학은 에너지 생산과 기타 중요한 세포 과정에 필수적인 미토콘드리아 기능을 최적으로 유지하는 데 중요한 역할을 합니다.

The pathophysiology of mitochondrial dynamics

The imbalanced mitochondrial dynamics are correlated with a series of diseases which are extensively marked by deficiencies in mitochondrial function and abnormal cellular fate (Table 1; Fig. 4). On the contrary, enhancing mitochondrial fitness by regulating mitochondrial dynamics is proven to reduce the risk of disease, and is beneficial for health.

불균형한 미토콘드리아 역학은 

미토콘드리아 기능의 결핍과 비정상적인 세포 운명으로 광범위하게 나타나는 

일련의 질병과 관련이 있습니다(표 1, 그림 4). 

반대로 

미토콘드리아 역학을 조절하여 

미토콘드리아 건강을 개선하면 질병의 위험이 감소하고 

건강에 유익한 것으로 입증되었습니다.

Table 1 Clinical syndromes associated with encoding fission and fusion machinery components

Full size table

Fig. 4

Mitochondrial dynamics and diseases. a The neuronal cells of Alzheimer’s disease patients exhibit small and fragmented mitochondria; the expression‎ levels of Opa1, MFN1, and MFN2 were reduced while Fis1 and Drp1 are increased; Beta-amyloid causes nitric oxide to produce and results in neuronal injury and mitochondrial fission by S-nitrosylation of Drp1. b Mitochondria in cells with Parkinson’s Disease are also small and fragmented. c The progression of non-alcoholic fatty liver disease is closely associated with mitochondrial fission and an increase in protein expression‎ of Drp1. A high-fat diet can cause mitochondrial fragmentation, which occurs prior to the generation of ROS. d Ischemia-reperfusion injury can lead to mitochondrial fragmentation through the activation of Drp1, and downregulation of Opa1

미토콘드리아 역학과 질병. 

a 알츠하이머병 환자의 신경세포는 작고 파편화된 미토콘드리아를 보이며, Opa1, MFN1, MFN2의 발현 수준은 감소하고 Fis1과 Drp1은 증가하며, 베타 아밀로이드는 산화질소를 생성하고 Drp1의 S-니트로실화에 의해 신경세포 손상과 미토콘드리아 분열을 초래한다. 

b 파킨슨병 세포의 미토콘드리아는 또한 작고 파편화되어 있습니다. 

c 비알코올성 지방간 질환의 진행은 미토콘드리아 핵분열 및 Drp1의 단백질 발현 증가와 밀접한 관련이 있습니다. 고지방 식단은 미토콘드리아 분열을 유발할 수 있으며, 이는 ROS 생성 전에 발생합니다. 

d 허혈-재관류 손상은 Drp1의 활성화와 Opa1의 하향 조절을 통해 미토콘드리아 분열을 유발할 수 있습니다.

Improved mitochondrial dynamics in healthExercise

Exercise training improves physical performance and provides health benefits by promoting skeletal muscle adaptations, particularly in mitochondrial quantity and quality.124 Recent research has shown that exercise training leads to positive outcomes by promoting mitochondrial adaptation, which involves improvements in mitochondrial dynamics and clearance in addition to traditional promotion of mitochondrial biogenesis. John Holloszy’s research in 1967 was groundbreaking as it established that exercise training can promote skeletal muscle mitochondrial biogenesis. In his pioneering study, he demonstrated that vigorous treadmill running in rats induced significant increases in the activity of mitochondrial proteins and enzymes in the recruited muscles.125 Subsequent studies utilizing stable isotope techniques have further substantiated these findings by providing definitive evidence that exercise stimulates protein synthesis in mitochondria and biogenesis of mitochondria, in muscle of human skeletal.126

운동 훈련은 특히 미토콘드리아의 양과 질에서 골격근 적응을 촉진하여 신체 능력을 향상시키고 건강상의 이점을 제공합니다.124 

최근 연구에 따르면 운동 훈련은 

전통적인 미토콘드리아 생성을 촉진하는 것 외에도 

미토콘드리아 역학 및 클리어런스를 개선하는 

미토콘드리아 적응을 촉진하여 긍정적인 결과를 가져온다는 것이 밝혀졌습니다. 

1967년 존 홀로지의 연구는 운동 훈련이 골격근 미토콘드리아 생성을 촉진할 수 있다는 사실을 밝혀낸 획기적인 연구였습니다. 그의 선구적인 연구에서 그는 쥐를 대상으로 러닝머신에서 격렬하게 달리게 하면 모집된 근육에서 미토콘드리아 단백질과 효소의 활동이 크게 증가한다는 사실을 입증했습니다.125 안정 동위원소 기술을 활용한 후속 연구에서는 운동이 인간 골격근에서 미토콘드리아의 단백질 합성과 미토콘드리아의 생성을 자극한다는 결정적인 증거를 제공함으로써 이러한 결과를 더욱 입증했습니다.126

AMPK, a critical biosensor of energy, is activated following exercise and promotes the biogenesis of mitochondria by phosphorylating PGC-1α.127 PGC-1α stimulates the biological production of mitochondria through the amplification of mitochondrial genes encoding nuclear protein, including those involved in mitochondrial fusion and OXPHOS.128 The MAPK signaling pathway is also activated during exercise and promotes the biogenesis of mitochondria via augmentation of mitochondrial transcription factor A and PGC-1α, which regulates mDNA transcription and replication.129

에너지의 중요한 생체 센서인 AMPK는 

운동 후 활성화되어 PGC-1α를 인산화함으로써 

미토콘드리아의 생체 생성을 촉진합니다.127 

PGC-1α는 

미토콘드리아 융합 및 OXPHOS에 관여하는 유전자를 포함하여 

핵 단백질을 암호화하는 미토콘드리아 유전자의 증폭을 통해

토콘드리아의 생물학적 생성을 자극합니다.128

또한 운동 중에는

MAPK 신호 전달 경로가 활성화되어

미토콘드리아 전사인자 A와 mDNA 전사 및 복제를 조절하는

PGC-1α의 증강을 통해 미토콘드리아의 생체 생성을 촉진합니다.129

In addition to inducing mitochondrial biogenesis, exercise also triggers mitophagy through various mechanisms, including PINK1/Parkin and BNIP3/NIX.130 The PINK1/Parkin pathway is activated when the mitochondria undergo a depolarizing condition, leading to the recruitment of Parkin under stress and the disposal of damaged mitochondria through autophagy.130 On the other hand, the BNIP3/NIX pathway is activated during exercise by hypoxia, which promotes mitochondrial turnover by inducing mitophagy.131

운동은 

미토콘드리아 생성을 유도하는 것 외에도 

PINK1/Parkin 및 BNIP3/NIX를 포함한 다양한 메커니즘을 통해 

미토파지를 촉발합니다.130 

PINK1/Parkin 경로는 미토콘드리아가 탈분극 상태를 겪을 때 활성화되어 스트레스를 받으면 파킨이 모집되고 손상된 미토콘드리아는 자가포식을 통해 폐기됩니다.130 반면, BNIP3/NIX 경로는 운동 중 저산소증에 의해 활성화되어 미토파지를 유도하여 미토콘드리아의 턴오버를 촉진합니다.131

Exercise regulates mitochondrial fusion and fission through various pathways. During exercise, as the bioenergetic demand increases, the ratio of AMP/ATP increases as well, a signal that is detected by AMPK.132 In response to exercise, AMPK phosphorylates OMM protein Mff and A-kinase anchoring protein 1 (AKAP1), indicating a pro-fission response following exercise.47,132 Upon phosphorylation, AKAP1 binds PKA to the OMM, leading to increased PKA activity that causes Drp1 to be phosphorylated at Ser637.132 This phosphorylation inhibits the GTPase activity of Drp1,133 resulting in an overall pro-fusion effect, and this process is dependent on AMPK.

운동은 다양한 경로를 통해 미토콘드리아의 융합과 분열을 조절합니다. 운동 중에는 생체 에너지 요구량이 증가함에 따라 AMP/ATP의 비율도 증가하며, 이 신호는 AMPK에 의해 감지됩니다.132 운동에 반응하여 AMPK는 OMM 단백질 Mff와 A-키나아제 고정 단백질 1(AKAP1)을 인산화하여 운동 후 핵분열 반응을 나타냅니다.47,132 인산화되면 AKAP1은 PKA와 OMM에 결합하여 PKA 활성을 증가시켜 Drp1이 Ser637에서 인산화되도록 합니다.132 이 인산화는 Drp1의 GTPase 활성을 억제하여,133 전반적인 융합 촉진 효과를 초래하며, 이 과정은 AMPK에 의존합니다.

Acute exercise is potentially connected with mitochondrial fragmentation, possibly due to elevated energy demands during exercise.134,135 However, subsequent recovery or exercise training have been shown to be associated with increased mitochondrial volume and connectivity, indicating a possible shift towards improved mitochondrial function and fusion.15,136 Recent studies have investigated gene and protein expression‎ patterns associated with fission and fusion resulting from both single exercise sessions and repeated exercise training. These studies aim to gain a deeper understanding of the molecular mechanisms that underlie the changes in mitochondrial dynamics induced by exercise. In particular, MFN1/2 gene transcript expression‎ remains constant 2 hours following a single bout of intensive exercise, but increases at 24 hours afterward. This increase has been attributed to the involvement of transcriptional co-activators that are crucial in the response to exercise, such as PGC-1α and the estrogen receptor, which are known to promote mitochondrial biogenesis.137 No significant changes in the protein levels of Fis1, Drp1, or MFN1/2 were observed 4 hours after a high-intensity interval training session in humans. However, an increase in the protein contents of MFN1, Fis1, and Drp1 was observed after a 2-week period.128 Several recent studies have also reported similar increases in MFN1/2 concentrations in skeletal muscles following exercise, although not all studies have consistently shown these changes.134,136

급성 운동은 운동 중 에너지 요구량 증가로 인해

 미토콘드리아 분열과 관련이 있을 수 있습니다.134,135 

그러나 후속 회복 또는 운동 훈련은 

미토콘드리아 부피 및 연결성 증가와 관련이 있는 것으로 나타나 

미토콘드리아 기능 및 융합 개선으로의 전환 가능성을 시사합니다.15,136 

최근 연구에서는 단일 운동 세션과 반복 운동 훈련으로 인한 핵분열 및 융합과 관련된 유전자 및 단백질 발현 패턴을 조사했습니다. 이러한 연구는 운동에 의해 유도되는 미토콘드리아 역학 변화의 기초가 되는 분자 메커니즘을 더 깊이 이해하는 것을 목표로 합니다. 

특히, 

한 번의 강도 높은 운동 후 2시간 동안은 

MFN1/2 유전자 전사체 발현이 일정하게 유지되지만, 

이후 24시간이 지나면 증가합니다. 

이러한 증가는 

미토콘드리아 생성을 촉진하는 것으로 알려진 PGC-1α 및 

에스트로겐 수용체와 같이 운동에 대한 반응에 중요한 전사 보조 인자의 관여에 기인합니다.137 

인간의 고강도 인터벌 트레이닝 세션 4 시간 후 Fis1, Drp1 또는 MFN1/2의 단백질 수준에는 큰 변화가 관찰되지 않았습니다. 그러나 2주 후에는 MFN1, Fis1, Drp1의 단백질 함량이 증가하는 것이 관찰되었습니다.128 최근의 여러 연구에서도 운동 후 골격근에서 MFN1/2 농도가 유사하게 증가하는 것으로 보고되었지만 모든 연구에서 이러한 변화가 일관되게 나타난 것은 아닙니다.134,136

The study of exercise as a means to improve disease by altering mitochondrial morphology holds immense potential for developing novel therapeutic approaches for various diseases. A study has revealed that physical activity training can reduce the activation of Drp1 on muscle cells in individuals with insulin resistance. This highlights a significant correlation between decreased Drp1 activity and enhancements in both the oxidation of fat and insulin sensitivity following this type of training.15

미토콘드리아 형태를 변화시켜 질병을 개선하는 수단으로서 운동에 대한 연구는 다양한 질병에 대한 새로운 치료법을 개발할 수 있는 엄청난 잠재력을 가지고 있습니다. 한 연구에 따르면 신체 활동 훈련이 인슐린 저항성이 있는 사람의 근육 세포에서 Drp1의 활성화를 감소시킬 수 있는 것으로 나타났습니다. 이는 이러한 유형의 훈련 후 Drp1 활성 감소와 지방 산화 및 인슐린 감수성 향상 사이에 유의미한 상관관계가 있음을 강조합니다.15

Longevity

The decline in mitochondrial function with age, which is accompanied by morphological changes and reduced respiration in various tissues and organisms, is not fully understood in terms of whether it is the initial cause of aging or simply a reflection of aging.138 Furthermore, there is a continuing debate regarding the possibility that some of these alterations are caused by mitochondria damage or if they are adaptive mechanisms designed to counteract impairments associated with aging.

다양한 조직과 유기체에서 형태학적 변화와 

호흡 감소를 동반하는 노화에 따른 미토콘드리아 기능의 감소는 

노화의 초기 원인인지 아니면 

단순히 노화의 반영인지에 대해 완전히 이해되지 않았습니다.138 

또한 이러한 변화 중 일부가 미토콘드리아 손상으로 인한 것인지 아니면 

노화와 관련된 손상에 대응하도록 설계된 적응 메커니즘인지에 대한 논쟁이 계속되고 있습니다.

In various animal models, researchers have found that the accumulation of mutations in mtDNA and the decrease in mitochondrial biosynthesis can lead to the deterioration of mitochondrial function due to aging.139,140 Furthermore, studies conducted on Caenorhabditis elegans, yeast, and mice demonstrate that impaired degradation of deficient mitochondria can lead a buildup of unhealthy mitochondria with the aging process.12,141,142,143 In yeast and C. elegans, downregulation of mitochondrial autophagy proteins results in mitochondrial damage and a shortening of lifespan.12,141 Whereas activating mitochondrial autophagy is linked to improved mitochondrial functionality and increased lifespan in mice and C. elegans.142,143 Additionally, modifications to mitochondrial dynamics, a mechanism that is crucial in maintaining the quality and functionality of mitochondria, have been implicated in changes in life expectancy in Drosophila, yeast, and C. elegans.12,13,14

다양한 동물 모델에서 연구자들은 

mtDNA의 돌연변이 축적과 미토콘드리아 생합성 감소가 

노화로 인한 미토콘드리아 기능 저하로 이어질 수 있다는 사실을 발견했습니다.139,140 

또한 대장균, 효모, 생쥐를 대상으로 실시한 연구에 따르면 결핍된 미토콘드리아의 분해 장애가 노화 과정에서 건강에 해로운 미토콘드리아의 축적을 유발할 수 있다는 사실이 밝혀졌습니다.12,141,142,143 효모와 꼬마선충에서 미토콘드리아 자가포식 단백질의 하향 조절은 미토콘드리아 손상과 수명 단축을 초래합니다.12,141 반면 미토콘드리아 자가포식 활성화는 생쥐와 꼬마선충에서 미토콘드리아 기능 개선과 수명 증가와 관련이 있습니다.142,143 또한 미토콘드리아의 품질과 기능을 유지하는 데 중요한 메커니즘인 미토콘드리아 역학의 변화는 초파리, 효모, 초파리(C. elegans)의 기대 수명 변화와 관련이 있는 것으로 나타났습니다.12,13,14

With age, there is a decrease in the protein levels required for mitochondrial fission. For example, aging mice show decreased Drp1 activity as well as morphological changes in mitochondria throughout various tissues, particularly in muscles and neurons.144 Similarly, cells from aged human endothelial tissue cultured in vitro also show decreased Fis1 and Drp1 expression‎, along with elongated mitochondrial networks.105 Notably, increasing Drp1 expression‎ in midlife Drosophila leads to prolonged lifespan and improved mitochondrial respiration and autophagy.145 Additionally, inducing fragmented mitochondria within the intestinal tract has been shown to promote longevity in both C. elegans and flies, indicating that maintaining fission of mitochondria may have a beneficial effect on extending life span.146

나이가 들면 

미토콘드리아 분열에 필요한 단백질 수치가 감소합니다. 

예를 들어, 

노화된 생쥐는

 다양한 조직, 특히 근육과 뉴런에서 미토콘드리아의 형태학적 변화뿐만 아니라 

Drp1 활성도 감소합니다.144 

마찬가지로 시험관 내에서 배양된 노화된 인간 내피 조직의 세포도 미토콘드리아 네트워크가 길어진 것과 함께 Fis1 및 Drp1 발현 감소를 보입니다.105 특히, 중년 초파리에서 Drp1 발현을 증가시키면 수명이 연장되고 미토콘드리아 호흡 및 자가포식이 개선됩니다.145 또한, 장내에서 조각난 미토콘드리아를 유도하는 것은 C. elegans와 파리 모두에서 수명을 촉진하는 것으로 나타났으며, 이는 미토콘드리아의 분열을 유지하는 것이 수명 연장에 유익한 영향을 미칠 수 있음을 시사합니다.146

In contrast, studies in yeast have revealed paradoxical results, indicating that eliminating Dmn1p, the ortholog of Drp1, slows down mitochondrial division, actually prevents aging in yeast without affecting fertility or growth rate.147 On the other hand, research in skeletal muscle from mice indicates that a rise of mitochondrial fragmentation is related to an impaired insulin response and dysfunctional mitochondria.148 Together the available research suggests that the impact of stimulating mitochondrial splitting on mitochondrial function and fitness is dependent on the context, with variations observed based on the type of tissue or organism under study. While the molecular mechanisms and signaling pathways involved in mitochondrial fission and their impact on longevity are not yet fully understood.

이와는 대조적으로 효모를 대상으로 한 연구에서는 역설적인 결과가 나타났는데, Drp1의 상동 단백질인 Dmn1p를 제거하여 미토콘드리아 분열 속도를 늦추면 생식력이나 성장률에 영향을 주지 않고 효모의 노화를 실제로 예방할 수 있다는 것입니다.147 반면에 생쥐의 골격근을 대상으로 한 연구에서는 미토콘드리아 분열의 증가가 인슐린 반응 장애 및 미토콘드리아 기능 장애와 관련이 있다는 것을 나타냅니다.148 지금까지의 연구를 종합해 보면 미토콘드리아 분열을 자극하는 것이 미토콘드리아 기능과 체력에 미치는 영향은 상황에 따라 다르며, 연구 대상 조직이나 유기체의 유형에 따라 차이가 있음을 알 수 있습니다. 미토콘드리아 분열에 관여하는 분자 메커니즘과 신호 경로, 그리고 장수에 미치는 영향은 아직 완전히 이해되지 않았습니다.

Mitochondrial fusion has been found to have an impact on longevity. A study in C. elegans shows that an increase in mitochondrial fusion supports the health of aged creatures in various ways.149 Insulin/IGF-1 signaling pathway (IIS) and the Cullin-RING ubiquitin ligase (CRL) regulate fusion of mitochondria in C. elegans. Specifically, IIS regulates the activity of CAND-1 protein, while the CRL complex SCFLIN-23 regulates mitochondrial fusion through ubiquitination of substrate proteins. These two signaling pathways work together to modulate the function of the mitochondrial fusion pathway, thereby influencing the morphology and function of cellular mitochondria.149

미토콘드리아 융합은

장수에 영향을 미치는 것으로 밝혀졌습니다.

초파리(C. elegans)를 대상으로 한 연구에 따르면 미토콘드리아 융합의 증가는 다양한 방식으로 노화된 생물의 건강을 지원합니다.149 인슐린/IGF-1 신호 전달 경로(IIS)와 컬린-링 유비퀴틴 리가제(CRL)는 초파리에서 미토콘드리아의 융합을 조절합니다. 구체적으로, IIS는 CAND-1 단백질의 활성을 조절하고, CRL 복합체 SCFLIN-23은 기질 단백질의 유비퀴틴화를 통해 미토콘드리아 융합을 조절합니다. 이 두 가지 신호 전달 경로는 함께 작용하여 미토콘드리아 융합 경로의 기능을 조절함으로써 세포 미토콘드리아의 형태와 기능에 영향을 미칩니다.149

Another study found that restricting dietary intake and activating AMPK extend life expectancy through peroxisome remodeling and mitochondrial network modulation.150 A restricted diet and activation of AMPK enable mitochondria to fuse, leading to large networks of mitochondria that enhance cellular energy production and biosynthetic capacity. Additionally, dietary restriction and AMPK activation promote peroxisome biogenesis and remodeling, enhancing cellular antioxidant and detoxification capabilities.150 These mechanisms may be important factors influencing dietary restriction and activation of AMPK in terms of extending lifespan.

또 다른 연구에 따르면 

식이 섭취를 제한하고 AMPK를 활성화하면 

퍼옥시좀 리모델링과 미토콘드리아 네트워크 조절을 통해 

수명이 연장되는 것으로 나타났습니다.150 

식이 제한과 AMPK 활성화는 

미토콘드리아의 융합을 가능하게 하여 

세포 에너지 생산과 생합성 능력을 향상시키는 

대규모 미토콘드리아 네트워크로 이어집니다. 

또한, 식이 제한과 AMPK 활성화는 

퍼옥시좀 생성과 리모델링을 촉진하여 

세포의 항산화 및 해독 능력을 향상시킵니다.150 

이러한 메커니즘은 

수명 연장 측면에서 식이 제한과 AMPK 활성화에 영향을 미치는 중요한 요인일 수 있습니다.

Furthermore, studies conducted on C. elegans have shown that TORC1 signaling plays a vital role in promoting healthy aging, particularly in neurons. Furthermore, it has been observed that lifespan can be extended by modulating mitochondrial dynamics through the reduction of TORC1 signaling151 Specifically, the regulation of mitochondrial fusion and fission in neurons is controlled by TORC1 signaling. By inhibiting TORC1 signaling, mitochondrial fusion is promoted, which ultimately contributes to a longer lifespan.151 These findings provide important clues towards a better understanding of the mechanism behind the regulation of mitochondrial merging and how it influences organismal survival and lifespan extension.

또한, 초파리(C. elegans)를 대상으로 한 연구에 따르면 TORC1 신호는 특히 신경세포에서 건강한 노화를 촉진하는 데 중요한 역할을 하는 것으로 나타났습니다. 또한, TORC1 신호의 감소를 통해 미토콘드리아의 역학을 조절함으로써 수명을 연장할 수 있음이 관찰되었습니다151 특히, 신경세포에서 미토콘드리아의 융합과 분열의 조절은 TORC1 신호에 의해 제어됩니다. TORC1 신호를 억제하면 미토콘드리아 융합이 촉진되어 궁극적으로 수명이 연장됩니다.151 이러한 연구 결과는 미토콘드리아 병합의 조절 메커니즘과 그것이 유기체의 생존과 수명 연장에 어떻게 영향을 미치는지 더 잘 이해하는 데 중요한 단서를 제공합니다.

In conclusion, aging has a negative effect on mitochondria, exhibiting reduced efficiency and alterations in mitochondrial dynamics. The effects of mitochondrial fission and fusion on longevity are dependent on the context and differ across various animal models. In C. elegans, mitochondrial fusion is controlled through the insulin/IGF-1 pathway and Cullin-RING ubiquitin ligase complex, and increased fusion promotes survival of older animals. AMPK activation and dietary restriction also modulate mitochondrial fusion as well as peroxisome remodeling, potentially contributing to their lifespan-extending effects. The underlying molecular mechanisms of this process require further investigation.

결론적으로 

노화는 

미토콘드리아에 부정적인 영향을 미쳐 

미토콘드리아의 효율성이 감소하고 

미토콘드리아 역학에 변화가 나타납니다. 

미토콘드리아 분열과 융합이 장수에 미치는 영향은 상황에 따라 다르며 다양한 동물 모델에 따라 다릅니다. 초파리(C. elegans)에서 미토콘드리아 융합은 인슐린/IGF-1 경로와 컬린-링 유비퀴틴 리가제 복합체를 통해 제어되며, 융합이 증가하면 노령 동물의 생존이 촉진됩니다. AMPK 활성화와 식이 제한은 미토콘드리아 융합과 퍼옥시좀 리모델링을 조절하여 잠재적으로 수명 연장 효과에 기여할 수 있습니다. 이 과정의 근본적인 분자 메커니즘은 더 많은 연구가 필요합니다.

Ketogenic diet

The ketogenic diet (KD) is a therapeutic dietary approach that has been used clinically for several decades to manage symptoms of various diseases, such as epilepsy, autism spectrum disorder, and diabetes.152,153,154 The KD works by reducing carbohydrate intake and promoting FAO. The process of metabolic shift enables the production of ketones in the hepatocytes. These ketones are then utilized as a primary source of fuel for crucial organ systems such as the central nervous system, cardiomyocytes, and muscular tissue.155

케톤 생성 식단(KD)은

간질, 자폐 스펙트럼 장애, 당뇨병 등 다양한 질병의 증상을 관리하기 위해

수십 년 동안 임상적으로 사용되어 온

치료적 식이요법입니다.152,153,154

KD는 탄수화물 섭취를 줄이고 FAO를 촉진하는 방식으로 작동합니다. 대사 전환 과정을 통해 간세포에서 케톤을 생성할 수 있습니다. 이렇게 생성된 케톤은 중추 신경계, 심근 세포, 근육 조직과 같은 중요한 장기 시스템의 주요 연료 공급원으로 활용됩니다.155

According to research conducted on the BTBRT+tf/j mouse, KD effect on mitochondrial dynamics is tissue-specific.156 In the brain, there are no difference between mitochondrial division and merging. In the liver, however, mitochondrial division and merging mediators are expressed at lower levels during the ketogenic diet. Specifically, expression‎ levels of MFN2 and Drp1, closely related to merging and division respectively, are decreased while other proteins tend to decline. Therefore, it appears that the ketogenic diet alters the dynamics of mitochondria within the liver and reduces the expression‎ of a number of regulators responsible for mitochondrial division and merging. The administration of ketogenic diets inhibites the fission of mitochondria and enhances mitochondrial activity in diabetic mice’s myocardium.157 It reduces mitochondrial number, increases mitochondrial size, improves respiratory rate, and increases heart ATP levels. In this study,157 the ketogenic diet affected mitochondrial dynamics through the regulation of AMPK/mTOR signaling. Particularly, the KD inhibites Drp1 expression‎ and enhances MFN2 expression‎ with the aim of reducing mitochondrial fragmentation and increasing mitochondrial fusion. Additionally, mitochondrial dysfunction is believed to be responsible for the occurrence of autism spectrum disorder. Dietary interventions, such as the ketogenic diet, may improve mitochondrial function.158

BTBRT+tf/j 마우스를 대상으로 한 연구에 따르면 

미토콘드리아 역학에 대한 KD 효과는 

조직에 따라 다릅니다.156 

뇌에서는 

미토콘드리아 분열과 병합 사이에 차이가 없습니다. 

그러나 

간에서는 케토제닉 식단을 섭취하는 동안 

미토콘드리아 분열과 병합 매개체가 낮은 수준으로 발현됩니다. 

특히, 병합 및 분열과 밀접한 관련이 있는 

MFN2와 Drp1의 발현 수준은 감소하는 반면 

다른 단백질은 감소하는 경향이 있습니다. 

따라서 

케토제닉 식단은 

간 내 미토콘드리아의 역학을 변화시키고 

미토콘드리아의 분열과 병합을 담당하는 

여러 조절 인자의 발현을 감소시키는 것으로 보입니다. 

케토제닉 식단의 투여는 

당뇨병 쥐의 심근에서 미토콘드리아의 핵분열을 억제하고 

미토콘드리아 활동을 향상시킵니다.157 

케토제닉 식단은 

미토콘드리아 수를 줄이고, 

미토콘드리아 크기를 늘리며, 

호흡수를 개선하고, 심

장 ATP 수치를 증가시킵니다. 

이 연구에서157 케토제닉 식단은 AMPK/mTOR 신호 조절을 통해 미토콘드리아 역학에 영향을 미쳤습니다. 특히, 케토제닉 다이어트는 미토콘드리아 분열을 줄이고 미토콘드리아 융합을 증가시키기 위해 Drp1의 발현을 억제하고 MFN2의 발현을 향상시켰습니다. 또한 미토콘드리아 기능 장애는 자폐 스펙트럼 장애 발생의 원인으로 여겨지고 있습니다. 케토제닉 식단과 같은 식이 요법은 미토콘드리아 기능을 개선할 수 있습니다.158

Overall, these findings indicate a significant association between KD and mitochondrial dynamics. It is, however, necessary to conduct further research in order to clarify the underlying mechanisms and develop appropriate strategies for disease treatment. With the development of research in this field, a deeper understanding of the correlation between function of the mitochondria and ketogenic diet can potentially pave the way for more effective therapeutic interventions in various diseases.

전반적으로 이러한 연구 결과는 KD와 미토콘드리아 역학 사이에 유의미한 연관성이 있음을 나타냅니다. 그러나 근본적인 메커니즘을 밝히고 질병 치료를 위한 적절한 전략을 개발하기 위해서는 추가 연구가 필요합니다. 이 분야의 연구가 발전함에 따라 미토콘드리아의 기능과 케톤 생성 식단 사이의 상관관계를 더 깊이 이해하면 다양한 질병에서 보다 효과적인 치료 개입의 길을 열 수 있을 것입니다.

Dysregulated mitochondrial dynamics in diseasesGenetic disorders

Mutations in genes regulating mitochondrial merging and division, including MFN2, Drp1, and Opa1, contribute significantly to the development of various neurological conditions. In particular, Charcot-Marie-Tooth disease (CMT) and autosomal dominant optic atrophy (ADOA) are genetic disorders associated with mitochondrial dysfunction.159

미토콘드리아의 병합과 분열을 조절하는 유전자(MFN2, Drp1, Opa1 등)의 돌연변이는 

다양한 신경 질환의 발병에 크게 기여합니다. 

특히 샤르코-마리-투스병(CMT)과 

상염색체 우성 시신경 위축증(ADOA)은 

미토콘드리아 기능 장애와 관련된 유전 질환입니다.159

Charcot-Marie-Tooth disease (CMT)

is a commonly occurring form of inheritable neurological disorder, with autosomal dominant being the most common inheritance pattern, although autosomal recessive and X-linked subtypes also exist.160 Research efforts have focused on identifying disease-modifying therapies for the most frequently encountered genetic mutations, such as gap junction protein beta 1 (GJB1), peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), and MFN2.160 CMT manifests as the degeneration of the axons and myelin sheaths of peripheral nerves, leading to impaired nerve conduction velocity.161 Based on specific characteristics, CMT can be categorized into four major subtypes.161 CMT1 is characterized by demyelination and follows an autosomal dominant inheritance pattern. CMT2 is an axonal subtype and may be transmitted either via an autosomal dominant or a recessive inheritance pattern. CMTX is characterized by intermediate nerve conduction velocities and is typically associated with X-linked inheritance, although recessive and autosomal dominant intermediate variations are also known. The CMT4 subtype is demyelinating, but it shows an autosomal recessive inheritance pattern.

CMT2A is the most preval‎ent subtype among CMT2 patients, due almost exclusively to dominant mutations in the MFN2 gene that inhibit the fusion and motility of mitochondria.162 In a clinical setting, patients diagnosed with CMT2A frequently exhibit more severe symptoms and experience an earlier onset of the condition when compared to those with classic CMT.163 In addition, CMT2A manifests as peripheral neuropathy, progressive weakness of the muscles, impaired motor function, and may also affect the central nervous system (CNS), causing spinal cord or brain abnormalities. Nowadays, the treatment approach for CMT2A typically involves both general and specific treatments. For general treatments, coenzyme Q10 (CoQ10) supplementation may ameliorated the phenotype of CMT2A. CoQ10 is a vital component of the ETC in mitochondria, where it participates in energy production through ATP synthesis. Additionally, CoQ10 acts as an antioxidant, helping to combat harmful free radicals and defend cells against oxidative damage.164 Moreover, mitofusin agonists have emerged as a promising potential treatment for CMT2A, as they directly target the MFN2 mutations. Studies have demonstrated that mitofusin agonists can restore normal transport of mitochondria in the sciatic nerves of mice carrying the MFN2 Thr105Met mutation, suggesting a promising therapeutic approach for managing CMT2A.165

Autosomal Dominant Optic Atrophy (ADOA)

is a genetic disorder in which the neurons of the retina degenerate, developing atrophy of the optic nerve and impairment of vision.166 Study has demonstrated that ADOA is associated with mutations in three known loci (OPA4, OPA5, OPA8) and two genes (OPA1, OPA3) that encode proteins found in the inner mitochondrial membrane. In addition, X-linked or recessive optic atrophy can be attributed to other genes and loci (OPA2, OPA6, OPA7).166 At present, no cure has been found for ADOA, so the treatment is mainly supportive, focusing on physical therapy and the management of symptoms. It’s noteworthy that gene therapy offers potential therapeutic benefits for ADOA. A gene therapy aims to repair or replace the defective gene responsible for the disease, thereby restoring normal gene function. For example, a recent study has indicated that redirecting U1 snRNA to non-canonical splice sites can effectively correct splicing defects in the OPA1 gene. This, in turn, can enhance the production of properly spliced transcripts of OPA1, potentially overcoming haploinsufficiency.167

Neuro-degenerative diseases

Parkinson’s Disease (PD) is a neurodegenerative disease due to cell death or degeneration in the region of the brain known as the substantia nigra, leading to the deterioration of dopamine neurons. Dopamine neurons are crucial for controlling body movement and coordination; hence PD patients typically exhibit symptoms such as muscle rigidity, tremors, and bradykinesia.168 Over the past few decades, accumulated evidences point towards a connection between PD and mitochondrial dysfunction. Mild deficiency in Complex I activity and oxidative damage have been observed to contribute to the development of neurodegeneration in PD.169 Changes in antioxidant levels and targets of oxidation have also been observed in PD, further supporting the oxidative stress’ involvement in the disease. Recent studies have identified various genetic changes in the genes responsible for encoding proteins that are targeted to mitochondria. Additionally, gene variants related to mitochondrial dynamics and function, such as DJ-1, PINK-1, Parkin, and leucine rich repeat kinase 2 (LRRK2), have been implicated in the association between mitochondria and PD.170

파킨슨병(PD)은 

흑질로 알려진 뇌 부위의 세포 사멸 또는 퇴행으로 인해 

도파민 뉴런의 기능이 저하되는 

신경 퇴행성 질환입니다. 

도파민 뉴런은 

신체 움직임과 협응력을 조절하는 데 

중요한 역할을 하므로 

파킨슨병 환자는 일반적으로 근육 경직, 떨림, 서동증과 같은 증상을 보입니다.168 

지난 수십 년 동안 축적된 증거는 

파킨슨병과 미토콘드리아 기능 장애 사이의 연관성을 시사하고 있습니다. 

복합체 I 활성의 경미한 결핍과 산화 손상이 

파킨슨병의 신경 퇴행에 기여하는 것으로 관찰되었습니다.169 

파킨슨병에서 

항산화 수준과 산화 표적의 변화도 관찰되어 

산화 스트레스가 질병에 관여하는 것을 더욱 뒷받침하고 있습니다. 

최근 연구에 따르면 미토콘드리아를 표적으로 하는 단백질을 암호화하는 유전자의 다양한 유전적 변화가 확인되었습니다. 또한, 미토콘드리아의 역학 및 기능과 관련된 유전자 변이, 예를 들어 DJ-1, PINK-1, 파킨, 류신 풍부 반복 키나아제 2(LRRK2)가 미토콘드리아와 PD 사이의 연관성에 관여하는 것으로 밝혀졌습니다.170

An essential characteristic of mitochondrial dynamics is the distribution of mitochondria to synapses, supporting synaptic function, and ensuring the health of mitochondria in general. The disruption of mitochondrial dynamics might represent the initial event in the neurodegenerative process of PD.171,172 The intricate and essential function of mitochondrial fusion/fission machinery in the formation of synapse and dendritic spine formation in neurons has been well established. Inhibiting mitochondrial fragmentation results in diminished mitochondrial concentration within dendritic spines and a decrease in synaptic development, while stimulating fission promotes the formation of synapses.173 For instance, mitochondrial dynamics contribute to the development of PD based on findings from studies using toxin-induced PD models. Moreover, absence of Drp1 hampers the distribution of mitochondria to synapses and disrupts synaptic function.174

미토콘드리아 역학의 필수적인 특징은 

미토콘드리아가 시냅스에 분포하여 

시냅스 기능을 지원하고 미토콘드리아의 건강을 전반적으로 보장하는 것입니다. 

미토콘드리아 역학의 붕괴는 

파킨슨병의 신경 퇴행성 과정의 초기 사건일 수 있습니다.171,172 

뉴런의 시냅스 및 수상돌기 척추 형성에서 

미토콘드리아 융합/분열 기계의 복잡하고 필수적인 기능은

 잘 알려져 있습니다. 

미토콘드리아 분열을 억제하면 

수지상 돌기 내 미토콘드리아 농도가 감소하고 

시냅스 발달이 감소하는 반면, 

분열을 자극하면 시냅스 형성이 촉진됩니다.173 

예를 들어, 독소 유도성 파킨슨병 모델을 사용한 연구 결과에 따르면 미토콘드리아 역학은 파킨슨병의 발달에 기여합니다. 또한, Drp1이 없으면 시냅스로의 미토콘드리아 분포를 방해하고 시냅스 기능을 방해합니다.174

Mutations in certain genes linked to familial PD have also highlighted the important role that mitochondrial dynamics play in this disorder. Emerging evidence strongly indicates that gene mutations influencing mitochondrial dynamics are crucial to the development of PD.175 Parkin, a protein encoded by the PARK2 gene, is implicated in PD.176 A cytosolic ubiquitin E3 ligase protein, Parkin plays an important role in the process of ubiquitin-dependent proteolysis and is known to affect mitochondrial health through its regulatory role in mitochondrial dynamics.177 In drosophila model, defective mutation of Parkin results in enhanced oxidative stress sensitivity, loss of dopaminergic cells, and severe mitochondrial dysfunction characterized by swollen mitochondria and fragmented cristae.178 Similarly, mutations in other PD-associated genes, such as PINK1, which codes for a mitochondrially-targeted kinase, add further evidence to a correlation between mitochondrial dynamics and PD pathogenesis.176

가족성 파킨슨병과 관련된 특정 유전자의 돌연변이도 이 질환에서 미토콘드리아 역학이 중요한 역할을 한다는 점을 강조하고 있습니다. 새로운 증거에 따르면 미토콘드리아 역학에 영향을 미치는 유전자 돌연변이가 파킨슨병 발병에 중요하다고 합니다.175 

PARK2 유전자에 의해 코딩되는 단백질인 파킨은 

파킨슨병에 관여합니다.176 

세포질 유비퀴틴 E3 리가제 단백질인 파킨은 

유비퀴틴 의존성 단백질 분해 과정에서 중요한 역할을 하며 

미토콘드리아 역학에서 조절 역할을 통해 

미토콘드리아 건강에 영향을 주는 것으로 알려져 있습니다.177 

초파리 모델에서 파킨의 결함 돌연변이는 산화 스트레스 민감성 증가, 도파민 세포 손실, 미토콘드리아 부종 및 조각난 크리스테를 특징으로 하는 심각한 미토콘드리아 기능 장애를 초래합니다.178 마찬가지로, 미토콘드리아 표적 키나제를 코딩하는 PINK1과 같은 다른 PD 관련 유전자의 변이는 미토콘드리아 역학과 PD 발병 사이의 상관 관계에 대한 추가적인 증거를 추가합니다.176

Alzheimer’s disease (AD)

accounts for a significant percentage of impaired cognitive function in elderly people. The main pathological features in AD are degeneration of brain neurons and synapses, as well as excessive deposition of neuronal proteins, especially β-amyloid (Aβ) plaques and tau protein tangles.179 Mitochondria contribute significantly to the development of AD. Metabolic disturbances in AD are well-documented, with reduced brain metabolism being a prominent feature.180 Deficiencies in key enzymes of OXPHOS in the brain, alongside damage to mitochondria and increased ROS are consistently documented in AD.181 Alterations in calcium homeostasis have also been observed among AD patients, which suggest that mitochondrial dysfunction may contribute to dysregulation of neuronal calcium levels in AD.182 Furthermore, genetic markers in mtDNA are associated with increased risks of AD.183

알츠하이머병(AD)은

노인의 인지 기능 장애의 상당 부분을 차지합니다.

알츠하이머병의 주요 병리학적 특징은

뇌 신경세포와 시냅스의 퇴행과

신경세포 단백질, 특히 β-아밀로이드(Aβ) 플라크와 타우 단백질 엉킴의 과도한 침착입니다.179

미토콘드리아는 알츠하이머병의 발병에 크게 기여합니다.

AD의 대사 장애는 잘 알려져 있으며,

뇌 대사 감소가 두드러진 특징입니다.180

미토콘드리아 손상 및 ROS 증가와 함께

뇌에서 옥스포스의 주요 효소 결핍이

AD에서 일관되게 보고되고 있습니다.181

칼슘 항상성의 변화도

AD 환자에서 관찰되었으며,

이는 미토콘드리아 기능 장애가 AD에서 신경 칼슘 수준의 조절 장애에 기여할 수 있음을 시사합니다.182

또한 mtDNA의 유전자 마커는 AD의 위험 증가와 관련이 있습니다.183

Usually, neurons of AD patient display both malfunctioning mitochondria and unfavorable mitochondrial dysfunction. For instance, compared to a control group of age-matched neurons, neurons from AD show a marked reduction in the proportion of normal mitochondria and a notable rise in the proportion of mitochondria with broken cristae.184 In addition, Opa1, Drp1, MFN1/2 expression‎ are significantly lower in AD, whereas Fis1 levels are higher in AD.185 Mitochondrial dynamics impact the pathological changes of AD involved in several signaling pathways, including Ca2+, AMPK, and nitric oxide signaling pathways. Non-canonical Wnt-5a/Ca2+ signaling is crucial in mitochondrial dynamics, and its activation shields hippocampal neurons from Aβ oligomer-induced damage.186 AdipoRon, an adiponectin receptor agonist that significantly improves synaptic efficiency, enhances fusion of mitochondria, and mitigates tau hyperphosphorylation in SY5Y cells, rescuing memory deficits in P301S tau transgenic mice.187 Mechanistically, AMPK/GSK3β and AMPK/SIRT3 signaling participate in enhancing the positive effects of AdipoRon on mitochondrial dynamics along with tau accumulation.187 Besides, Aβ-induced nitric oxide mediates mitochondrial fission and neuronal injury through Drp1 S-nitrosylation, which may facilitate the progression of AD.188 Therefore, prevention of Drp1 S-nitrosylation eliminate these neurotoxic events.188

일반적으로 

알츠하이머병 환자의 신경세포는 

미토콘드리아의 오작동과 

좋지 않은 미토콘드리아 기능 장애를 모두 나타냅니다. 

예를 들어, 

연령이 일치하는 대조군 뉴런과 비교했을 때, 

AD 뉴런은 정상 미토콘드리아의 비율이 현저히 감소하고 

크리스테가 손상된 미토콘드리아의 비율이 현저히 증가합니다.184 

또한, Opa1, Drp1, MFN1/2 발현은

 AD에서 현저히 낮은 반면, Fis1 수준은 

AD에서 높습니다.185 

미토콘드리아의 역학은 

Ca2+, AMPK 및 산화 질소 신호 경로를 비롯한 

여러 신호 경로에 관련된 AD의 병리학적인 변화에 영향을 미칩니다. 

비규범적 Wnt-5a/Ca2+ 신호는 미토콘드리아 역학에서 매우 중요하며, 

이 신호의 활성화는 해마 뉴런을 Aβ 올리고머에 의한 손상으로부터 보호합니다.186 

아디포넥틴 수용체 작용제인 아디포론은 

시냅스 효율성을 크게 개선하고 미토콘드리아의 융합을 강화하며 

SY5Y 세포에서 타우 과인산화를 완화하여 P301S 타우 형질전환 마우스의 기억 결손을 회복시켜 줍니다.187 

기계적으로 AMPK/GSK3β 및 AMPK/SIRT3 신호는 타우 축적과 함께 미토콘드리아 역학에 대한 아디포론의 긍정적인 효과를 강화하는 데 관여합니다.187 또한, Aβ에 의한 산화질소는 Drp1 S-니트로실화를 통해 미토콘드리아 핵분열과 신경세포 손상을 매개하여 AD의 진행을 촉진합니다.188 따라서 Drp1 S-니트로실화를 방지하면 이러한 신경독성 사건을 제거할 수 있습니다.188

Huntington’s disease (HD)

is a progressive neurodegenerative condition that is both fatal and progressive, with limb tremors and decreased cognition, and it is inherited autosomally dominantly.189 The brains of HD patients were subjected to histopathological examination, which revealed that multiple brain regions such as the caudate, putamen, and cortex of the striatum as well as the subthalamus and hypothalamus had been affected. HD-associated mutations are caused by a gene that contains an enlarged repeat of the polyglutamine encoding sequence (CAG repeat), which is located within exon 1 in the HD gene.190

Mechanisms responsible for the degeneration of neurons in individuals with HD are not yet fully comprehended. Current research efforts to understand the pathogenesis of HD have primarily focused on investigating abnormalities in mitochondrial dynamics, especially increased mitochondrial division, resulting in malfunctioning mitochondria, and deficits in the trafficking of axons and synaptic transmission in neurons suffering from HD.191,192,193,194 Several genes that are implicated in the ETC and mitochondrial structure, among which are Fis1, Drp1, MFN1/2, Tomm40, Opa1, and CypD, were examined in individuals suffering from stage III and IV HD. It was found that Fis1 and Drp1 expression‎ increased in HD patients, while MFN1/2, Tomm40 and Opa1 expression‎ decreased. These abnormalities impact mitochondrial function, neuronal transport, and cell death, potentially accelerating the progression of HD.191 Another study found that increased mutant huntingtin (HTT)-Drp1 interaction alters Drp1 structural and functional properties, causing increased mitochondrial division and decreased ATP production, resulting in neuronal dysfunction.193

Metabolic diseases

Diabetes refers to a metabolic disease associated with insulin resistance, inadequate insulin secretion, and abnormal glucose metabolism. The etiology and progression of this disease are associated with several factors. Evidences suggest that mitochondrial fragmentation is responsible for insulin resistance. Mitochondrial dynamics disturbances, particularly mitochondrial fission, may exacerbate insulin resistance and impaired glucose metabolism of hybrid cells bearing mitochondrial haplogroup B4, thereby facilitating the onset and progression of diabetes.195

당뇨병은 

인슐린 저항성, 

부적절한 인슐린 분비 및 비정상적인 포도당 대사와 관련된 대사 질환을 말합니다. 

이 질병의 원인과 진행은 여러 가지 요인과 관련이 있습니다. 

미토콘드리아 단편화가 

인슐린 저항성의 원인이라는 증거가 있습니다. 

미토콘드리아 역학 장애, 특히 

미토콘드리아 분열은 미토콘드리아 하플로그룹 B4를 가진 

잡종 세포의 인슐린 저항성과 포도당 대사 장애를 악화시켜 

당뇨병의 발병과 진행을 촉진할 수 있습니다.195

Evidence demonstrated that palmitate (PA) overabundance resulted in the fragmentation of mitochondria and increased levels of the mitochondrial proteins Fis1 and Drp1 in maturing C2C12 muscle cells.148 This fragmentation correlates with elevated levels of oxygen-free radicals, depolarization of mitochondria, decreased ATP synthesis, as well as impaired glucose uptake upon insulin stimulation. Furthermore, inhibition of Drp1 using genetic and pharmacological approaches effectively mitigate C2C12 cells’ mitochondrial depolarization, fragmentation, and insulin resistance as a result of PA-induced mitochondrial fragmentation, suggesting a potential therapeutic strategy for managing these detrimental effects.148 Besides, hyperglycemia during gestational diabetes mellitus poses a threat to the functioning of placental tissue. It disrupts mitochondrial fusion thereby alters the equilibrium of the dynamics of mitochondria in placental tissue. When mitochondrial fission is chemically inhibited in cultured placental trophoblast cells, the mitochondrial fusion is alternatively activated.196 Inhibiting mitochondrial fission results in a reduction in the generation of ROS, expression‎ of markers for unfolded proteins in mitochondria, and mitochondrial depolarization. Additionally, it improves insulin sensitivity in placental cells during hyperglycemia.196

팔미테이트(PA)의 과잉 섭취는 

성숙한 C2C12 근육 세포에서 미토콘드리아의 분열과 

미토콘드리아 단백질 Fis1 및 Drp1의 수치 증가를 초래한다는 증거가 있습니다.148 

이러한 분열은 활성 산소 수치 상승, 미토콘드리아의 탈분극, ATP 합성 감소, 인슐린 자극 시 포도당 섭취 장애와 관련이 있습니다. 또한, 유전적 및 약리학적인 접근법을 사용하여 Drp1을 억제하면 PA에 의한 미토콘드리아 단편화의 결과로 나타나는 C2C12 세포의 미토콘드리아 탈분극, 단편화 및 인슐린 저항성을 효과적으로 완화하여 이러한 해로운 영향을 관리할 수 있는 잠재적인 치료 전략을 제시합니다.148 또한 임신성 당뇨병 중 고혈당은 태반 조직의 기능에 위협을 가합니다. 고혈당은 미토콘드리아 융합을 방해하여 태반 조직에서 미토콘드리아의 역학 평형을 변화시킵니다. 배양된 태반 영양막 세포에서 미토콘드리아 핵분열을 화학적으로 억제하면 미토콘드리아 융합이 반대로 활성화됩니다.196 미토콘드리아 핵분열을 억제하면 ROS 생성, 미토콘드리아에서 펼쳐진 단백질의 마커 발현 및 미토콘드리아 탈분극이 감소합니다. 또한 고혈당 상태에서 태반 세포의 인슐린 감수성을 개선합니다.196

Diabetes development is closely associated with impaired function of pancreatic β-cells, which can be triggered by various factors, including ER stress.197 The expression‎ of Drp-1 significantly enhance apoptosis induced by ER stress in the Drp1 WT activated β-cell line, as opposed to Drp1 K38A (a dominant negative mutant of Drp1) inducible β-cell line.198 Rhein, a compound derived from rhubarb and belonging to the anthraquinone family, displays potential in ameliorating glucose metabolism disorders in mice with diabetes. Mechanically, rhein prevents the apoptosis of pancreatic beta-cells caused by increased glucose levels via stabilizing mitochondrial morphology. Through its localization at β-cell mitochondria, rhein can preserve mitochondrial integrity through inhibition of mitochondrial fission protein Drp1, which is induced by hyperglycemia.199

당뇨병 발병은 

ER 스트레스를 포함한 다양한 요인에 의해 유발될 수 있는 

췌장 베타세포의 기능 손상과 밀접한 관련이 있습니다.197 

Drp-1의 발현은 

Drp1 K38A(Drp1의 우성 음성 돌연변이) 유도성 베타세포 라인과는 대조적으로 

Drp1 WT 활성화 베타세포 라인에서 ER 스트레스에 의해 유도된 세포 사멸을 크게 향상시킵니다.198 

루바브에서 추출한 안트라퀴논 계열 화합물인 라인은 당뇨병 쥐의 포도당 대사 장애를 개선하는 잠재력을 보여줍니다. 기계적으로 라인은 미토콘드리아 형태를 안정화하여 포도당 수치 증가로 인한 췌장 베타세포의 세포 사멸을 방지합니다. 베타세포 미토콘드리아에 국한되어 있는 라인은 고혈당에 의해 유도되는 미토콘드리아 핵분열 단백질 Drp1의 억제를 통해 미토콘드리아의 완전성을 보존할 수 있습니다.199

In summary, diabetic individuals often display resistance to insulin and abnormal glucose metabolism. Recent studies have suggested that mitochondrial fission, which affects mitochondrial dynamics, can contribute to insulin resistance, pancreatic beta-cell malfunction, and the production of reactive oxygen species. Therefore, inhibiting mitochondrial division may have therapeutic potential for managing diabetes.

요약하면, 

당뇨병 환자는 

종종 인슐린에 대한 저항성과 

비정상적인 포도당 대사를 나타냅니다. 

최근 연구에 따르면 

미토콘드리아 역학에 영향을 미치는 미토콘드리아 분열이 

인슐린 저항성, 

췌장 베타세포 기능 장애 및 활성 산소 종 생성에 기여할 수 있다고 합니다.

 따라서 미토콘드리아 분열을 억제하면 당뇨병을 관리할 수 있는 치료적 잠재력을 가질 수 있습니다.

Non-alcoholic fatty liver disease (NAFLD)

comprises a range of hepatic diseases manifested by an abnormal fat deposition within the liver in the absence of an excessive alcohol consumption history. Steatosis, which is the accumulation of fat in >5% of hepatocytes, is a hallmark of NAFLD.200 Diabetes, insulin resistance, metabolic syndrome, and mutations in the genes PNPLA3 (patatin-like phospholipase domain-containing protein 3) and TM6SF2 (transmembrane 6 superfamily member 2) are contributing factors to NAFLD.201,202,203 Accumulating evidence suggests that structural and bioenergetic changes to the mitochondria are involved in the pathogenesis causing NAFLD, which may progress into non-alcoholic steatohepatitis.

The occurrence and advancement of NAFLD are closely linked to mitochondrial fission. According to in vitro studies, treating hepatocytes with PA results in mitochondrial fragmentation, impairing transmembrane voltage, excretion of Cyt C, and increased ROS activity.204 Using high-fat diet induced NAFLD as a model, increased protein levels of Drp1, mitochondrial fragmentation, as well as heightened hepatocyte lipolysis are observed in liver.205 Moreover, inhibition of mitochondrial division through expressing the dominant-negative fission mutant (Drp1-K38A) alleviates the oxidative stress and impairment of liver function resulting from excess intake of fat, exerting protective effect against liver steatosis.205 This study offers mechanistic evidence supporting the role of mitochondrial fission in regulating liver lipid metabolism and oxidative injury, both of which are linked to the development of NAFLD.

On the other hand, hepatocytes from mice with NAFLD exhibit lower expression‎ levels of MFN1, which correlates with the development of steatohepatitis.206,207 Additionally, treatment of hepatocytes with PA leads to downregulation of both transcript and protein levels of MFN2.208 Furthermore, diminished levels of MFN2 are observed in livers of patients with non-alcoholic steatohepatitis (NASH) as well as in murine models of NAFLD. Interestingly, deletion of hepatic MFN2 significantly promotes inflammatory responses, accumulation of triglycerides, fibrosis, and HCC in mouse models of NASH, whereas restoring MFN2 expression‎ using adenovirus in mutant (liver-specific) mice lacking MFN2 observably alleviate disease symptoms of NASH.209

The underlying mechanism through which fission in mitochondria facilitates the development of NAFLD remains poorly understood. Due to mitochondria’s central role in coordinating hepatic metabolism of lipids, studies have proposed that division of mitochondria is connected with ROS and dysfunction within the mitochondria, which potentially contribute to NAFLD. Indeed, after exposing to PA, HepG2 cells display more mitochondrial fragmentation, elevation of superoxide levels, and overall oxidative stress.208 Importantly, mitochondrial fragmentation occurs prior to the generation of ROS, with signs of fragmentation observed as early as 12 hours, whereas increased ROS generation is not evident until after 12 hours of exposure to PA.208 As previously reported, overexpressing Drp1-K38A (the dominant-negative fission mutant) reduces oxidative stress and ROS levels in the context of hyperglycemia.210 Furthermore, Drp1-K38A expression‎ lowers oxidative damage and inflammation within a model of NAFLD.205 Suppression of mitochondrial fission causes proton leak when PA is present in vitro. Given that proton leak refers to the nonproductive dissipation of energy during OXPHOS, the increased proton leak contributes to reduction of ROS under the conditions of inhibiting of mitochondrial fission.205

Cardiovascular diseases

Ischemia-reperfusion injury

Acute myocardial infarction accounts for a significant amount of disability and mortality around the world. In order to limit the size of myocardial infarction and reduce acute myocardial ischemic injury, rapid and effective reperfusion of the myocardium is preferred for patients with myocardial infarction. This can be achieved through either primary percutaneous coronary intervention or thrombolysis. However, it is important to note that reperfusion itself can lead to cardiomyocyte death, which is known as myocardial reperfusion injury.211 Currently, no effective treatments are available for this condition.212 Ischemia-reperfusion injury (IRI) to the heart entails a complicated process resulting in tissue damage and cells dying. Ischemia causes a lack of oxygen and nutrients in the heart, which results in anaerobic metabolism and the production of lactic acid. When blood flow is reintroduced during reperfusion, it can trigger harmful events such as the ROS production, calcium overload, inflammation, mitochondrial dysfunction, and ER stress. These events can lead to cellular dysfunction and ultimately cell death.212,213 Therefore, comprehending the intricacies of cardiac IRI is essential for developing effective preventative measures or minimize the damage caused by this phenomenon.

Increasing evidences point to the role played by mitochondrial dynamics in IRI. Ischemia cause mitochondrial fragmentation, which mainly depends on Drp1 and links to increased release of ROS and calcium overload.10,11 High level of ROS can induce mitochondrial fission during acute IRI, while pre-treatment with scavengers of mitochondrial ROS-SkQ1 or Trolox, reduces the phosphorylation of Ser616 in Drp1 and mitochondrial fission after IRI.43,214 During acute IRI, cytosolic calcium overload can activate calcineurin, which is responsible for activating Drp1 by dephosphorylating Ser637, inducing Drp1-mediated mitochondrial fission.215

Increasing mitochondrial fusion or inhibiting mitochondrial fission can provide a protective effect on heart against IRI. Transfection of these cells with mitochondrial fusion proteins, including MFN1/2 or Drp1K38A (a recessive variation in Drp1), resulted in more cells with prolonged mitochondria, reduce mitochondrial permeability transition pore sensitivity, along with decreased cellular death following IRI.10 Besides, in the prediabetic rats, administration of Mdivi-1 at any time point during IRI effectively reduces ROS production, mitochondrial swelling and depolarization, as well as dynamic imbalance.216 Additionally, dual-specificity protein phosphatase1 (DUSP1) is involved in regulating cardiac metabolism, and its expression‎ decreases after acute cardiac IRI. Nevertheless, the reintroduction of DUSP1 suppresses Mff activation, thus mitigating fatal mitochondrial fission by deactivating the JNK pathway.217 Moreover, in the context of IRI, there is an upregulation of mitochondrial calcium uniporter (MCU), which triggers calpain activation. Calpain activation, subsequently, triggers the downregulation of Opa1, ultimately leading to mitochondrial fission.218 MCU suppression using Ru360 during IRI appears to minimize the area of myocardial infarction and apoptosis in cardiomyocytes, reduce mitochondrial fractures and promote mitochondrial fusion and mitophagy.218 Furthermore, Opa1 inactivation and mitochondrial fusion is a significant phenomenon during IRI, but it is reversible when treated with melatonin.219 Melatonin helps to normalize the fusion of mitochondria associated with Opa1 via AMPK pathway, which corrects excessive mitochondrial division, promotes mitochondrial energy metabolism, maintains mitochondrial function, and blocks mitochondrial apoptosis in cardiac myocytes.219

Heart Failure (HF)

refers to a condition in which the heart cannot provide enough oxygen and nutrients to the body, leading to decreased physical function and often accompanied with symptoms such as breathing difficulty, fatigue, and edema.220 An impaired mitochondrial function has been identified as a key characteristic of HF, which decreases ATP synthesis and increases ROS generation, leading to a reduced energy supply to the heart muscle cells, impairing contractile function and worsening HF progression.221 Increasing studies indicate that improper mitochondrial merging and division augment the development of HF. Reduced Opa1 expression‎ and small mitochondrial fragmentation appear in the failing hearts, indicating decreased mitochondria fusion in the failing hearts.222 In mice, specific deletion of Yme1l in the heart activates OMA1, leads to increased Opa1 degradation, fragmented mitochondria, and altered metabolism of the heart, finally, resulting in dilated cardiomyopathy and HF.223 However, deletion of Oma1 prevents cleavage of Opa1, which in turn rescues cardiac function and mitochondrial morphology. It is noteworthy that high-fat feeding of mice or deletion of the Yme1l gene in skeletal muscle restores heart metabolism and preserves cardiac activity, irrespective of inhibiting mitochondrial fission.223

Promotion of mitochondrial fusion prevents the aggravation of HF. Omentin1, a newly identified adipokine, has been shown to safeguard against HF induced by myocardial ischemia.224 In mice with HF, administering omentin1 enhances mitochondrial fusion while decreasing mitochondrial fission, with an upregulation of Opa1 and MFN2, whereas a decrease in Drp1(Ser616).224 Doxycycline (DOX) exerts protective effects in animal models of HF. Mechanically, in H9c2 cardiomyocytes, the action of DOX alleviating the severity of HF involves reducing mitochondrial depolarization and fragmentation induced by oxidative stress, as well as positively modifying the levels of Opa1, MFN2, and Drp1.225

Cardiomyopathy

Maintaining a balance between mitochondrial division and merging is crucial for maintaining the structural integrity of the myocardium. Research has shown that a disturbance in mitochondrial fusion in mature cardiac tissue can lead to cardiomyopathy and disrupt cardiac homeostasis in mice.226 In Drosophila, knocking down of mitochondrial assembly regulatory factor (MARF), which is similar to Opa1 or MFN1/2, causes mitochondrial fragmentation and dilated cardiomyopathy.227 Structure and function abnormalities of the heart, causing diabetes-related cardiomyopathy (DCM), are commonly associated with diabetes.228 Specifically, for db/db mice, diabetes-induced hearts exhibite increased mitochondrial fission accompanied by a significantly lower expression‎ of MFN2. However, reintroducing MFN2 into hearts suffering from diabetes preventes the progression of DCM by inhibiting mitochondrial fission.229

Paeonol, a bioactive compound with potential pharmacological benefits in protecting the heart and mitochondria, promotes the fusion of mitochondrial mediated by Opa1, alleviates the accumulation of oxidative stress in mitochondria, sustains mitochondrial respiration, and boosts cardiac performance both in vitro and in vivo models involving DCM.230 Paeonol has been found to promote fusion of mitochondria through Opa1 activation by activating STAT3. This mechanism involves the transcription factor attaching to Opa1 promoters and subsequently increasing its transcription.230 The deficiency of the Mff gene in mice leads to dilated cardiomyopathy, which ultimately results in heart failure and death. Mutant tissue exhibits lower mitochondrial content and reduced activity of the respiratory chain, with an increase in mitophagy. However, the removal of MFN1 simultaneously restores respiratory chain function, life span, and heart dysfunction, thereby preventing Mff-deficient cardiomyopathy.231

Cancer

Recent studies provide mounting evidence that mitochondria play a crucial role in tumorigenesis and progression. In addition to their essential bioenergetic functions, mitochondria are also responsible for cancer anabolism, calcium homeostasis, redox regulation, gene transcription, and the orchestration of cell fate.232 Moreover, numerous immune functions depend on the proper efficiency of mitochondrial metabolism in immunocytes.233 Dysregulations of mitochondrial dynamics are implicated leading to the occurrence and development of various cancers, influencing aspects such as tumor cell proliferation, metastasis, drug resistance and tumor microenvironment (TME) (Fig. 5), indicating that addressing mitochondrial dynamics may be a promising anticancer therapeutic approach.

최근 연구에 따르면 

미토콘드리아가 종양 발생과 진행에 중요한 역할을 한다는 증거가 

점점 더 많아지고 있습니다. 

미토콘드리아는 

필수적인 생체 에너지 기능 외에도 

암 대사, 

칼슘 항상성, 

산화 환원 조절, 

유전자 전사, 

세포 운명 조율에도 관여합니다.232 

또한 수많은 면역 기능이 면역세포에서 미토콘드리아 대사의 적절한 효율성에 의존합니다.233 미토콘드리아 역학의 조절 장애는 종양 세포 증식, 전이, 약물 내성 및 종양 미세 환경(TME)과 같은 측면에 영향을 미쳐 다양한 암의 발생과 발달에 관여하며(그림 5), 이는 미토콘드리아 역학을 다루는 것이 유망한 항암 치료법이 될 수 있음을 시사합니다.

Fig. 5

Mitochondrial dynamics in cancer. a Mitochondrial division in cancer cells show increased levels of Drp1 and decreased levels of MFN2. Cancer-promoting factors such as the oncogene Ras or activation of the MAPK pathway can trigger the phosphorylation of Drp1 at Serine 616 by ERK2, leading to mitochondrial fission and increased fragmentation. b Mitochondrial fission induces glycolytic reprogramming in CAFs, driving stromal lactate production, and tumor growth. TILs commonly experience exhaustion during cancer progression. PD-1 signaling inhibits mitochondrial fragmentation in T cells by downregulating Drp1 phosphorylation on Ser616, likely through regulation of the ERK1/2 and mTOR pathways; TAMs recruitment and polarization is facilitated by mitochondrial fission causing cytosolic mtDNA stress, which increases CCL2 secretion by cancer cells; tumor-infiltrating NK cells have small and fragmented mitochondria due to excessive fission caused by the sustained activation of mechanistic target of mTOR-Drp1 in the hypoxic TME. This mitochondrial fragmentation leads to decreased cytotoxicity and enables tumors to evade NK cell-mediated surveillance. CAFs cancer-associated fibroblasts, TIL tumor-infiltrating T lymphocytes, TAMs tumor-associated macrophages

암의 미토콘드리아 역학 암세포의 미토콘드리아 분열은 Drp1의 수치가 증가하고 MFN2의 수치가 감소하는 것으로 나타났습니다. 발암 유전자 Ras 또는 MAPK 경로의 활성화와 같은 암 촉진 인자는 ERK2에 의해 세린 616에서 Drp1의 인산화를 유발하여 미토콘드리아 분열과 단편화를 증가시킬 수 있습니다. b 미토콘드리아 분열은 CAF에서 해당 과정 재프로그래밍을 유도하여 기질 젖산염 생성 및 종양 성장을 촉진합니다. TIL은 일반적으로 암이 진행되는 동안 소진을 경험합니다. PD-1 신호는 ERK1/2 및 mTOR 경로의 조절을 통해 Ser616의 Drp1 인산화를 하향 조절하여 T세포의 미토콘드리아 단편화를 억제하고, 미토콘드리아 분열로 인해 암세포의 CCL2 분비를 증가시키는 세포질 mtDNA 스트레스를 유발하여 TAM의 모집 및 분극화가 촉진됩니다; 종양 침윤 NK 세포는 저산소성 TME에서 mTOR-Drp1의 기계적 표적의 지속적인 활성화로 인한 과도한 핵분열로 인해 작고 파편화된 미토콘드리아를 가지고 있습니다. 이러한 미토콘드리아 단편화는 세포 독성을 감소시키고 종양이 NK 세포 매개 감시를 회피할 수 있도록 합니다. CAF 암 관련 섬유아세포, TIL 종양 침윤 T 림프구, TAM 종양 관련 대식세포

Cell proliferation

The uncontrolled growth of cells, disrupted cell cycle regulation, in addition to abnormalities in programmed cell death, are hallmarks of cancer.234 A significant role is played by mitochondrial dynamics during these processes. Therefore, recent research has provided compelling evidence linking the merging and division of mitochondria to the advancement of different types of cancer. Mitochondrial division is detected in cancerous cells,235 and hindering this process causes reduced proliferative activity and enhanced death of cells in some cancer model systems. For instance, lung cancer samples obtained from patients show the same pattern of increased Drp1 and decreased MFN2 levels compared with tissue adjacent to healthy lung tissue. Manipulating the mitochondrial network formation, such as through overexpression‎ of MFN2 or inhibition of Drp1, has been found to decrease growth and increase the occurrence of spontaneous apoptosis in lung cancer cells.236 Similarly, knocking down Drp1 stimulates increased numbers of mitochondrial elongation, proliferation retardation and an increase in apoptosis of both HCT116 and SW480 human colon cancer cells.236

Furthermore, compared to normal gastric mucosal tissue, MFN2 expression‎ on gastric cancer cells is downregulated, its level negatively correlates to tumor growth, suggesting a potential anti-tumor function for MFN2.237 A higher level of MFN2 appears to restrict gastric cancer cell reproduction in vitro.238 The expression‎ of FUN14 domain-containing 2 (FUNDC2) is increased in HCC at the transcriptional level. Notably, elevated levels of FUNDC2 expression‎ correlate with reduced patient survival, while its knockdown has been shown to inhibit liver tumor development in mice. The mechanism of action involves FUNDC2’s amino terminus interacting with the GTPase domain of MFN1, which inhibits MFN1 activity that normally promotes the fusion of the OMM.237

Dysfunctional mitochondrial dynamics can influence the signaling of intracellular carcinogens. The activation of ERK2 by oncogene Ras or the MAPK pathway can trigger the phosphorylation of Drp1 at Ser616, leading to mitochondrial fragmentation. This process has been linked to tumor growth.239 Moreover, reducing the expression‎ of Drp1 dampens the growth of tumors caused by MAPK-mediated malignancies.239 In HCC, the extracellular matrix-associated protein CCBE1 significantly promote mitochondrial fusion and inhibit the progression of HCC. The function of CCBE1 involves inhibiting fission of mitochondria by impeding the localization of Drp1 to mitochondria by preventing phosphorylation of Drp1 at Ser616.240 In cervical carcinoma Hela cells, MFN2 inhibits proliferation and cell-cycle by inhibiting the expression‎ of key proteins, including NF-κB p65, Myc, and mTOR, and by suppressing Ras protein activity.241

Metastasis

Tumor metastasis is closely linked with mitochondrial fission. Metastatic breast cancer cells exhibit an increase in mitochondrial fragmentation as a result of their elevated levels of active Drp1 and reduced MFN1 expression‎.85 Mitochondria elongation or clustering can greatly reduce the metastasis potential in cancerous breast cells, which can be caused by either Drp1 deficiency or MFN1 overexpression‎. Alternatively, silencing the MFN1 gene results in the fragmentation of mitochondria in breast cancer cells, which in turn increases their ability to metastasize.85 Rab32, a protein related to Ras, is significantly upregulated in glioblastoma multiforme (GBM), particularly in its highly malignant mesenchymal form. Reduction of Rab32 levels decreases the migration and invasion potential in GBM cells.242 Mechanisms underlying Rab32 promoting GBM aggressiveness involves the ERK/Drp1 pathway, i.e., Rab32 facilitates the transport of Drp1 into mitochondria, where it recruits ERK1/2 to phosphorylate the Ser616 region of Drp1.242

An elevated Drp1 expression‎ has been connected to malignant thyroid tumors. By genetically and pharmacologically blocking Drp1 activity, it was possible to attenuate the migration ability of thyroid cancer cells.243 In addition, excessive mitochondrial fission is observed in highly metastatic HCC. One of the main downregulated candidates, MFN1, is closely related to the metastasis of HCC.244 The protein MFN1 has been found to inhibit the growth, spread, and movement of HCC cells in both living organisms and laboratory settings. This is achieved through its ability to encourage the merging of mitochondria. Conversely, when MFN1 is absent, the dynamics of mitochondria are disrupted, leading to the process of EMT in liver cancer cells.244

The activation of the Ca2+/CaMKII/ERK/FAK pathway has been shown to be important in the promotion of focal-adhesion dynamics and lamellipodia formation during HCC cell reprogramming, which is largely facilitated by mitochondrial fission.245 A high level of EGFR expression‎ is present within mitochondria from highly aggressive non-small cell lung cancer (NSCLC) cells, which can stimulate NSCLC invasion and metastasis by interacting with MFN1 and causing disruption in mitochondrial fusion.246 Furthermore, the protein SIRT4 achieves cancer cell invasion and expansion via impeding mitochondrial dynamics and inhibiting the ERK-Drp1 pathway.247

Overall, proteins that promote mitochondrial fission tend to be elevated in tumorous and metastasized patient samples in comparison with the normal tissue. The increased levels of such proteins are commonly associated with unfavorable clinical outcomes and affect numerous cellular characteristics critical to the progression of tumors, such as tumor growth, migration, and invasion. These observations underscore the usefulness of the mitochondrial division mechanism for therapeutic purposes in treating metastatic disease.

Drug resistance

Mitochondrial dynamics have been identified as crucial for drug resistance development in cancerous cells.248 Breast cancer stem cells (BCSCs) play a crucial role in chemotherapy resistance and recurrence in breast cancer. Studies have shown that compared to 2D cultured parent cells, BCSCs exhibit significantly increased levels of Fis1 and MFN1 proteins. Treatment with AZD5363 (Capivasertib) is believed to affect mitochondrial dynamics in BCSCs by suppressing MFN1 expression‎, thus increasing the sensitivity of BCSCs to doxorubicin chemotherapy.249 Furthermore, Transferred breast carcinoma cells have been found to spread to organs that display a more favorable microenvironment characterized by elevated mitochondrial division mediated by Drp1 and mitochondrial elongation factor (MIEF)1/2. The pharmacological inhibition of Drp1 has been shown to restore sensitivity to cisplatin (DDP) and restrain diffuse neoplastic cell awakening. These findings suggest that modulating mitochondrial dynamics may be a potential strategy to prevent metastatic chemotherapy resistance.250 Additionally, Opa1 contributes to resistance to gefitinib, an inhibitor of tyrosine kinases, in a lung adenocarcinoma (LUAD) cell line.251 Tht gefitinib-resistant LUAD cells exhibit elongated mitochondria with narrower cristae and elevated Opa1 expression‎ levels. Inhibiting Opa1, either through genetic or pharmacological means, restores mitochondrial morphology and sensitizes the cells to the discharge of Cyt C accompanied by death of the cells induced by gefitinib.251

미토콘드리아 역학은 

암세포의 약물 내성 발달에 중요한 것으로 밝혀졌습니다.248 

유방암 줄기세포(BCSC)는 유방암의 화학 요법 내성 및 재발에 중요한 역할을 합니다. 연구에 따르면 2D 배양 모세포에 비해 BCSC는 Fis1 및 MFN1 단백질 수치가 현저히 증가합니다. AZD5363(카피바서팁)으로 치료하면 MFN1 발현을 억제하여 BCSC의 미토콘드리아 역학에 영향을 미쳐 독소루비신 화학요법에 대한 BCSC의 민감성을 증가시키는 것으로 여겨집니다.249 

또한, 전이된 유방암 세포는 Drp1 및 미토콘드리아 신장 인자(MIEF)1/2에 의해 매개되는 미토콘드리아 분열이 증가된 더 유리한 미세 환경을 나타내는 장기로 퍼지는 것으로 밝혀졌습니다. Drp1의 약리학적 억제는 시스플라틴(DDP)에 대한 민감성을 회복하고 확산성 종양 세포 각성을 억제하는 것으로 나타났습니다. 이러한 연구 결과는 미토콘드리아 역학을 조절하는 것이 전이성 화학요법 내성을 예방하는 잠재적 전략이 될 수 있음을 시사합니다.250 또한 Opa1은 폐 선암(LUAD) 세포주에서 티로신 키나제 억제제인 게피티닙에 대한 내성에 기여합니다.251 게피티닙 내성 LUAD 세포는 크리스테가 좁아지고 Opa1 발현 수준이 높아진 길어진 미토콘드리아를 나타냅니다. 유전적 또는 약리학적인 방법으로 Opa1을 억제하면 미토콘드리아 형태가 회복되고 게피티닙에 의해 유도된 세포의 사멸과 함께 Cyt C의 배출에 세포가 민감하게 반응합니다.251

DDP is widely utilized in advanced cancer therapy. The Mff protein is extensively expressed in HCC cell lines and tissues resistant to DDP.252 In Huh-7/DDP cells, knocking down Mff prevents mitochondrial division and reduces Drp1 levels, which enhances the sensitivity of Huh-7/DDP xenografts to the treatment with DDP in vivo.252 Meanwhile, another study also revealed that Mdivi-1 sensitizes chemo-resistant breast and lung cancer cells to DDP.253 However, in ovarian carcinoma, decreased fission protein expression‎ was found to enhance cisplatin resistance.254 In DPP-resistant SKOV3 cells, a markedly increased mitochondrial length, down-regulated Drp1 expression‎ and up-regulated MFN2 expression‎ are observed. Furthermore, inhibiting Drp1 or increasing MFN2 expression‎ can enhance SKOV3 cells’ resistance to DDP.254 MFN2 expression‎ increases significantly in leukemic Jurkat cells that are resistant to doxorubicin treatment. Additionally, there is a notable increase in the expression‎ of the OXPHOS complex (respiratory system) and the synthetase of ATP in these cells. When MFN2 is knocked down using CRISPR, the LD50 of doxorubicin is lower than in wild-type cells exposed to the drug, indicating that mitochondrial fusion hinders the cell’s ability to respond to chemotherapy.255

An effect of bone marrow-derived MSCs on T-cell acute lymphoblastic leukemia (T-ALL) cells has been found to promote chemoresistance by altering the mitochondrial dynamics. When T-ALL cells are cultured with MSCs, their mitochondrial structure undergoes a shift from elongation to fragmentation. This shift is due to the phosphorylation of Drp1 at residue Ser616, which is primarily mediated by the activation of extracellular signal-regulated protein kinase.256 Chemoresistant cells can induce high-mobility group box 1 (HMGB1) to be released into conditioned media following the death of cells, which triggers the phosphorylation of Drp1 through the receptor for advanced glycation end product (RAGE). Based on these results, it appears that HMGB1 released by dead tumor cells promotes chemical resistance as well as tumor development through RAGE-dependent ERK/Drp1 phosphorylation.257

In summary, mitochondrial dynamics play a crucial role in the development of drug resistance in cancer cells. Targeting specific molecules that are associated with the merging or division of mitochondria has been shown to increase the effectiveness of chemotherapy and targeted therapy in inhibiting tumor growth. Therefore, it is crucial to understand the mechanisms that underlie drug resistance and to develop efficient methods to combat it, in order to improve cancer treatment outcomes.

Tumor microenvironment.

Tumor immunotherapy has achieved several advancements in recent years that have resulted in increased survival rates for cancer patients.258 However, the efficacy of immunotherapy is limited as only a portion of patients exhibit a response to the treatment. This is partly due to the hindrance of immune cell migration and infiltration caused by TME, which leads to the exhaustion of immune cells.259 Recent research suggests that mitochondrial dynamics have a profound effect upon immune surveillance within the TME.

During HCC progress, the interaction between TME and HCC cells is of vital importance. The dynamic modifications in mitochondrial division and merging are pivotal in maintaining mitochondrial homeostasis and mtDNA distribution.260 Fission mediated by Drp1 induces the cytoplasmic stress of mtDNA, which promotes the release of CCL2 by HCC cells via activating the TLR9-mediated NF-B pathway, thereby facilitating M2-polarization and the recruitment of tumor-associated macrophages (TAMs).261 Moreover, blocking CCL2/CCR2 signaling by antagonists significantly reduces TAM invasion thereby restrains the advancement of HCC in orthotopic murine models. These observations suggest that mtDNA damage induced by mitochondrial fragmentation enhances invasion of TAMs and HCC progress via CCL2 secretion.261

Tumor-infiltrating T lymphocytes (TIL) commonly display exhaustion, and their fate is believed to be regulated by mitochondrial dynamics.81 In different types of TME, various signaling molecules impact mitochondrial dynamics in distinct ways, ultimately affecting T cell function. Specifically, programmed cell death-1 (PD-1) signaling is found to downregulate the T-cell response through Drp1-dependent mitochondrial fission.262 The activation of T-cells leads to mitochondrial fragmentation, but this process is inhibited by PD-1 signaling. This inhibition occurs through a reduction in the phosphorylation of Drp1 at Ser616, which is likely regulated by the mTOR and ERK1/2 pathways. In an MC38-derived murine tumor mass, CD8+ T cells expressing PD-1 have reduced Drp1 activities and longer mitochondria compared to their PD-1-negative counterparts, which may explain their reduced motility and proliferation.262 In hypoxic nasopharyngeal carcinoma microenvironments, mitochondrial fusion protein MFN1/2 expression‎ is decreased, leading to small and fragmented mitochondria in TILs.263 It is affected due to increased expression‎ of exosomal miR-24 in response to hypoxia, which inhibits its target gene Myc. Myc directly regulates the transcription of MFN1, which influences mitochondrial morphology, thereby establishing a miR-24-Myc-MFN1 axis. Consequently, increased miR-24 level results in decreased MFN1 expression‎ and small and fragmented mitochondria. However, removing exosomal miR-24 can reverse T cell depletion and reduce tumor cell growth.263 Thus, mitochondrial dynamics and metabolites are essential for optimizing T cells’ anti-tumor function.

TAMs make up the largest component of immunological cellular populations in TME. TAMs have been classified for alternately active (M2) macrophages within the TME, where they facilitate metastasis, angiogenesis, and suppression of the immune in a variety of cancers.264 Compared to normal macrophages, the mitochondrial morphology of TAMs is more static and unstable.56 They exhibit more elongated or sheet-like structures, while normal macrophages have more circular structures. In addition, TAMs have a lower mitochondrial membrane potential, leading to reduced ATP synthesis.56 Inhibiting the expression‎ of the FAM73b protein promotes mitochondrial fission and increases IL-12 production. This transition in TAMs leads to activation of T cells enhancing antitumor immunity.56

Tumor-infiltrating NK cells take part in immunological reactions against cancerous cells through destroying them and secreting cytokines. Nevertheless, within immune-suppressive TME, inhibitory proteins generated from malignant cells leads to an abnormal function of NK cells, resulting in the escape of tumor cells. In liver cancers of humans, NK cells that infiltrate tumors display small and shattered mitochondria. The fragmentation of mitochondria is referred to aberrant mitochondrial metabolism, decreased cytotoxicity, enabling tumor evasion of NK cell detection.265 Oxygen shortage in TME is responsible for the sustained activity of mechanistic targets of the mTOR-Drp1 pathway in NK cells, which leads to excessive fission of mitochondria. However, inhibiting fragmentation of mitochondria improves mitochondrial ATP synthesis and the tumor-fighting ability of NK cells.265 In triple negative breast cancer (TNBCs), ELK3 (E26 transformation-specific transcription factor ELK3)-dependent mitochondrial fission/fusion status is a main determinant of NK cell-mediated immune responses. ELK3 expression‎ is inversely correlated with Mid51, a protein involved in mitochondrial dynamics. This connection between Mid51 and ELK3 has a significant impact on mitochondrial dynamics, which in turn affects the anti-tumor effectiveness of NK cells for treating TNBCs.266

Cancer-associated fibroblasts (CAFs) are extremely plastic cells in TME, are closely associated with tumorigenesis and progression. Multiple studies have shown that CAFs participate in metabolic reprogramming of tumor and exert regulatory effects via their dysregulation of metabolic pathways. More specifically, oxidative stress induced by tumor cell drives an initiation of mitophagy, autophagy, and glycolysis in CAFs.267,268 Metabolic reprogramming towards glycolytic metabolism of fibroblasts occurs as a result of the overexpressing of Mff, which triggers extensive mitochondrial fragmentation and mitochondrial dysfunction. Furthermore, Mff-overexpressing fibroblasts display that they are depleted of ATP and secrete L-lactate, leading to accelerated early tumor growth.269 These results suggest that mitochondrial division leads to a reprogramming of glycolysis in CAFs, contributing to the production of lactate in the stroma, as well as the early development of tumors.

The regulatory T cell (Treg), a CD4+ T cell subset that exhibits immunosuppressive properties, has a crucial function in restricting the activity of T lymphocytes inside the TME and promotes the development of tumors. Tregs undergo metabolic reprogramming that permits utilization of alternative substrates and engagement of various metabolism pathways for fulfilling the energy requirements in TME.270 Tregs often switch their metabolism towards mitochondrial OXPHOS from glycolysis, which is partly regulated by Foxp3 transcriptional activity. Moreover, the expansion of TIL-Tregs and their ability to suppress the immune system rely heavily on mitochondrial metabolic activity.271 For example, the capacity of Tregs in suppressing cancer-fighting immunity is determined by complex III of mitochondria.272 During differentiation of Treg cells, fusion of mitochondria triggered by transforming growth factor-beta1 (TGFβ1) is a checkpoint which directs reprogramming of metabolic processes.273,274 PGC1α participates in mitochondrial biogenesis and mitochondrial dynamics. Its deficiency in Tregs display attenuated suppressive functions in vivo and in vitro.275,276 Evidences from these studies suggest that mitochondrial dynamics are closely regulated in Tregs, which allows for precise coordination in anti-tumor immunity.

At present, the investigation into the crosstalk between immune cells and mitochondrial dynamics, like dendritic cells, neutrophils, and B cells, within the TME is lacking. Thus, there is a significant knowledge gap in terms of the interrelationship between mitochondrial dynamics and these immune cells, which are integral components of the tumor immune microenvironment. The further investigation of this field will be necessary for gaining a complete knowledge of the complex mechanisms underlying tumor progression and immune evasion, and to develop effective therapeutic strategies for cancer treatment.

Strategies for targeting mitochondrial dynamics

In recognition of the crucial contribution of mitochondrial function and structure in cell biology, numerous disease model systems have focused on manipulating mitochondrial dynamics. Researchers have shown that restoring balances of mitochondrial dynamics by using both pharmacological and genetic approaches can enhance tissue function and increase lifespan in an animal model.167 Various methods have been employed to achieve this, including genetic therapies which modify gene expression‎ to affect the division and merging of mitochondrial proteins, and chemical therapeutics which target different mechanisms crucial to mitochondrial division and merging, such as enzyme activities, interactions between proteins, and modifications post-translationally. (Table 2).

세포 생물학에서 미토콘드리아 기능과 구조의 중요한 기여를 인식하여 수많은 질병 모델 시스템에서 미토콘드리아 역학을 조작하는 데 중점을 두고 있습니다. 연구자들은 약리학 및 유전학적 접근법을 모두 사용하여 미토콘드리아 역학의 균형을 회복하면 동물 모델에서 조직 기능을 향상시키고 수명을 늘릴 수 있음을 보여주었습니다.167 이를 위해 미토콘드리아 단백질의 분열과 병합에 영향을 미치도록 유전자 발현을 수정하는 유전자 치료법과 효소 활성, 단백질 간의 상호작용, 번역 후 변형 등 미토콘드리아 분열과 병합에 중요한 여러 메커니즘을 표적으로 하는 화학 치료법을 포함한 다양한 방법이 사용되어 왔습니다. (표 2).

Table 2 Compounds and gene Intervention regulate mitochondrial dynamics for diseases

Full size table

Compounds regulating mitochondrial dynamics

Regulating mitochondrial fission

Various diseases are characterized by excessive fragmentation of mitochondria and reduced fusion. To address this, fission inhibitors have been developed to decrease levels of Drp1, suppress mitochondrial division, and promote mitochondrial fusion. These inhibitors show promise in alleviating the onset and progression of disease. In recent years, research has made significant strides towards the discovery and formulation of effective fission inhibitors for mitochondria. Notable among them are Mdivi-1,277 P110278, Dynasore279 and DRP1i27.

Mdivi-1 is the initial inhibitor that specifically targets mitochondrial division proteins, selectively blocking the function of Drps by interacting primarily with an orthosteric domain, which is not intended to only affect GTPase domains.277 Mdivi-1 can correct mitochondrial shape in models of disease characterized by excess mitochondrial fission. For instance, for neuronal cells, increased research findings suggest that the compound Mdivi-1 may be a potential pharmacological agent to reduce the death of neurons due to neural degenerative disorders. Mdivi-1 treatment inhibits both apoptosis and mitophagy in genetic and environmental models of PD.280,281 Similarly, Mdivi-1 is capable of restoring the equilibrium of mitochondrial dynamics, and alleviating mitochondrial dysfunction correlates to an increase in autophagy triggered by Aβ in neuronal models for AD.282 Moreover, treatment with Mdivi-1 markedly improves behavior outcomes and reduces neurodegeneration in animal models of AD and PD.283,284 Besides, Mdivi-1 prevents excessive cellular necrosis in cardiomyocytes during IRI as well.285 In addition, Mdivi-1 prevents the development of diabetes by reducing oxidative stress and avoiding diabetes-related cardiovascular damage.286 Furthermore, it is also effective in preventing the reproduction and spread of cancerous cells,246 reversing resistance to tumor therapy,253 as well as enhancing MHC-I expression‎ in mouse tumor models.287 Together, Mdivi-1 is a potentially new treatment for a wide range of disease states with aberrant mitochondrial fission.288

As a small peptide, P110 specifically inhibits the communication between Fis1 and Drp1, suppresses mitochondrial fission process.278 Like Mdivi-1, P110 inhibits mitochondrial division and improves performance in various neurodegenerative disease models. In particular, P110 has been found to diminish division of mitochondria and necrosis in neurons derived from patients with HD and PD.278,289 Dynasore is discovered from a screening of 16,000 small molecules and is the initial inhibitor of mitochondrial fission.279 It does not exhibit selectivity in inhibiting mitochondrial fission proteins, but affects the GTPase activities of Drp1 and Dynamin 1/2 in vitro.279 Studies have demonstrated that Dynasore attenuates cardiac disease and reduces neuronal damage caused by degenerative diseases via inhibiting excessive mitochondrial division.290,291

DRP1i27, a potent inhibitor of human Drp1, interacts with the GTPase domain within Drp1 by forming a hydrogen bond with Asp218 and Gln34.292 In fused mitochondria, DRP1i27 appears to exert dose-dependent effects, whereas Drp1-deficient cells are not affected. Moreover, DRP1i27 treatment suppresses mitochondrial fission and protects against simulated IRI.292

Several other small molecules have been reported to have therapeutic potential in various diseases by inhibiting Drp1 and reducing mitochondrial fission. Some of these include exenatide, which belongs to the family of glucagon-like peptides, can contribute to the improvement of heart failure.293 The inhibiting influence of this compound on mitochondrial division is due to its phosphorylation of Ser-637 in Drp1, which disrupts the localization of Drp1 within the mitochondria.294 1H-pyrrole-2-carboxamide compounds have been found to improve AD symptoms.295 These newly identified molecules have demonstrated potential in preclinical research, but additional study is needed to eval‎uate their safety and efficacy in humans. Nevertheless, their discovery has opened new avenues in the search for new therapeutic approaches that target mitochondrial fission and related diseases.

Regulating mitochondrial fusion

Chemical therapeutics have shown promising results in restoring abnormal mitochondrial dynamics by activating and regulating mitochondrial fusion machinery. However, while mitochondrial fission inhibitors have been extensively studied, there is a lack of reported small molecule compounds that directly impact mitochondrial fusion proteins.

In mice with dilated cardiomyopathy, heme oxygenase-1 (HO-1) overexpression‎ increased mitochondrial fusion by upregulating MFN1/2 expression‎.296 Melatonin is another MFN-promoting agent. The chemical activates the Notch1/MFN2 pathway, increasing the expression‎ of MFN2.219,297 Hydrazone M1 is a compound that promotes MFN by restoring fusion of mitochondria in MFN1/2 knockout MEFs.298 Although the mechanism behind its action remains unclear, hydrazone M1 treatment appears to shield cells from apoptosis and modulate components of the ATP synthase complex.298,299 15-oxospiramilactone (S3), a derivative of diterpenoid, is capable of targeting deubiquitinase USP30 present in mitochondria. USP30 is an isopeptidase that governs mitochondrial shape by deubiquitinating MFN1/2. Thus, S3 can amplify ubiquitination without degradation of MFN1/2, thereby eventually augments the activity of MFN1/2 and triggers mitochondrial fusion.300

In terms of promoting Opa1-mediated mitochondrial fusion, there are also various options. Punicalagin prevents cardiomyopathy caused by diabetes by regulating the STAT3-PTP1B pathway, thereby promoting mitochondrial fusion mediated by Opa1.301 Activating the κ-opioid receptor is another way to promote the fusion of mitochondria through the OPA1-STAT3 pathway, which improves cardiac adaptation to IRI.302 Moreover, paeonol is a compound that enhances mitochondrial fusion mediated by Opa1 through activation of the STAT3-CK2α pathway in cardiomyopathy due to diabetes.230

Gene intervention alters mitochondrial dynamics

Overexpressing genes of mitochondrial dynamic proteins

Across both in vivo and in vitro prion disease models, reduced Opa1 expression‎ triggered structural damage in mitochondria and neuronal apoptosis.303 On the other hand, overexpression‎ of Opa1 helps to mitigate prion-induced fragmentation of mitochondrial networks, loss of mitochondrial DNA, and prevents neuron apoptosis.303 Moreover, Opa1 overexpression‎ normalizes the quality control of mitochondria and maintains the function of cardiomyocytes in a model of cardiomyocyte damage induced by hypoxia.263 An improper balance in the level of MFN2/Drp1 leads to mitochondrial division in lung cancer cells, but when MFN2 is overexpressed, cancer cell proliferation significantly decreases, and the spontaneous apoptosis is enhanced.236 In individuals with NASH, MFN2 levels are significantly reduced. However, MFN2 overexpression‎ in HepG2 cells significantly reduces ROS production and mitigates insulin resistance.304

Exhaustion of chimeric antigen receptor (CAR)-T cells is associated with the metabolic and mitochondrial dysfunction. Nowadays, increasing evidences have proven the significance of the mitochondria function and the metabolic status of CAR-T cells before they are infused into patients.305,306 In patients with complete remissions of chronic lymphocytic leukemia, CD8+ CAR T cells exhibit a greater mass of mitochondria and FAO/OXPHOS compared to cytotoxic T cell of unresponsive patients. Moreover, enhanced mitochondrial biogenesis and function positively correlated to CAR-T cell expansion and maintenance. Bezafibrate, a complex agonist of PPAR/PGC-1α, can facilitate function and fission of mitochondria in cells lacking DNM1L.307 It has been reported that bezafibrate can enhance OXPHOS and glycolysis of mitochondria in CTL, as well as promote naïve T cells proliferation and function. In addition, the enhancement of FAO and PPAR-α signal partially maintain the activation of CD8+ T cells under hypoxia and hypoglycemia.308 Multiple studies suggest that the reprogramming of mitochondria and metabolism during T cell expansion could potentially enhance therapeutic outcomes.309,310,311 Hence, introducing transcription factors (PGC-1α/PPARγ) or small molecules targeting mitochondrial dynamics can enhance the mitochondrial function and metabolic ability of CAR-T cells. This can potentially improve their anti-tumor efficacy in certain solid malignancies.

Knockdown or siRNA genes of dynamic proteins

Knockdown Drp1 promotes the development of mitochondria with elongated shapes in colon cancer cells SW480 and HCT116.312 An alteration in the morphology of mitochondria from fragmented granular structure in multipotential stem cell to filamentous reticular networks is required for the differentiation of cardiac mesoderm. Targeting Drp1 may be a potential strategy to stimulate human iPSCs differentiation towards heart cells for individualized regenerative cardiology.313 In glioma tissues, protein expression‎ levels of Drp1 are significantly increased compared to normal brain tissues. Down-regulating Drp1 decreases invasion and proliferation of cells and inhibits the formation of pseudopodias and microvillis.314 Blocking Drp1 leads to compromised mitochondrial autophagy and augmented apoptosis of HCC cells during hypoxia, leading to decreased membrane potential of mitochondria as well as the release of Cyt C and apoptosis-inducing factor. Therefore, in hypoxia, inhibiting mitochondrial division and mitophagy mediated by Drp1 can increase apoptotic rates in HCC cells.315

Prospects and remarks

In this review, we present characteristics and machinery of mitochondrial dynamics, the impact of mitochondrial dynamics on mitochondrial and cellular function, describe the alterations of mitochondrial dynamics in health and diseases, and provide new insights for targeting modulation of mitochondrial dynamics. However, there are still many problems to be solved in this area, and more research needs to be devoted.

Mitochondria are hubs of metabolism, as well as organelles of cellular signaling production and transmission. Mitochondrial dynamics is an adaptive change to response to the complex environments or perform specific functions.79 However, the molecular mechanism and regulatory signal underlying these fission-fusion balance remain largely unknown, especially for certain immune cell types. For instance, accumulation of depolarized mitochondria characterized by loss of mitochondrial mass disrupted membrane structures, which caused by decreased mitophagy activity, link with epigenetic programs toward terminal exhaustion in exhausted tumor-infiltrating CD8+ T cells.316

Since mitochondrial dynamics is an adaptive change, hindering mitochondrial morphological remodeling by interventions may impair the ability of cell adapt to the environment, even cause apoptosis and cell death.317 For example, TAMs always possess longer mitochondria, higher membrane potential and more ATP production per unit of glucose compared with normal macrophages, and these mitochondrial morphological changes help them to survive and perform functions in nutrient-deprived and hypoxic TME.318 Whether conversion TAMs into glycolysis-dependent M1-type macrophages by induction of mitochondrial fission will causes their losing the metabolic adaptation to the TME and even death?

Mitochondrial dynamics are essential for almost all living cells, and deletion of fission or fusion proteins causes lethal consequences.79 For instance, deletion of Drp1 or Opa1 leads to the death of mouse embryos;319 application of kinetic regulatory protein inhibitors (e.g. Mdivi-1) for indiscriminate inhibition of mitochondrial fission may cause cardiovascular disease.320 Hence, in order to precisely modulate mitochondrial dynamics, it is necessary to identify specific targets that regulate the process of mitochondrial dynamics.

Furthermore, mitochondrial dynamics exert a profound influence on cellular metabolism.79 In turn, whether metabolites can affect mitochondrial fission and fusion is unknown. In addition, whether there are cross-links between mitochondrial dynamics and other organs, and what are the pathways that transmit messages between them remain unclear.

In conclusion, maintaining cell and body homeostasis by adjusting mitochondrial dynamics is a promising strategy. With the advancement of research in this field, targeting mitochondrial dynamics can be an effective treatment for various diseases with mitochondrial disorders and can also improve overall health.

References

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