Re: cell death의 다양성과 복잡성 2023 historical review ..nature...

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• Review Article
• Open access
• Published: 23 August 2023

Diversity and complexity of cell death: a historical review

Abstract

Death is the inevitable fate of all living organisms, whether at the individual or cellular level. For a long time, cell death was believed to be an undesirable but unavoidable final outcome of nonfunctioning cells, as inflammation was inevitably triggered in response to damage. However, experimental evidence accumulated over the past few decades has revealed different types of cell death that are genetically programmed to eliminate unnecessary or severely damaged cells that may damage surrounding tissues.

Several types of cell death, including apoptosis, necrosis, autophagic cell death, and lysosomal cell death, which are classified as programmed cell death, and pyroptosis, necroptosis, and NETosis, which are classified as inflammatory cell death, have been described over the years.

Recently, several novel forms of cell death, namely, mitoptosis, paraptosis, immunogenic cell death, entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis, have been discovered and advanced our understanding of cell death and its complexity. In this review, we provide a historical overview of the discovery and characterization of different forms of cell death and highlight their diversity and complexity. We also briefly discuss the regulatory mechanisms underlying each type of cell death and the implications of cell death in various physiological and pathological contexts. This review provides a comprehensive understanding of different mechanisms of cell death that can be leveraged to develop novel therapeutic strategies for various diseases.

요약

죽음은 

개체 또는 세포 수준에서 

모든 생명체의 피할 수 없는 운명입니다. 

오랫동안 세포 사멸은 

손상에 대한 반응으로 염증이 필연적으로 촉발되기 때문에 

바람직하지 않지만 기능하지 않는 

세포의 피할 수 없는 최종 결과로 여겨져 왔습니다. 

그러나 

지난 수십 년 동안 축적된 실험적 증거를 통해 

주변 조직을 손상시킬 수 있는 불필요하거나 심하게 손상된 세포를 제거하도록 

유전적으로 프로그래밍된 

다양한 유형의 세포 사멸이 밝혀졌습니다. 

프로그램된 세포 사멸로 분류되는 

세포 사멸, 괴사, 자가포식 세포 사멸, 리소좀 세포 사멸과 

염증성 세포 사멸로 분류되는 

열사, 괴사, 네토시스 등 

여러 유형의 세포 사멸이 수년에 걸쳐 설명되어 왔습니다. 

Several types of cell death, including apoptosis, necrosis, autophagic cell death, and lysosomal cell death, which are classified as programmed cell death, and pyroptosis, necroptosis, and NETosis, which are classified as inflammatory cell death, have been described over the years.

최근에는 

세포 사멸의 새로운 형태인 

미토시스, 파라토시스, 면역원성 세포 사멸, 엔토시스, 메투시스, 파르타나토스, 페로옵토스, 오토시스, 알칼립토스, 옥시옵토스, 큐프로옵토스, 에레보시스 등이 발견되어 

세포 사멸과 그 복잡성에 대한 이해가 더욱 발전하고 있습니다. 

mitoptosis, paraptosis, immunogenic cell death, entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis

이 리뷰에서는 

다양한 형태의 세포 사멸의 발견과 특성화에 대한 역사적 개요를 제공하고 

그 다양성과 복잡성을 강조합니다. 

또한 각 유형의 세포 사멸의 근간이 되는 

조절 메커니즘과 다양한 생리적 및 병리학적인 맥락에서 

세포 사멸의 의미에 대해 간략하게 논의합니다. 

이 리뷰는 

다양한 질병에 대한 새로운 치료 전략을 개발하는 데 활용할 수 있는 

세포 사멸의 다양한 메커니즘에 대한 포괄적인 이해를 제공합니다.

Introduction

Cell death is a biological process that results in the cessation of cell function and, eventually, cell death1. Its main function is to maintain tissue homeostasis by removing nonfunctional, damaged, and harmful cells2. Although this is a natural process involved in tissue formation, maintenance, and repair, it can also be triggered in response to injury, disease, or damage, leading to pathological cell death3,4,5.

Until the 19th century, death was understood only at the individual organism level, and the concept of cell death was not readily accepted by physicians and biologists. After the development of light microscopy, tissue sectioning practices, and staining techniques, death at the cellular level was recognized6,7. Despite cellular theory advocates such as botanist Mathias Jakob Schleiden and zoologist Theodore Schwann in the 1830s–1860s, the use of microscopes in medicine was limited. The application of technical advances in light microscopy and the concept that organisms are composed of cells to medicine was led by the German pathologist Rudolf Virchow6. In his papers published in 18558 and a book, “Cellular Pathology,” based on a compilation of lectures he gave in 18589, Virchow formalized cellular pathology as the fundamental basis of pathology. This new perspective radically changed the way pathology was viewed1,6. Virchow first recognized necrosis as death at the cellular level during his study of cellular changes accompanying tissue damage caused by inflammation6,10.

In 1842, German anatomist Carl Vogt first proposed that spontaneous cell death was a physiological phenomenon. He reported that cell death during metamorphosis in the midwife toad eliminated the notochord and allowed vertebrae to develop7. In 1882, the Russian biologist Elie Metchnikoff, considered a pioneer in modern immunology, observed that phagocytic cells engulfed dying cells in several organisms11. Metchnikoff’s discovery meaningfully contributed to our understanding of the role of the immune system in eliminating dying cells and maintaining tissue homeostasis. Later, in 1972, pathologist John F. Kerr and his colleagues discovered a kind of cell death that differed from necrosis, which they named “apoptosis”12,13. The discovery of apoptosis was a fundamental hallmark in the study of cell death and expanded our understanding of various types of cell death.

Traditional classifications of cell death include necrosis and programmed cell death (PCD). Necrosis, a nonprogrammed form of cell death, is often caused by traumatic injury; PCD, a controlled form of cell death, results from a series of molecular events in response to various physiological or developmental signals14. Apoptosis is a well-characterized PCD mechanism15. Other types of PCD, including autophagic cell death16, lysosomal cell death17, mitoptosis18, paraptosis19, pyroptosis20, NETosis21, necroptosis22, immunogenic cell death23, entosis24, methuosis25, parthanatos26, ferroptosis27, autosis28, alkaliptosis29, oxeiptosis30, cuproptosis31, and erebosis32, have also been identified (Fig. 1; Table 1). To date, the study of cell death is a major field of research in biology2. Morphological features are the primary basis for the traditional classification of cell death. In 2018, the Nomenclature Committee on Cell Death (NCCD) published comprehensive information, which expanded our knowledge of cell death pathways, and the assays commonly used in cell death study2. It emphasized the importance of accurately characterizing and differentiating different types of cell death and highlighted the importance of molecular pathways, genetic factors, biochemical markers, and functional criteria. With increasing understanding of the complexity of cell death, this classification system became more complicated and now includes additional categories. Understanding the various types of cell death and their regulatory mechanisms is essential for eval‎uating the pathogenesis of various illnesses, such as cancer, neurodegenerative diseases, and autoimmune disorders4,5.

소개

세포 사멸은

세포 기능이 중단되고

결국에는 세포가 사멸하는 생물학적 과정입니다1.

세포 사멸의 주요 기능은

기능이 없거나 손상되고 해로운 세포를 제거하여

조직의 항상성을 유지하는 것입니다2.

이는 조직의 형성, 유지 및 복구에 관여하는 자연스러운 과정이지만

부상, 질병 또는 손상에 대한 반응으로 촉발되어

병적인 세포 사멸로 이어질 수도 있습니다3,4,5.

19세기까지만 해도 죽음은

개별 유기체 수준에서만 이해되었고,

세포 사멸이라는 개념은 의사와 생물학자들에게 쉽게 받아들여지지 않았습니다.

하지만

광학 현미경, 조직 절개법, 염색 기술이 발달하면서

세포 수준에서의 죽음이 인식되기 시작했습니다6,7.

1830년대부터 1860년대까지 식물학자 마티아스 야콥 슐라이덴과 동물학자 테오도르 슈반과 같은 세포 이론 옹호자들이 있었지만, 의학에서 현미경의 사용은 제한적이었습니다. 광학 현미경의 기술적 발전과 유기체가 세포로 구성되어 있다는 개념을 의학에 적용한 것은 독일의 병리학자 루돌프 비르초우6에 의해 주도되었습니다. 18558년에 발표한 논문과 18589년에 강연한 내용을 정리한 "세포 병리학"이라는 저서를 통해 비르초우는 세포 병리학을 병리학의 기본으로 공식화했습니다. 이 새로운 관점은 병리학을 바라보는 방식을 근본적으로 변화시켰습니다1,6. 비르초우는 염증으로 인한 조직 손상에 수반되는 세포 변화를 연구하는 과정에서 괴사를 세포 수준에서의 죽음으로 처음 인식했습니다6,10.

1842년 독일의 해부학자 칼 보그트는 자연적인 세포 사멸이 생리적 현상이라는 것을 처음으로 제안했습니다. 그는 산파 두꺼비의 변태 과정에서 세포가 죽으면 노토코드가 제거되고 척추가 발달할 수 있다고 보고했습니다7. 1882년, 현대 면역학의 선구자로 여겨지는 러시아 생물학자 엘리 메치니코프는 식세포가 여러 유기체에서 죽어가는 세포를 포식하는 것을 관찰했습니다11. 메치니코프의 발견은 죽어가는 세포를 제거하고 조직의 항상성을 유지하는 면역 체계의 역할에 대한 이해에 의미 있는 기여를 했습니다.

그 후 1972년

병리학자 John F. Kerr와 그의 동료들은

괴사와는 다른 일종의 세포 사멸을 발견하고

이를 "아포토시스"12,13라고 명명했습니다.

세포 사멸의 발견은 세포 사멸 연구의 근본적인 특징이 되었으며 다양한 유형의 세포 사멸에 대한 이해를 넓혔습니다.

세포 사멸의 전통적인 분류에는

괴사와 프로그램된 세포 사멸(PCD)이 있습니다.

세포 사멸의 비프로그램화된 형태인 괴사는

종종 외상성 손상으로 인해 발생하며,

세포 사멸의 제어된 형태인 PCD는

다양한 생리적 또는 발달 신호에 반응하는

일련의 분자적 사건으로 인해 발생합니다14.

세포 사멸은

잘 특징지어지는 PCD 메커니즘입니다15.

자가포식 세포 사멸16,

리소좀 세포 사멸17, 미토시스18, 파라토시스19, 파이로옵토시스20, 네토시스21, 네크로옵토시스22, 면역원성 세포 사멸23, 엔토시스24, 메투시스25, 파르타나토스26, 페로옵토시스27, 오토시스28, 알칼립토시스29, 옥셉토시스30, 큐프로옵토스31 및 에레보시스32 등 다른 유형의 PCD도 확인되었습니다(그림 1, 표 1).

현재까지 세포 사멸에 대한 연구는 생물학의 주요 연구 분야입니다2.

형태학적 특징은

세포 사멸의 전통적인 분류의 주요 근거입니다. 2

018년에 세포 사멸에 관한 명명 위원회(NCCD)는

세포 사멸 경로와 세포 사멸 연구에서

일반적으로 사용되는 분석법에 대한 지식을 확장하는 포괄적인 정보를 발표했습니다2.

다양한 유형의 세포 사멸을 정확하게 특성화하고 구별하는 것이 중요하다는 점을 강조하고

분자 경로, 유전적 요인, 생화학적 마커 및 기능적 기준의 중요성을 강조했습니다.

세포 사멸의 복잡성에 대한 이해가 높아지면서

이 분류 체계는 더욱 복잡해졌고

현재는 추가 범주를 포함하고 있습니다.

다양한 유형의 세포 사멸과 그 조절 메커니즘을 이해하는 것은

암, 신경 퇴행성 질환, 자가 면역 질환과 같은

다양한 질병의 발병 기전을 평가하는 데 필수적입니다4,5.

Fig. 1: Timeline of the discovery of cell death.

This timeline depicts the important discoveries and advancements in cell death research, including the recognition of multiple forms of cell death.

Full size image

Table 1 Characteristics of the major types of cell death.

In this historical review, we provide an overview of different types of cell death and the morphological and biochemical characteristics of cells undergoing these types of cell death. We also discuss the current understanding of the molecular mechanisms underlying the different types of cell death and the significance of these mechanisms in normal physiology and disease. We hope that this review serves as an excellent resource for researchers investigating cell death.

이 역사 리뷰에서는 다양한 유형의 세포 사멸과 이러한 유형의 세포 사멸을 겪는 세포의 형태학적 및 생화학적 특성에 대한 개요를 제공합니다. 또한 다양한 유형의 세포 사멸의 기초가 되는 분자 메커니즘에 대한 현재의 이해와 정상적인 생리와 질병에서 이러한 메커니즘이 갖는 중요성에 대해서도 논의합니다. 

이 리뷰가 

세포 사멸을 연구하는 연구자들에게 

훌륭한 자료가 되기를 바랍니다.

Discovery of diverse types of cell death

Necrosis

Necrosis is an uncontrolled form of cell death that is triggered in response to injury, trauma, or infection33. The term “necrosis” comes from the Greek words “nekros,” meaning dead or corpse, and “osis,” meaning process, referring specifically to destruction and degeneration34. It is unclear who initially coined the term necrosis, but the earliest reference to necrosis recently found on PubMed is “Observation on Necrosis” written by Bouffelin, a surgeon in the Polish army, in 178635. In the literature, necrosis refers to tissue necrosis caused by infection and inflammation, not cell death. As mentioned in the Introduction, Rudolf Virchow was the first scientist to use the term necrosis at the cellular level. He defined necrosis at the cellular level as “the mortified cell is left in its external form” and “necrobiosis or shrinkage necrosis being where the cell vanishes and can no longer be seen in its present form”6,10. In 1877, Carl Weigert and Julius Konheim described certain lesions as exhibiting coagulative necrosis, a basic form of necrosis, and necrobiosis1,6.

The cellular mechanisms that lead to necrosis are complex and not yet fully understood; however, they generally involve a series of events that result in the breakdown of cellular components and the release of cell contents into the extracellular space (Fig. 2A)36. In contrast to apoptosis, necrosis is frequently associated with inflammation and damage to surrounding tissues because the intracellular contents released by dying cells can activate the immune system and harm neighboring cells37.

다양한 유형의 세포 사멸 발견

괴사 necrosis

괴사는

부상, 외상 또는 감염에 대한 반응으로 촉발되는

통제되지 않은 세포 사멸의 한 형태입니다33. '

괴사'라는 용어는 죽은 또는 시체를 의미하는 그리스어 '네크로스'와 과정을 의미하는 '오시스'에서 유래되었으며, 특히 파괴와 퇴행을 의미합니다34. 괴사라는 용어를 처음 만든 사람이 누구인지는 불분명하지만, 최근 PubMed에서 발견된 괴사에 대한 최초의 언급은 1786년 폴란드 군대의 외과의사인 부펠린이 쓴 "괴사에 대한 관찰"입니다35. 이 문헌에서 괴사는 세포 사멸이 아닌 감염과 염증으로 인한 조직 괴사를 의미합니다. 서론에서 언급했듯이 루돌프 비르초프는 세포 수준에서 괴사라는 용어를 사용한 최초의 과학자였습니다. 그는 세포 수준에서의 괴사를 "괴사된 세포가 외부 형태로 남아 있는 것"과 "세포가 사라져 더 이상 현재의 형태로 볼 수 없는 것을 괴사 또는 수축 괴사"6,10로 정의했습니다. 1877년 칼 바이거트와 줄리어스 콘하임은 특정 병변이 괴사의 기본 형태인 응고성 괴사 및 괴사증을 나타내는 것으로 설명했습니다1,6.

괴사로 이어지는 세포 메커니즘은 복잡하고 아직 완전히 이해되지 않았지만 일반적으로 세포 구성 요소가 분해되고 세포 내용물이 세포 외 공간으로 방출되는 일련의 사건을 수반합니다(그림 2A)36.

세포 사멸과 달리

괴사는 죽어가는 세포가 방출하는 세포 내 내용물이

면역 체계를 활성화하고

주변 세포를 해칠 수 있기 때문에

주변 조직의 염증 및 손상과 관련이 있는 경우가 많습니다37.

Fig. 2: Necrosis and apoptosis: morphological features and signaling pathways.

A Hallmarks of necrosis and apoptosis are illustrated. Necrosis is an uncontrolled and pathological form of cell death, marked by cell swelling, membrane rupture, and intracellular content release, leading to inflammation and tissue damage. In contrast, apoptosis is a tightly controlled form of cell death that involves characteristic morphological features, such as cell shrinkage, chromatin condensation, membrane blebbing, nuclear fragmentation, and apoptotic body formation. 

B The two signaling pathways that lead to apoptosis are described. The extrinsic pathway is initiated by the binding of death ligands, such as tumor necrosis factor (TNF)-α or Fas ligand (FasL), to death receptors, which activates caspase 8. The intrinsic pathway, regulated by the Bcl-2 family, is triggered by intracellular stressors, such as DNA damage and oxidative stress, resulting in the release of cytochrome c from mitochondria and activation of caspase 9. The two pathways ultimately converge on caspase 3, which mediates the execution of apoptosis.

A  괴사 및 세포 사멸의 특징이 설명되어 있습니다.

괴사는

세포 부종, 세포막 파열, 세포 내 내용물 방출로 특징지어지는

통제되지 않은 병리적 형태의 세포 사멸로,

염증과 조직 손상을 유발합니다.

이와 대조적으로

세포 사멸은

세포 수축, 염색질 응축, 막 출혈, 핵 단편화, 세포 사멸체 형성 등의

특징적인 형태적 특징을 포함하는

엄격하게 통제된 형태의 세포 사멸입니다.

B 세포 사멸로 이어지는 두 가지 신호 경로가 설명되어 있습니다.

외인성 경로는

종양 괴사 인자(TNF)-α 또는 파스 리간드(FasL)와 같은

사멸 리간드가 사멸 수용체에 결합하여

카스파제 8을 활성화함으로써 시작됩니다.

Bcl-2 계열에 의해 조절되는 내재적 경로는

DNA 손상 및 산화 스트레스와 같은

세포 내 스트레스 요인에 의해 촉발되어

미토콘드리아에서 시토크롬 c를 방출하고

카스파제 9를 활성화합니다.

이 두 경로는

궁극적으로

세포 사멸을 매개하는 카스파제 3에 수렴합니다.

Apoptosis

Apoptosis is characterized by the organized breakdown of cells in response to particular signals38. The term “apoptosis” comes from the Greek words “apo,” meaning leaf, and “ptosis,” meaning “falling off,” which describe the process of cells undergoing controlled self-destruction and detachment from the surrounding tissue12. The apoptotic process was first described by Carl Vogt in 1842, and it was rediscovered and named “apoptosis” by Kerr in 197239. As mentioned in the Introduction, Carl Vogt was the first to present the concept of spontaneous cell death as a physiological phenomenon7. In 1885, Walther Flemming described and illustrated a cellular process called chromatolysis, which he discovered while studying the degeneration of ovarian follicles; Franz Nissen, who observed pigment degradation in lactating mammary glands, published similar results1,6. In 1914, Ludwig Gräffer published a paper proposing the premise that some mechanism must balance mitosis and that this process likely involves the process Fleming described as chromatolysis; this paper was subsequently rediscovered by Alfred Glücksmann in 19511. Subsequently, experimental pathologists began to investigate more intensively how cells in different organs die during development and in response to stimuli or injuries.

We now know that spontaneous cell death, such as chromatolysis, is caused by apoptosis. The description of apoptosis as a distinct form of cell death that differs from necrosis was formalized in the early 1970s by Australian pathologist John Kerr and his colleagues6,39. As a graduate student in London in 1962, Kerr found that when the portal venous blood supply to the liver is cut off, a different type of death occurs in cells around distal hepatic veins. This form of cell death was characterized by cytoplasmic shrinkage and condensed nuclear chromatin fragments, in addition to certain manifestations of classical necrosis. Upon further investigation using histochemical and electron microscopy, the newly discovered mode of cell death appeared to be nondegenerative in nature and was called shrinkage necrosis40. In 1972, Kerr was on sabbatical at the University of Aberdeen in Scotland working with Professor Currie and graduate student Andrew Wiley, who realized that a newly characterized type of cell death was regulated by hormones and played an essential role in normal development. Recognizing the inappropriateness of using the term necrosis for cell death under physiological conditions, they proposed that this process be called apoptosis41,42.

Apoptosis is characterized by cell shrinkage, chromatin condensation, and fragmentation into small membrane-bound apoptotic bodies, which are phagocytosed by adjacent parenchymal cells, neoplastic cells, or macrophages15 (Fig. 2A). Apoptosis is a genetically regulated and controlled cell death process, whereas necrosis is an uncontrolled cell death process caused by external stimuli. Apoptosis leads to cell fragmentation and removal by phagocytic cells, whereas necrosis resulted in cell membrane rupture and inflammation43 (Fig. 2A).

Two main pathways lead to the activation of apoptosis: the extrinsic and intrinsic pathways44. The extrinsic pathway is activated by extracellular ligands (tumor necrosis factor [TNF]-α and Fas ligand [FasL]) binding to death receptors, namely, TNF and Fas receptors, respectively45,46. After extracellular ligands bind to death receptors, death-inducing signaling complexes (DISCs) are formed and recruit and activate initiator caspases, such as caspase-8 and caspase-1047. These initiator caspases then cleave and activate effector caspases, such as caspase-3, -6, and -7, leading to the degradation of intracellular components and the induction of apoptosis48. The intrinsic pathway is activated by intracellular stressors, such as DNA damage, oxidative stress, and loss of survival signaling, which lead to permeabilization of the outer mitochondrial membrane49. This pathway is regulated by the Bcl-2 family of antiapoptotic proteins (Bcl-2 and Bcl-xL), proapoptotic proteins (Bax and Bak), and BH3-only proteins (Bim and Bid)50. In response to intracellular stress, the activation of proapoptotic BH3-only proteins inhibits antiapoptotic proteins, allowing Bax and Bak to form mitochondrial pores and release cytochrome c into the cytosol51. The released cytochrome c forms an apoptosome with apoptotic protease activating factor-1 (Apaf-1) and activates caspase-9 (Fig. 2B)52.

세포 사멸 apoptosis

세포 사멸은

특정 신호에 반응하여

세포가 조직적으로 파괴되는 것을 특징으로 합니다38.

"아포토시스"라는 용어는

잎을 뜻하는 그리스어 "아포"와

"떨어지다"라는 뜻의 "프토시스"에서 유래한 것으로,

세포가 통제된 자멸을 거쳐

주변 조직으로부터 분리되는 과정을 설명합니다12.

세포 사멸 과정은 1842년 칼 보그트가 처음 설명했으며, 197239년 커에 의해 재발견되어 "세포 사멸"로 명명되었습니다. 서론에서 언급했듯이 칼 보그트는 생리적 현상으로서 자발적 세포 사멸의 개념을 최초로 제시했습니다7. 1885년 발터 플레밍은 난소 난포의 퇴화를 연구하던 중 발견한 색소 분해라는 세포 과정을 설명하고 그림으로 설명했으며, 수유 중인 유선의 색소 분해를 관찰한 프란츠 니센도 비슷한 결과를 발표했습니다1,6. 1914년 루드비히 그라퍼(Ludwig Gräffer)는 어떤 메커니즘이 유사 분열의 균형을 유지해야 하며 이 과정에 플레밍이 색소 분해로 설명한 과정이 포함될 가능성이 있다는 전제를 제시하는 논문을 발표했고, 이 논문은 19511년 알프레드 글뤽스만(Alfred Glücksmann)에 의해 재발견되었습니다. 그 후 실험 병리학자들은 다양한 기관의 세포가 발달 과정에서 그리고 자극이나 부상에 대한 반응으로 어떻게 죽는지 더 집중적으로 조사하기 시작했습니다.

이제 우리는 염색질 분해와 같은 자발적인 세포 사멸이 세포 자멸에 의해 발생한다는 것을 알고 있습니다. 괴사와는 다른 세포 사멸의 한 형태인 세포 사멸에 대한 설명은 1970년대 초 호주의 병리학자 John Kerr와 그의 동료들에 의해 공식화되었습니다6,39. 1962년 런던에서 대학원을 다니던 커는 간으로 가는 문맥혈 공급이 차단되면 원위 간정맥 주변의 세포에서 다른 유형의 사멸이 일어난다는 사실을 발견했습니다. 이러한 형태의 세포 사멸은 고전적인 괴사의 특정 증상 외에도 세포질 수축과 응축된 핵 염색질 조각이 특징적으로 나타났습니다. 조직화학 및 전자 현미경을 사용한 추가 조사 결과, 새로 발견된 세포 사멸 방식은 본질적으로 비퇴행성인 것으로 나타났으며 수축 괴사40라고 불렀습니다.

1972년 스코틀랜드 애버딘 대학교에서 안식년을 보내고 있던 커는

커리 교수 및 대학원생 앤드류 와일리와 함께 연구하던 중

새롭게 특징지어진 세포 사멸 유형이

호르몬에 의해 조절되고 정상적인 발달에 필수적인 역할을 한다는 사실을 깨달았습니다.

이들은 생리적 조건에서

세포 사멸에 괴사라는 용어를 사용하는 것이 부적절하다는 것을 인식하고

이 과정을 아포토시스41,42라고 부르자고 제안했습니다.

세포 사멸은

세포 수축, 염색질 응축, 작은 막 결합 세포 사멸체로의 단편화가 특징이며,

이 세포 사멸체는 인접한 실질 세포, 종양 세포 또는

대식세포에 의해 포식됩니다15 (그림 2A).

세포 사멸은

유전적으로 조절되고 통제되는 세포 사멸 과정인 반면,

괴사는 외부 자극으로 인한

통제되지 않는 세포 사멸 과정입니다.

세포 사멸은

세포 조각화와 식세포에 의한 제거로 이어지는 반면,

괴사는 세포막 파열과 염증을 초래합니다43(그림 2A).

세포 사멸을 활성화하는

두 가지 주요 경로는

외인성 경로와 내인성 경로44입니다.

외인성 경로는 세포 외 리간드(종양괴사인자[TNF]-α 및 Fas 리간드[FasL])가

사멸 수용체, 즉 TNF 및 Fas 수용체에 각각 결합하여

활성화됩니다45,46.

세포 외 리간드가 사멸 수용체에 결합한 후,

사멸 유도 신호 복합체(DISC)가 형성되어

caspase-8 및 caspase-1047과 같은 개시 카스파제를 모집하고 활성화합니다.

이러한 개시 카스파제는

카스파제-3, -6, -7과 같은 이펙터 카스파제를 절단하고 활성화하여

세포 내 성분을 분해하고

세포 사멸을 유도합니다48.

내재적 경로는

DNA 손상, 산화 스트레스, 생존 신호의 손실과 같은

세포 내 스트레스 요인에 의해 활성화되어

외부 미토콘드리아 막의 투과성으로 이어집니다49.

이 경로는

Bcl-2 계열의 항세포사멸 단백질(Bcl-2 및 Bcl-xL),

세포사멸 촉진 단백질(Bax 및 Bak),

BH3 전용 단백질(Bim 및 Bid)50에 의해 조절됩니다.

세포 내 스트레스에 대한 반응으로,

세포 사멸 유도 BH3 전용 단백질의 활성화는

항세포 사멸 유도 단백질을 억제하여 Bax와 Bak가

미토콘드리아 기공을 형성하고

사이토크롬 c를 세포질로 방출할 수 있게 합니다51.

방출된 사이토크롬 c는

세포사멸 프로테아제 활성화 인자-1(Apaf-1)과 함께

아폽토솜을 형성하고

카스파제-9를 활성화합니다(그림 2B)52.

Autophagic cell death

Autophagic cell death, also known as type 2 cell death, occurs as a result of the activation of the autophagy pathway53. Autophagy is a cellular process in which cytoplasmic components, including organelles and macromolecules, are sequestered in double-membrane autophagosomes and targeted for lysosomal degradation54. The term “autophagy” comes from the Greek words “auto,” meaning self and “phagy,” meaning eating or devouring, and describes the process by which cells degrade and recycle their components55. The term “autophagy” has been used since the mid-19th century, but Christian de Duve defined the word as it is currently used in 1963 based on his research on lysosomal functions56. The mechanisms underlying autophagy were deduced in the 1990s with the identification of autophagy-related genes by Yoshinori Ohsumi57. Autophagic cell death was first described by Timo J. Neval‎ainen in 197558.

Under normal conditions, autophagy helps maintain cell homeostasis and recycle nutrients while removing toxic cellular components59. However, under certain conditions, such as nutrient deprivation, oxidative stress, or exposure to cytotoxic agents, autophagy can become dysregulated and result in cell death60.

The first step in the activation of autophagy is the formation of an isolation membrane, or phagophore, which is a double-membrane structure that sequesters cytoplasmic components to be degraded61. Phagophore formation requires the action of the unc-51-like kinase 1 (ULK1) complex, which is composed of several proteins, namely, ULK1, ATG13, FIP200/RB1CC1, and ATG10162. The ULK1 complex is regulated by several signaling pathways, including the mTOR pathway. Under normal conditions, the activation of mTOR suppresses autophagy by inhibiting the formation of the ULK1 complex; however, under stress or nutrient-deprivation conditions, mTOR inhibition leads to the formation of the ULK1 complex and the initiation of autophagy63. The phagophore expands and sequesters the cytoplasmic components to be degraded and then fuses with lysosomes to form autolysosomes, where the sequestered contents are degraded by lysosomal enzymes64. Autophagy is regulated by a complex network of proteins, including the ATG family of proteins, Beclin-1, and microtubule-associated protein light chain 3 (LC3)65. ATG proteins are involved in various steps in the autophagy pathway, including phagophore formation, elongation, and closure66. The Beclin-1 protein is required for the formation of the phagophore, whereas the LC3 protein is involved in the elongation and closure of the phagophore and the maturation of the autophagosome (Fig. 3A)61. Autophagy activation initially leads to the development of large cytoplasmic vacuoles, which in turn cause autophagic cell death16. Autophagy promotes both cell survival and cell death67. Notably, in some cases, autophagy contributes to cancer cell resistance to chemotherapy68. However, in other cases, autophagy can induce cell death and inhibit tumor growth69.

자가포식 세포 사멸 Autophagic cell death

제2형 세포 사멸이라고도 하는

자가포식 세포 사멸은

자가포식 경로의 활성화로 인해 발생합니다53.

자가포식은

세포 소기관과 거대 분자를 포함한 세포질 성분이

이중막 자가포식체에서 격리되어

리소좀 분해를 표적으로 삼는 세포 과정입니다54.

"자가포식"이라는 용어는

자기를 의미하는 그리스어 "auto"와

먹다 또는 삼키다를 의미하는 "phagy"에서 유래되었으며,

세포가 구성 요소를 분해하고 재활용하는 과정을 설명합니다55.

'오토파지'라는 용어는 19세기 중반부터 사용되어 왔지만,

1963년 크리스찬 드 듀브가 리소좀 기능에 대한 연구를 바탕으로

현재와 같은 용어로 정의했습니다56.

오토파지의 기본 메커니즘은

1990년대에 오스미 요시노리가

오토파지 관련 유전자를 규명하면서 추론되었습니다57.

자가포식 세포 사멸은

1975년 티모 네발라이넨에 의해 처음 설명되었습니다58.

정상적인 조건에서 자가포식은

세포 항상성을 유지하고

독성 세포 성분을 제거하면서

영양분을 재활용하는 데 도움이 됩니다59.

그러나

영양소 부족, 산화 스트레스 또는 세포 독성 물질에 대한 노출과 같은 특정 조건에서

자가포식은 조절 장애를 일으켜

세포 사멸을 초래할 수 있습니다60.

자가포식 활성화의 첫 번째 단계는

분해될 세포질 성분을 격리하는

이중 막 구조인 분리막 또는 식세포의 형성이라고 할 수 있습니다61.

식세포가 형성되려면

ULK1, ATG13, FIP200/RB1CC1, ATG10162 등

여러 단백질로 구성된 ULK1(unc-51-like kinase 1) 복합체의 작용이 필요합니다.

ULK1 복합체는 mTOR 경로를 비롯한 여러 신호 전달 경로에 의해 조절됩니다. 정상적인 조건에서 mTOR의 활성화는 ULK1 복합체의 형성을 억제하여 자가포식을 억제하지만, 스트레스 또는 영양소 결핍 조건에서 mTOR 억제는 ULK1 복합체의 형성과 자가포식의 시작을 유도합니다63.

식세포는

분해할 세포질 성분을 확장하여 격리한 다음

리소좀과 융합하여 자가 리소좀을 형성하고,

격리된 내용물은 리소좀 효소에 의해 분해됩니다64.

자가포식은 ATG 단백질군, Beclin-1, 미세소관 관련 단백질 경쇄3(LC3)65을 포함한 복잡한 단백질 네트워크에 의해 조절됩니다. ATG 단백질은 식세포 형성, 신장 및 폐쇄를 포함하여 자가포식 경로의 다양한 단계에 관여합니다66. 베클린-1 단백질은 식세포의 형성에 필요한 반면, LC3 단백질은 식세포의 신장과 폐쇄 및 오토파지솜의 성숙에 관여합니다(그림 3A)61. 자가포식 활성화는 처음에 큰 세포질 액포의 발달로 이어지며, 이는 다시 자가포식 세포 사멸을 유발합니다16. 오토파지는 세포 생존과 세포 사멸을 모두 촉진합니다67. 특히, 어떤 경우에는 자가포식이 화학요법에 대한 암세포의 내성에 기여하기도 합니다68. 그러나 다른 경우에는 오토파지가 세포 사멸을 유도하고 종양 성장을 억제할 수 있습니다69.

Fig. 3: Progression and morphological features of autophagy-mediated cell death.

A The figure shows three types of autophagy, namely, macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy involves the formation of double-membrane vesicles that engulf cytoplasmic components and organelles and then fuse with lysosomes to form autolysosomes. Microautophagy involves engulfing cytoplasmic components and organelles directly into lysosomes. Chaperone-mediated autophagy degrades specific proteins via chaperone proteins that transport them to lysosomes. 

B The figure highlights the contrast between autophagy and autosis, two processes involving autophagy. While autophagic cell death is a result of excessive autophagy, autosis is characterized by three distinct phases characterized by cells with unique morphological features and is triggered by various signals, such as Na+/K+-ATPase, Tat-Beclin 1, and hypoxia–ischemia.

A 그림은 세 가지 유형의 오토파지, 즉 거대 오토파지, 미세 오토파지 및 샤프론 매개 오토파지를 보여줍니다. 거대 오토파지는 세포질 구성 요소와 소기관을 삼킨 다음 리소좀과 융합하여 자가 리소좀을 형성하는 이중 막 소포의 형성을 포함합니다. 미세 오토파지는 세포질 구성 요소와 소기관을 리소좀에 직접 집어넣는 것을 포함합니다. 샤페론 매개 자가포식은 특정 단백질을 리소좀으로 운반하는 샤페론 단백질을 통해 분해합니다.

B 그림은 자가포식과 관련된 두 가지 과정인 자가포식과 자가증식 사이의 대조를 강조합니다. 자가포식 세포 사멸은 과도한 자가포식의 결과인 반면, 자가증식은 독특한 형태적 특징을 가진 세포가 특징인 세 가지 단계가 특징이며 Na+/K+-ATPase, Tat-Beclin 1, 저산소증-허혈과 같은 다양한 신호에 의해 유발되는 특징이 있습니다.

According to the NCCD, autophagic cell death is a regulated form of cell death that relies on autophagy machinery and can be prevented only by blocking autophagy2. Autophagic cell death has been implicated in various physiological and pathological processes, including cancer, neurodegeneration, ischemic injury, and heart disease70,71,72,73,74. However, the precise role of autophagy in cell death is still unclear16. Therefore, further research is necessary to clarify the role of autophagy in cell death. This research may have important implications for the understanding and treatment of various diseases.

NCCD에 따르면

자가포식 세포 사멸은

자가포식 메커니즘에 의존하는 조절된 형태의 세포 사멸로,

자가포식을 차단해야만 예방할 수 있습니다2.

자가포식 세포 사멸은

암, 신경 퇴화, 허혈성 손상, 심장 질환 등

다양한 생리적 및 병리학적 과정에 관여합니다70,71,72,73,74.

그러나

세포 사멸에서 오

토파지의 정확한 역할은 아직 명확하지 않습니다16.

따라서 세

포 사멸에서 오토파지의 역할을 명확히 밝히기 위해서는

추가 연구가 필요합니다.

이 연구는 다양한 질병의 이해와 치료에 중요한 영향을 미칠 수 있습니다.

Autosis

Autosis is an autophagy-dependent type of cell death that was discovered in 2013, and its name is derived from the Greek words “autos,” meaning self, and “osis,” meaning a process or condition75. Autosis is characterized by unique cell morphology and depends on cellular Na+/K+-ATPase activity75. Autosis is triggered by various signals, such as cerebral hypoxia–ischemia, nutrient deprivation, and autophagy-inducing peptides (Tat-Beclin)75.

The morphological features of autosis are acquired in three distinct phases: phase 1a, marked by a dilated and fragmented endoplasmic reticulum (ER) and an increase in the number of autophagosomes, autolysosomes, and empty vacuoles; phase 1b, involving swelling of the perinuclear space (PNS) in the presence of cytoplasmic materials and electron-dense mitochondria; and phase 2, marked by a reduced number of cytoplasmic organelles, focal nuclear concavity, and PNS ballooning (Fig. 3B)76. Autosis is triggered in vitro in Tat-Beclin 1-treated cells and in vivo in the brains of neonatal rats undergoing challenged with hypoxia–ischemia75.

Rubicon levels significantly increase during autosis, which prevents the fusion of autophagosomes with lysosomes and inhibits autophagosome maturation and degradation77,78. Autosis is likely caused by the excessive accumulation of autophagosomes, which can deplete intracellular organelle membranes, such as ER and mitochondrial membranes, leading to reduced organelle function and, in the case of mitochondria, depolarization and loss of mitochondrial membrane potential79,80. Cardiac glycosides that inhibit the Na+/K+-ATPase pump can prevent autosis and contribute to the treatment of heart injuries75. However, the molecular mechanisms underlying the regulation of autosis by Na+/K+-ATPases remain unclear.

A recent study revealed that myxoma virus can infect and proliferate in human tumor cells but not in normal cells and that infected chimeric antigen receptor (CAR)-T and T-cell receptor (TCR)-T cells can efficiently trigger autotic cell death both in vitro and in vivo81. Autosis has also been observed in patients with severe liver diseases, including acute liver insufficiency associated with severe anorexia nervosa82. Although much remains unknown about autosis, its discovery has opened new avenues of research into the complex and diverse mechanisms underlying PCD.

오토시스 Autosis

오토시스는

2013년에 발견된

자가포식 의존성 세포 사멸 유형으로,

자기를 의미하는 그리스어 '오토스'와 과정 또는 상태를 의미하는 '오시스'에서 유래한 이름입니다75.

오토시스는

독특한 세포 형태가 특징이며

세포의 Na+/K+-ATPase 활성에 따라 달라집니다75.

오토시스는 뇌 저산소증-허혈, 영양소 결핍, 자가포식 유도 펩타이드(Tat-Beclin)와 같은 다양한 신호에 의해유발됩니다75.

autophagy-dependent type of cell death

오토시스의 형태학적 특징은 세 가지 단계로 진행됩니다:

확장되고 파편화된 소포체(ER)와 자가포식소체, 자가리소체, 빈 액포의 수가 증가하는 1a 단계;

세포질 물질과 전자 밀도가 높은 미토콘드리아가 있는 상태에서 핵 주변 공간(PNS)이 팽창하는 1b 단계; 세포질 소기관 수 감소, 국소 핵 오목, PNS 팽창이 나타나는 2단계(그림. 3B)76.

Tat-Beclin 1로 처리된 세포에서는 시험관 내에서, 저산소증-허혈을 겪은 신생아 쥐의 뇌에서는 생체 내에서 자가증이 유발됩니다75. 루비콘 수치는 자가증 동안 크게 증가하여 오토파지와 리소좀의 융합을 방지하고 오토파지의 성숙 및 분해를 억제합니다77,78. 자가증은 오토파지가 과도하게 축적되어 ER 및 미토콘드리아 막과 같은 세포 내 소기관 막이 고갈되어 소기관 기능이 저하되고 미토콘드리아의 경우 탈분극 및 미토콘드리아 막 전위 손실79,80이 발생하기 때문에 발생할 수 있습니다. Na+/K+-ATPase 펌프를 억제하는 심장 배당체는 자가증을 예방하고 심장 손상 치료에 기여할 수 있습니다75. 그러나 Na+/K+-ATPase에 의한 자가증 조절의 기본이 되는 분자 메커니즘은 아직 명확하지 않습니다.

최근 연구에 따르면 점액종 바이러스는 인간 종양 세포에서는 감염 및 증식할 수 있지만 정상 세포에서는 감염 및 증식할 수 없으며 감염된 키메라 항원 수용체(CAR)-T 및 T세포 수용체(TCR)-T 세포는 시험관 및 생체 내에서 효율적으로 자가 세포사를 유발할 수 있는 것으로 밝혀졌습니다81. 중증 신경성 식욕부진증과 관련된 급성 간 기능 부전을 포함한 중증 간 질환 환자에서도 자가증이 관찰되었습니다82. 자가증에 대해 아직 밝혀진 바는 많지 않지만, 자가증의 발견으로 PCD의 기저에 있는 복잡하고 다양한 메커니즘에 대한 새로운 연구의 길이 열렸습니다.

Lysosomal cell death

Lysosomal cell death results from lysosomal membrane permeabilization, which causes the release of lysosomal enzymes into the cytoplasm and activation of cell death pathways83. The concept of lysosomal cell death was first proposed by Christian de Duve in the late 1990s84. Lysosomes are organelles that contain hydrolases critical for degrading intracellular and extracellular material. Under normal physiological conditions, lysosomes play roles in maintaining cellular homeostasis85,86. However, after the lysosomal membrane is damaged, lysosomal hydrolases are released into the cytoplasm, triggering various cell death pathways87.

Lysosomal cell death can be induced by various stimuli, including changes in lysosomal pH, oxidative stress, and lysosomotropic agents88. Lysosomal proteases, such as cathepsins, have been identified as potential causes of lysosomal cell death because they can be released into the cytoplasm and activate the lysosomal apoptotic pathway by cleaving Bid and degrading antiapoptotic Bcl-2 homologs following lysosomal injury and targeted destabilization of the lysosomal membrane (Fig. 4)89,90.

리소좀 세포 사멸 Lysosomal cell death

리소좀 세포 사멸은

리소좀 효소가 세포질로 방출되고

세포 사멸 경로가 활성화되는 리소좀 막 투과성으로 인해 발생합니다83.

리소좀 세포 사멸의 개념은 1990년대 후반 크리스티앙 드 듀브(Christian de Duve)에 의해 처음 제안되었습니다84.

리소좀은

세포 내 및 세포 외 물질을 분해하는 데 중요한

가수분해효소를 포함하는 세포 소기관입니다.

정상적인 생리적 조건에서 리소좀은

세포 항상성을 유지하는 역할을 합니다85,86.

그러나

리소좀 막이 손상되면

리소좀 가수분해효소가 세포질로 방출되어

다양한 세포 사멸 경로를 촉발합니다87.

리소좀 세포 사멸은

리소좀 pH의 변화,

산화 스트레스,

리소좀 모트로픽 제제 등 다양한 자극에 의해 유도될 수 있습니다88.

카텝신과 같은 리소좀 프로테아제는 리소좀 손상 및 리소좀 막의 표적 불안정화 이후 세포질로 방출되어 Bid를 절단하고 항아포토시스 Bcl-2 동족체를 분해함으로써 리소좀 세포 사멸 경로를 활성화할 수 있기 때문에 리소좀 세포 사멸의 잠재적 원인으로 확인되었습니다(그림 4)89,90).

Fig. 4: Mechanism of lysosomal cell death.

This figure illustrates lysosomal cell death caused by lysosomal membrane permeabilization and the release of lysosomal enzymes into the cytoplasm, leading to the activation of apoptotic cell death pathways. Lysosomal cell death can be induced by stimuli, such as changes in lysosomal pH, oxidative stress, and lysosomotropic agents. The release of lysosomal proteases, such as cathepsins, activates the lysosomal apoptotic pathway by cleaving Bid and degrading antiapoptotic Bcl-2 homologs.

이 그림은 리소좀 막 투과성 및 리소좀 효소가 세포질로 방출되어 세포 사멸 경로가 활성화되어 발생하는 리소좀 세포 사멸을 보여줍니다. 리소좀 세포 사멸은 리소좀 pH의 변화, 산화 스트레스, 리소좀 모트로픽 제제와 같은 자극에 의해 유도될 수 있습니다. 켑신과 같은 리소좀 프로테아제의 방출은 Bid를 절단하고 항아포토시스 Bcl-2 동족체를 분해하여 리소좀 세포 사멸 경로를 활성화합니다.

Lysosomal cell death is thought to be involved in various pathological conditions, such as neurodegenerative diseases, cancer, and age-related disorders, and the inhibition of lysosomal cell death may hold therapeutic potential for these diseases91. Further research is necessary to fully understand the mechanisms underlying lysosomal cell death and its role in pathological conditions.

리소좀 세포 사멸은 신경 퇴행성 질환, 암, 노화 관련 질환 등 다양한 병리적 상태에 관여하는 것으로 생각되며, 리소좀 세포 사멸을 억제하면 이러한 질환에 대한 치료 잠재력을 가질 수 있습니다91. 리소좀 세포 사멸의 근본적인 메커니즘과 병리적 상태에서의 역할을 완전히 이해하려면 추가 연구가 필요합니다.

Mitoptosis

Mitoptosis, also known as mitochondrial suicide, is a PCD that involves dysfunctional mitochondria and was first proposed by Vladimir P. Skulachev in 199992. Dysfunctional mitochondria are associated with numerous diseases, including cancer, neurodegenerative disorders, and metabolic diseases93. Mitoptosis and mitophagy (autophagic degradation of mitochondria) are crucial for preventing the accumulation of dysfunctional mitochondria, which can lead to various cellular pathologies94.

Mitoptosis is triggered by mitochondrial dysfunction and reactive oxygen species (ROS) production95. Mitoptosis is involved in several biological processes, such as cell differentiation, hematopoietic stem cell self-renewal, metabolic remodeling, and elimination of paternal mitochondria in organisms for which mitochondrial DNA is maternally inherited96. The steps involved in mitoptosis include the fission of mitochondrial filaments to form spherical mitochondria, clustering of these spherical mitochondria in the perinuclear area, occlusion of these mitochondrial clusters via a membrane that forms a "mitoptotic body," decomposition of mitochondria inside this body into small membrane vesicles, protrusion of the body from the cell, and finally, disruption of the boundary membrane (Fig. 5A)95. Notably, autophagy is not involved in the mitoptotic process. Different forms of mitoptosis have been observed, including inner- and outer-membrane mitoptosis18. In inner membrane mitoptosis, only the internal matrix and cristae of mitochondria are degraded, and the external mitochondrial envelope remains unaltered18. During outer membrane mitoptosis, the internal cristae of mitochondria swell and undergo fragmentation, and the outer mitochondrial membrane bursts, releasing the remnants of cristae into the cytoplasm18.

미토콘드리아 자살 Mitoptosis

미토콘드리아 자살이라고도 알려진 미토콘드리아 세포사멸은

기능 장애 미토콘드리아와 관련된 PCD로, 199992년 블라디미르 P. 스쿨라체프가 처음 제안했습니다92.

기능 장애 미토콘드리아는

암, 신경 퇴행성 질환 및 대사 질환을 포함한 수많은 질병과 관련이 있습니다93.

세포 사멸과 미토파지(미토콘드리아의 자가포식 분해)는

다양한 세포 병리를 유발할 수 있는 기능 장애 미토콘드리아의 축적을 방지하는 데 매우 중요합니다94.

미토콘드리아 기능 장애와 활성 산소 종(ROS) 생성에 의해 세포 사멸이 촉발됩니다95. 세포 분화, 조혈 줄기세포 자가 재생, 대사 리모델링, 미토콘드리아 DNA가 모계로 유전되는 유기체에서 부계 미토콘드리아 제거와 같은 여러 생물학적 과정에 세포 사멸이 관여합니다96. 미토콘드리아 필라멘트의 핵분열로 구형 미토콘드리아가 형성되고, 핵 주변 영역에서 이러한 구형 미토콘드리아가 군집을 이루고, 이러한 미토콘드리아 군집이 막을 통해 폐색되어 "미토토시스체"를 형성하고, 이 체 내부의 미토콘드리아가 작은 막 소포로 분해되고, 세포에서 체가 돌출되고, 마지막으로 경계막이 파괴됩니다(그림 5A)95. 주목할 점은 세포 자멸사 과정에는 오토파지가 관여하지 않는다는 것입니다. 세포 내막 및 세포 외막 세포 자멸사를 포함하여 다양한 형태의 세포 자멸사가 관찰되었습니다18. 내막 세포사멸에서는 미토콘드리아의 내부 매트릭스와 크리스테만 분해되고 외부 미토콘드리아 외피는 변하지 않습니다18. 외막 세포사멸 과정에서 미토콘드리아의 내부 크리스타는 부풀어 올라 분열을 겪고, 외막 세포막은 파열되어 잔여 크리스타가 세포질로 방출됩니다18.

Fig. 5: Comparison of mitoptosis and mitophagy.

This figure illustrates the crucial processes of mitoptosis and mitophagy that maintain mitochondrial quality and prevent cell pathology. A Mitoptosis is characterized by several events, including mitochondrial fission, the clustering of spherical mitochondria in the perinuclear area, enwrapping of these clusters by a membrane to form a “mitoptotic body,” decomposition of mitochondria into small vesicles, protrusion of the body from the cell, and disruption of the boundary membrane. This process is driven by mitochondrial dysfunction and reactive oxygen species (ROS) production. B Mitophagy is a selective autophagic mechanism for the degradation of damaged or unnecessary mitochondria. This procedure requires activation of general autophagy and priming of injured mitochondria via the Pink1/Parkin signaling pathway. Autophagosomes engulf targeted mitochondria, which are then digested and degraded in lysosomes.

Full size image

In contrast to mitoptosis, mitophagy selectively degrades damaged mitochondria through autophagy, which requires the induction of general autophagy and priming of damaged mitochondria mediated by the Pink1/Parkin signaling pathway (Fig. 5B)97. The main difference between mitoptosis and mitophagy is that mitoptosis targets dysfunctional mitochondria, which are subsequently degraded inside the “mitoptotic body,” leading to membrane disruption. In contrast, mitophagy selectively degrades damaged or otherwise undesirable mitochondria. Although both processes are important for maintaining cellular homeostasis by eliminating dysfunctional or excessive mitochondria, their mechanisms of action differ.

Mitoptosis is important for the elimination of damaged or dysfunctional mitochondria and the maintenance of cellular homeostasis18. Recent research on mitoptosis has been focused on understanding the mechanisms that regulate this process and developing strategies for targeting dysfunctional mitochondria in disease contexts.

Immunogenic cell death

Immunogenic cell death (ICD) is a type of PCD in which an immune response is triggered by the release of damage-associated molecular patterns (DAMPs) from dying cells, which attract immune cells to the site of cell death98. The ICD concept was first proposed by the group led by Guido Kroemer and Laurence Zitvogel in 200599.

During ICD, dying tumor cells express calreticulin on their surface, which functions as an “eat me” signal to dendritic cells (DCs) and other phagocytic cells100. This signaling promotes phagocytosis of the dying cells by the DCs, leading to the activation of an immune response. ICD also involves the release of DAMPs, such as ATP, high-mobility group box 1, and heat shock proteins (HSPs), from dying cells101. These DAMPs activate DCs and other immune cells, thereby promoting antigen presentation and immune activation102. Moreover, IFNγ and TNFα released by effector T cells attract and activate other immune cells, including natural killer cells and macrophages, which detect and eradicate cancer cells (Fig. 6)103.

Fig. 6: Mechanism underlying immunogenic cell death (ICD).

This figure illustrates the mechanism of ICD and its potential as a cancer therapeutic strategy. During ICD, dying cells release damage-associated molecular patterns (DAMPs), such as ATP, high-mobility group box 1 (HMGB1), and heat shock proteins (HSPs), which activate dendritic cells (DCs) and other immune cells, promoting antigen presentation and immune activation. Effector T cells release interferon (IFN)-γ and TNFα, which activate other immune cells, such as natural killer cells and macrophages that detect and eliminate cancer cells.

ICD has emerged as a promising strategy for cancer therapy. It potentially enhances the effectiveness of cancer treatments, such as chemotherapy and radiotherapy, which in turn induce ICD in cancer cells104. ICD-based therapies provide long-lasting protection against cancer recurrence and metastasis by promoting immune responses against cancer cells.

Pyroptosis

Pyroptosis is a type of PCD that involves inflammation and is mediated by caspase-1105. It was first discovered by Brad Cookson and Molly Brennan in 2001; it is a novel form of caspase-1-dependent PCD in immune cells, such as macrophages and dendritic cells, that defends the body against intracellular pathogens106. However, in contrast to other forms of PCD, pyroptosis contributes to tissue damage in inflammatory disorders107.

Pyroptosis is initiated by the activation of pattern recognition receptors (PRRs) in response to pathogen-associated molecular patterns (PAMPs) or DAMPs, which trigger inflammasome assembly108. The inflammasome is a protein complex consisting of PRRs, adaptor proteins, and caspase-1, with caspase-1 cleaving gasdermin D (GSDMD) to produce an N-terminal GSDMD fragment that forms membrane pores109. Caspase-1 also activates the proinflammatory interleukins, interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) activity, also via proteolysis110. The actions of caspases result in the release of proinflammatory cytokines and the recruitment of immune cells to the site of infection or injury (Fig. 7A)111.

Fig. 7: Mechanisms of pyroptosis, NETosis, and necroptosis.

A Pyroptosis is characterized by cell swelling, plasma membrane rupture, and the release of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18. Pyroptosis is triggered by the activation of inflammasomes, cytoplasmic complexes that sense danger signals, and initiate a caspase-1-dependent cascade that ultimately leads to cell death. 

B NETosis is a process in which neutrophils release DNA fibers coated with antimicrobial peptides to trap and kill pathogens. During NETosis, neutrophils undergo marked morphological changes, including chromatin decondensation, nuclear envelope rupture, and granule mixing, leading to the formation of neutrophil extracellular traps (NETs). The release of NETs is triggered by various stimuli, such as pathogens, cytokines, and immune complexes. 

C Necroptosis is mediated by death receptors. Upon activation of death receptors, such as TNFR1, receptor-interacting protein kinase 1 (RIPK1) binds to RIPK3 to form a necrosome. The necrosome complex promotes the oligomerization and phosphorylation of the mixed lineage kinase domain-like protein (MLKL). The oligomeric form of MLKL is translocated from the cytosol to the plasma membrane, leading to the formation of membrane pores and subsequent plasma membrane rupture. This results in the release of damage-associated molecular patterns (DAMPs), which trigger inflammation.

Pyroptosis has been implicated in several pathological conditions, including infectious diseases, autoimmune disorders, cancer, and neurodegenerative diseases112,113. Studies have shown that inhibition of pyroptosis can alleviate inflammation and tissue damage in the contexts of these conditions114,115. Therefore, targeting pyroptosis may be a potential therapeutic strategy for the treatment of inflammatory diseases.

NETosis

NETosis is a type of PCD characterized by the release of neutrophil extracellular traps (NETs) into the extracellular space116. NETs are web-like structures composed of chromatin, histones, and granular proteins that are released by neutrophils, a type of white blood cell, to capture and kill invading pathogens, including bacteria, viruses, and fungi117. NETosis was first described by Volker Brinkmann et al. in 2004118.

The mechanism of NETosis activation involves a series of complex molecular events, including ROS production, nuclear envelope disassembly, chromatin decondensation, and NET release (Fig. 7b)116. One of the key events in NETosis is the activation of the NADPH oxidase complex, which depends on an increase in the cytoplasmic concentration of Ca2+ and subsequent ROS production116. When ROS are activated, protein complexes known as “azurosomes” dissociates from azurophil granules dissociates and causes NE, cathepsin G, azurocidin, and MPO to be released into the cytosol, where they contribute to chromatin decondensation and nuclear envelope disintegration119. Another important factor in NETosis is peptidyl-arginine deaminase 4 (PAD4), which is transferred from the cytoplasm to the nucleus to catalyze the citrullination of histones, leading to chromatin decondensation120. Histones can also undergo acetylation during NETosis; however, the role of this process is not clearly understood121. In the final stage of NETosis, pores are formed in the plasma membrane, and chromatin is released into the extracellular environment, and NETs are formed. GSDMD plays a critical role in the formation of these membrane pores. In contrast to pyroptosis, in which GSDMD is activated through caspase-induced cleavage, NETosis is activated mainly by NE122,123. In addition, both the ER and mitochondria play important roles in NETosis. NETosis is initiated by calcium release from the neutrophil ER, which triggers the assembly of the NADPH oxidase complex and the generation of ROS124,125,126. Mitochondrial ROS production also promotes NETosis, potentially by regulating NADPH oxidase activity127. Overall, the coordinated activation of multiple pathways and organelles is required for successful NETosis.

NETosis plays an important role in the innate immune response because it allows neutrophils to directly combat pathogens128. However, excessive or inappropriate NETosis can contribute to the development of inflammatory and autoimmune diseases, such as sepsis, rheumatoid arthritis, lupus, and cancer129,130. Therefore, regulation of NETosis is a topic of ongoing research in the field of immunology.

Necroptosis

Necroptosis is a form of PCD that differs from necrosis and apoptosis in terms of morphology and biochemistry131. Necroptosis was first identified and described by Dr. Francis Chan et al. in 2005132. It is mediated by a signaling cascade involving the activation of receptor-interacting protein kinase 1 (RIPK1) and RIPK3 and the formation of a complex called the necrosome133.

TNFα and TNFR1 ligation triggers a well-characterized necroptosis-inducing pathway134. Under normal conditions, stress signals activate caspase-8, leading to the initiation of apoptosis135. However, when caspase-8 activity is suppressed, RIPK1 and RIPK3 are activated, leading to necroptosis136. During TNF-induced necroptosis, RIPK1 can recruit RIPK3 through the RIP homotypic interaction motif (RHIM) to form necrosomes, which promote the oligomerization and phosphorylation of mixed lineage kinase domain-like protein (MLKL)137. The oligomeric form of MLKL is translocated from the cytosol to the plasma membrane, leading to the formation of membrane pores and the subsequent rupture of the plasma membrane, resulting in the release of DAMPs138. The released DAMPs are recognized by PRRs on immune cells, leading to the activation of inflammatory responses (Fig. 7c)108. This inflammatory response can contribute to the clearance of dead cells and the initiation of tissue repair processes139. However, excessive or prolonged inflammation can cause tissue damage and contribute to the pathogenesis of various diseases140.

Research results suggest that necroptosis is involved in the pathogenesis of several diseases, including neurodegenerative diseases, viral infections, ischemic injury, and cancer141,142,143,144. The inhibition of necroptosis has shown therapeutic potential in some disease models, making it an attractive target for drug development145.

Cuproptosis

Cuproptosis is a form of PCD triggered by copper (Cu)146. The term “cuproptosis” is derived from the Latin word “cuprum,” which means copper, and the Greek word “ptosis,” meaning falling off. This was first described and the term was initially defined by Tsvetkov, P. et al. in 2019 (Nat Chem Biol 15, 681–689, 2019)147. Cuproptosis differs from other types of oxidative stress-related cell death, such as apoptosis and ferroptosis, and is characterized by mitochondrial stress caused by the aggregation of lipoylated mitochondrial enzymes and the loss of Fe–S cluster proteins31.

Copper is an essential trace element that plays vital roles in various biological processes, including oxygen transport, energy production, and antioxidant defense148,149. However, excess copper can be toxic to cells and tissues, leading to a condition known as copper overload or copper toxicity150. Two mitochondrial proteotoxic stress pathways mediate cuproptosis. The mitochondrial matrix reductase ferredoxin 1 (FDX1) catalyzes the reduction of ES–Cu2+ to Cu+, releasing it into mitochondria151. FDX1 has also been identified as a novel effector of lipoylation that contributes to the accumulation of toxic lipoylated dihydrolipoamide S-acetyltransferase (DLAT)152. Cu+ binds to lipoylated DLAT, promoting the disulfide bond-dependent aggregation of lipoylated DLAT, which leads to the accumulation of toxic lipoylated DLAT and subsequent cuproptotic cell death153. In addition, FDX1-dependent degradation of Fe-S cluster proteins may favor cuproptosis (Fig. 8A)31. This type of cell death depends on the amount of copper in cells and the lipoylation status of tricarboxylic acid (TCA) cycle enzymes.

Fig. 8: Copper and iron-driven cell death: cuproptosis and ferroptosis.

A Cuproptosis is triggered by the accumulation of copper. It results in mitochondrial stress due to the aggregation of lipoylated mitochondrial enzymes and the loss of Fe–S cluster proteins, which can be mediated by ferredoxin 1 (FDX1). B Ferroptosis is characterized by the depletion of intracellular glutathione and decreased activity of glutathione peroxidase 4 (GPX4), which leads to the accumulation of unmetabolized lipid peroxides and increased ROS production. Membrane damage is also a result of lipid peroxidation.

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Cuproptosis has been implicated in several pathological conditions, such as Wilson’s disease, a genetic disorder characterized by the accumulation of copper in the liver, brain, and other organs154. Therefore, understanding the mechanisms underlying coproptosis may provide insights into the pathogenesis and treatment of copper-related diseases.

Ferroptosis

Ferroptosis is an iron-dependent form of PCD that involves the accumulation of lipid peroxides and oxidative stress leading to membrane damage155. Ferroptosis was first described in 2012 by a research team led by Brent Stockwell155. The name ferroptosis comes from the Latin word “ferrum,” meaning iron, and the Greek word “ptosis,” meaning falling, which together refer to the iron-dependent process of cellular demise27. Ferroptosis is thought to play a role in various physiological processes, including ischemia, cancer, and neurodegeneration156.

Ferroptosis is regulated by several factors, such as iron metabolism, lipid peroxidation, and antioxidant systems157. Ferroptosis is initiated by the accumulation of lipid peroxides generated through the oxidation of polyunsaturated fatty acids via lipoxygenases or other enzymes158. Lipid peroxides accumulate through the oxidation of polyunsaturated fatty acids, a process that can be further amplified via the iron-catalyzed Fenton reaction, generating ROS and hydroxyl radicals that attack and damage cellular components, particularly the cell membrane, resulting in cell death (Fig. 8B)159. The cystine/glutamate antiporter system imports cystine, a precursor of the antioxidant glutathione, and thus plays a significant role in regulating the accumulation of lipid peroxides and iron160. Glutathione neutralizes free radicals and ROS and protects cells from oxidative stress and lipid peroxidation161. Ferroptosis is characterized by the depletion of intracellular glutathione and decreased activity of glutathione peroxidase 4 (GPX4), leading to the accumulation of unmetabolized lipid peroxides and the production of high levels of ROS27,162. Other factors that can regulate ferroptosis include iron metabolism; the activity of lipid metabolism enzymes, such as acyl-CoA synthetase long-chain family member 4 (ACSL4); and the expression‎ of genes involved in cell stress response pathways, such as the p53 pathway163,164. In cancer treatment, inhibition of the cystine/glutamate antiporter system induces ferroptosis165. In addition, the use of ferroptosis-inducing agents, such as erastin and RSL3, may become a novel approach to cancer therapy166.

Ferroptosis is a unique and important form of PCD with broad implications in various physiological processes and disease states. Further studies may provide new insights into the mechanisms underlying this form of cell death and potential therapeutic interventions.

Paraptosis

Paraptosis, the name of which is derives from the combination of “para”, meaning next to or related to, and “apoptosis,” is a type of PCD that was initially discovered by Sabina Sperandio et al. in 2000167. Paraptosis and apoptosis are typically induced simultaneously in cells. In contrast to apoptosis, paraptosis does not involve caspase activation or DNA fragmentation167. Paraptosis is characterized by the swelling and vacuolization of the ER and mitochondria, resulting in the formation of large cytoplasmic vacuoles168.

Multiple mechanisms can trigger paraptosis. Impaired proteostasis due to proteasomal inhibition or altered protein thiol homeostasis, as well as unbalanced ion homeostasis, can lead to paraptosis169. Paraptosis is characterized by cytoplasmic vacuolization resulting from swelling of the ER and mitochondria. The accumulation of misfolded proteins within the ER lumen leads to the development of an osmotic force that causes water to be drawn away from the cytoplasm, causing ER distension (Fig. 9)170. ER stress and dilation can contribute to the release of Ca2+ from the ER, which can cause mitochondrial Ca2+ overload via an intracellular Ca2+ flux mechanism located at the ER-mitochondrial axis and thus mitochondrial dilatation169. Stimulation of the MEK-2 and JNK pathways by IGF-IR, as well as its inhibition mediated by AIP-1/Alix, is known to promote paraptosis171. Paraptosis is believed to play a role in various physiological and pathological processes, including embryonic development, neurodegeneration, and cancerogenesis172. In cancer cells, paraptosis is induced by various chemotherapeutic agents, including the proteasome inhibitor bortezomib and histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA)173,174.

Fig. 9: Mechanism underlying paraptosis.

Paraptosis is characterized by the development of large vacuoles in the endoplasmic reticulum (ER) and mitochondria, ultimately leading to the formation of large cytoplasmic vacuoles. Impaired proteostasis, altered ion homeostasis, and ER stress cause paraptosis, resulting in the discharge of Ca2+ from the ER and accumulation of Ca2+ in mitochondria. Paraptosis can be facilitated by the activation of mitogen-activated protein kinase (MAPK) signaling pathways via IGF-IR and inhibited by AIP-1/Alix.

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In summary, paraptosis is a type of PCD characterized by the formation of large cytoplasmic vacuoles and activation of multiple signaling pathways. Further research is required to fully elucidate the mechanisms underlying paraptosis and its potential as a therapeutic target for various diseases.

Methuosis

Methuosis is a nonapoptotic form of cell death characterized by the accumulation of vacuoles derived from macropinosomes, which are large endocytic vesicles175. The term methuosis is derived from the Greek word for “methuo,” meaning to drink to intoxication, and refers to the fact that the vacuoles in methuotic cells appear to be filled with an unknown substance25. Methuosis was first described by Overmeyer et al. in 2008176.

Methuosis is triggered by sustained high-level expression‎ of the activated form of Ras (G12V) and chronic stimulation of Rac1177. This stimulation increases the rate of macropinocytic, which is the process of molecules uptake into the extracellular fluid through the formation of large vesicles called macropinosomes178. However, methuosis impairs macropinosome recycling by decreasing the pool of active Arf6, which is a protein involved in vesicle trafficking25. Thus, macropinosomes accumulate and fuse to form large vacuoles that displace the nucleus and other organelles in a cell. Eventually, the vacuoles become sufficiently large to rupture the cell membrane, leading to cell death (Fig. 10)179. However, the exact molecular mechanisms underlying this form of cell death are not fully understood.

Fig. 10: Molecular basis of methuosis.

This image depicts the working model of methuosis. Methuosis is initiated by prolonged high-level expression‎ of RAS (G12V) and chronic activation of Rac1, which leads to enhanced macropinocytic activity. Moreover, this mechanism hampers macropinosome recycling by lowering the active Arf6 pool. Nascent macropinosomes, which are created from lamellipodial membrane projections, penetrate the cell and merge to form large fluid-filled vacuoles that, in contrast to typical macropinosomes, cannot be recycled. These vacuoles grow rapidly, resulting in a stable population with certain late endosomal features (Rab7 and LAMP1).

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Methuosis has been observed in various cancer cell lines and has been proposed to be a potential therapeutic target for cancer treatment180,181. However, further research is required to fully understand the molecular mechanisms underlying methuosis and the potential of these mechanisms as targets for cancer therapy.

Entosis

Entosis is a nonapoptotic form of cell death in which one living cell actively internalizes and degrades another living cell175. Entosis is derived from the Greek word “entos,” meaning inside or within, and was first described by Overholtzer et al. in 2007182. The internalization of a living cell by another cells leads to the formation of a double-membrane vesicle called the entotic vacuole183. During normal development, entosis is thought to play a role in the removal of excess cells and in shaping tissues and organs184. In cancer, entosis has been shown to contribute to tumor growth and tumor cell invasion by facilitating the engulfment of neighboring cells183.

Entosis is triggered when cells detach from the extracellular matrix (ECM) leading to the internalization of one cell by another cell. Entosis requires the activation of multiple molecular signaling pathways. One of the crucial pathways involved in entosis is the Rho/Rho-associated protein kinase (ROCK)/actomyosin pathway, which regulates actin and myosin II activities and is essential for cell engulfment185. The Rho/ROCK/actomyosin signaling pathway is involved in various processes, including cell migration, division, and shape changes175. This pathway involves the activation of the Rho family of small GTPases, which activate downstream effectors, such as ROCK186. In turn, ROCK activates myosin II, a motor protein that generates contractile forces by interacting with actin filaments186. During entosis, an invading (engulfed) entotic cell forms an actin-rich structure that protrudes into the cytoplasm of the engulfing cell183. Myosin II is recruited to this structure and contracts it, pulling the invading cell into the engulfing cell187. The internalized cells are subsequently degraded by lysosomes within the engulfing cell (Fig. 11)182.

Fig. 11: Cell-in-cell structures: a hallmark of entosis.

Entosis is a biological process characterized by the internalization of one living cell into the cytoplasm of another. It is caused by adherent cell matrix separation, which results in the establishment of E-cadherin-mediated cell connections (shown in red) between the engulfing cell and the entotic cell. RhoA activity within the entotic cell causes actomyosin buildup at the cell cortex, resulting in the creation of cell-in-cell structures that mimic an active invasion-like process. Most internalized cells die as a result of entotic cell death, which is followed by lysosome fusion or apoptosis, especially when macroautophagy has been inhibited. However, certain entotic cells may divide within their hosts or even escape death.

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Entosis is induced by various stimuli, such as nutrient starvation and ultraviolet radiation. Nutrient starvation, particularly glucose starvation, plays a pivotal role in inducing entosis by activating AMP-activated protein kinase (AMPK) in internal cells188, while ultraviolet radiation induces JNK and p38 stress-activated kinase signaling to activate entosis189. Entosis differs from anoikis, which is triggered by a lack of cell attachment to the ECM but not by matrix detachment182. Entosis shares more similarities to cell invasion than to a cell engulfment mechanism182. Entosis is also distinct from phagocytosis, which involves phagocyte engulfment of a dead or dying cell190.

Recent studies provided crucial insights into the mechanisms underlying entosis and its relevance in cancer development191,192. Specifically, Orai1, a Ca2+ channel protein, has emerged as a key player in entosis193. Orai1 plays a critical role in regulating intracellular Ca2+ levels during entosis, thereby influencing the activation of signaling pathway involved in cell engulfment and degradation. Dysregulation of Orai1-mediated Ca2+ signaling has been implicated in enhanced entosis, tumor growth, and invasion194. Although much is still unknown about the molecular mechanisms underlying entosis, this form of cell death has emerged as an important area of research with potential implications for both developmental biology and cancer therapeutics.

Parthanatos

Parthanatos is a form of PCD that is mediated by the activation of poly ADP-ribose polymerase (PARP)195. The name is a combination of “PAR” and “thanatos” (the Greek word for death), reflecting the role of PAR-mediated cell death in various pathological conditions. It was first discovered by Karen Kate David in 200926. This type of cell death was first identified in neurons and plays an important role in several neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases196.

Parthanatos is triggered by various agents, such as ROS, hydrogen peroxide, ionizing radiation, and alkylating agents195. When DNA damage is mild, PARP-1 recruits DNA damage repair proteins to repair damaged DNA197. Severe DNA damage leads to PARP-1 overactivation and PAR polymer formation198. Accumulated PAR polymers bind to apoptosis-inducing factor (AIF) and mediate AIF release from mitochondria199. AIF interacts with MIF to form the AIF/MIF complex, which is translocated to the nucleus, causing DNA fragmentation and leading to parthanatos200 (Fig. 12).

Fig. 12: Mechanism underlying parthanatos.

This diagram depicts the molecular processes underlying parthanatos. ROS, ischemia, alkylating chemicals, and radiation activate PARP-1 by activating NOS, resulting in the creation of excess NO and subsequent synthesis of peroxynitrite (ONOO−). Peroxynitrite activates PARP-1, resulting in the formation of copious amounts of PAR polymer in the nucleus. Certain poly(ADP)-ribosylated carrier proteins escape from the nucleus, prompting the outer mitochondrial membrane to release apoptosis-inducing factor (AIF). AIF then enters the cytoplasm and attaches to macrophage migration inhibitory factor (MIF). AIF and MIF enter the nucleus and cause widespread DNA degradation, ultimately resulting in cell death.

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Overall, parthanatos is a complex form of PCD that plays an important role in several disease processes. Further research is needed to fully understand the mechanisms underlying parthanatos and its potential therapeutic applications.

Alkaliptosis

Alkaliptosis is a recently discovered form of regulated necrosis triggered by exposure to alkaline agents, such as ammonia, sodium hydroxide, or high-pH buffers201. Alkaliptosis was first discovered and named by Daolin Tang in 2018201. Alkaliptosis is a sequential molecular mechanism modulated by several factors.

Alkaliptosis can be activated by the upregulation of nuclear factor-kappa B (NF-κB) pathways and subsequent downregulation of carbonic anhydrase 9 (CA9) (Fig. 13)29. CA9 is a member of the carbonic anhydrase family that plays a role in regulating pH levels29. NF-κB negatively regulates CA9 activity, which in turn inhibits alkaliptosis29. Depletion of CA9 can restored the sensitivity of cancer cells that lack functional NF-κB to alkaliptosis29,202. Another study showed that ACSS2-mediated NF-κB activation promoted alkaliptosis in human pancreatic cancer cells203. ACSS2 has been found in the nucleus and cytoplasm and provides AcCoA, which is important for lipogenesis and histone acetylation204. ACSS2 plays a role in alkaliptosis by maintaining NF-κB activation and increasing the pH value via histone acetylation in human PDAC cells203.

Fig. 13: Molecular pathways in alkaliptosis.

This figure illustrates the activation mechanism of alkaliptosis, which is characterized by intracellular alkalinization and subsequent cell death. JTC801 activates the IKK protein complex, which includes CHUK (IKKα), IKBKB (IKKβ), and IKBKG (IKKγ). Then, the IKK protein complex phosphorylates and degrades NFKBIA (IκBα), leading to the nuclear translocation of NFKB1 (p50) or RELA (p65), which regulate gene expression‎. Furthermore, NF-κB negatively regulates the expression‎ of CA9, a member of the carbonic anhydrase family, to inhibit alkaliptosis.

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Alkaliptosis is a promising strategy for cancer therapy because cancer cells have a profoundly unbalanced pH, and their proliferation, metastasis, and metabolic adaptation are determined by their pH sensitivity205. Drugs developed to target alkaliptosis may be a new approach to cancer treatment, especially for those resistant to conventional therapies29. However, further research is required to fully understand the mechanism of alkaliptosis and its potential for cancer therapy.

Oxeiptosis

The term “oxeiptosis” was coined by Holze et al. in 2018 to describe a caspase-independent, ROS-sensitive, and noninflammatory cell death pathway that protects against inflammation induced by ROS or ROS-generating agents, such as viral pathogens30. Oxeiptosis is characterized by the activation of the KEAP1/PGAM5/AIFM1 signaling pathway206. Under oxidative stress conditions, AIFM1 is dephosphorylated, and its activity is regulated by KEAP1 and PGAM5. Dephosphorylated AIFM1 is translocated from mitochondria to the nucleus, where it induces chromatin condensation and DNA fragmentation, leading to cell death (Fig. 14)30. Activation of the KEAP1/PGAM5/AIFM1 signaling pathway is a hallmark of apoptosis and differs from other cell death pathways, such as the apoptosis and necrosis pathways. The mechanisms underlying oxeiptosis are not yet fully understood, but it is thought to involve the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway207.

Fig. 14: Mechanism underlying oxeiptosis.

This figure illustrates the key features of oxeiptosis. Oxeiptosis is activated in response to oxidative stress induced by ROS or ROS-generating agents, such as viral pathogens. The KEAP1/PGAM5/AIFM1 signaling pathway plays a central role in oxeiptosis, in which AIFM1 is dephosphorylated under oxidative stress conditions via the regulatory action of PGAM5. Dephosphorylated AIFM1 is translocated from mitochondria to the nucleus, leading to chromatin condensation and DNA fragmentation, ultimately resulting in cell death.

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Many conditions, such as allergies, autoimmune diseases, allograft rejection, cancer, and infection with pathogens, lead to ROS production, indicating that oxeiptosis may be triggered under various pathological conditions208. Notably, excessive or dysregulated oxeiptosis can lead to tissue damage and contribute to disease development. Understanding the mechanisms underlying oxeiptosis and its role in health and disease is an active area of research that may identify new therapeutic intervention targets.

Erebosis

In 2022, Sa Kan Yoo et al. reported a novel form of cell death called erebosis during the natural turnover of gut enterocytes, which are the cells that make up the gut epithelium (Fig. 15)32. The term “erebosis” is derived from the Greek word “erebos,” meaning complete darkness32. Erebotic cells undergo membrane blebbing and actin cytoskeleton changes, eventually leading to cell disintegration32. This process is marked by the loss of cell adhesion, organelles, and fluorescence emitted from labeled proteins and the accumulation of angiotensin-converting enzyme (ACE)209. In contrast to cell undergoing apoptosis, necrosis, and autophagic cell death, cells undergoing erebosis do not exhibit distinguishing features. Notably, apoptosis inhibition does not affect apoptosis or gut cell turnover209. The authors suggested that erebosis may play a vital role in maintaining gut barrier function through the natural shedding of gut enterocytes32. In contrast, abnormal erebosis may contribute to the development of gastrointestinal conditions, such as inflammatory bowel disease32. Although this phenomenon has only been discovered in Drosophila, further research is required to determine whether it also occurs in other organisms, including humans. Such investigations may provide insights into the evolutionary origins and physiological significance of erebosis and enhance our understanding of gut physiology and related disorders.

Fig. 15: Structural characteristics of erebosis.

This figure depicts the process of erebosis, a novel form of cell death observed during the natural turnover of enterocytes that constitute the gut epithelium. Nuclear expansion and accumulation of angiotensin-converting enzyme (ACE) are observed in the early stages of erebosis. Subsequently, cell shrinkage and nuclear fragmentation are observed. Late erebotic cells are surrounded by stem cells that eventually undergo division to generate new epithelial cells, contributing to the replenishment of the gut epithelium.

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The complexity underlying cell death

The complexity of cell death classification

The categorization system for cell death is intrinsically complexity. Initially, cell death was classified primarily based on morphological characteristics, as described below2. Type 1 cell death, known as apoptosis, is characterized by cytoplasm shrinkage, chromatin condensation, membrane blebbing, and the formation of apoptotic bodies, which are cleared through phagocytosis and lysosomal degradation by the surrounding cells210. Type 2 cell death is characterized by intense autophagy or cytoplasmic vacuolization, leading to phagocytosis by neighboring cells and degradation via lysosomes210. Type 3 cell death, or necrosis, results in cell death without triggering phagocytosis or lysosomal degradation and is not characterized by any of the features used to identify type 1 and 2 cell death modalities210. As more forms of cell death were identified, type 4 cell death modalities were classified, and these types of cell death includes those that cannot be classified into one of the three previously defined categories211. However, the current classification system of cell death, based on morphological changes, is limited because newly discovered forms of cell death cannot be integrated into it. Furthermore, the existing classification system does not account for the increasingly recognized importance of molecular pathways, specifically their greater importance than morphological changes, in identifying forms of cell death210. Thus, there is a need for more comprehensive guidelines that are based on genetic, biochemical, and functional criteria.

To address this need, the NCCD issued guidelines on the “classification of cell death” in 2005212, 2009213, and 20182. The 2018 classification system aimed to establish a more comprehensive system based on genetic, biochemical, and functional criteria, not merely morphological features (Fig. 16)2. However, this system also has several limitations. First, certain forms of cell death, namely, paraptosis, methuosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis, were not classified. Second, although pyroptosis, NETosis, and necroptosis are categorized as different types of cell death67, these modalities all involve immunogenic cell death98. Finally, the current classification system may not account for the potential interplay and crosstalk among different forms of cell death because cell death processes are mediated via a complex network of interactions contributing to cellular processes that may not be fully reflected in the classification system.

Fig. 16: Classification of cell death.

This figure illustrates the classification of the different forms of cell death and nonlethal processes based on their underlying mechanisms and morphological features. This figure was generated according to the 2018 guidelines for the classification of cell death issued by the Nomenclature Committee on Cell Death (NCCD).

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Complexity of the interconnectedness among different types of cell death

The interconnectedness among the various forms of cell death is an important factor that contributes to cell death complexity (Fig. 17). Necroptosis, a regulated form of necrosis, shares similarities with necrosis and apoptosis131,133. Autophagy is required for both autosis and autophagic cell death programs, which are triggered via different molecular pathways53,75. Similarly, cells undergoing parthanatos display morphological and cytological characteristics of both apoptosis and necrosis26. Recent studies have suggested that autophagy and ferroptosis pathways interact in a complex manner. Autophagy has been suggested to regulate ferroptosis by eliminating damaged mitochondria and peroxidized lipids214. However, excessive or prolonged autophagy can lead to ferritin degradation, which can trigger ferroptosis215.

Fig. 17: Complexity of cell death.

This figure illustrates the complex and interconnected nature of cell death pathways. The figure shows the mechanisms by which different types of cell death pathways interact and influence each other and the ways in which they can be regulated by various signaling pathways and environmental factors.

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Cell death is influenced by various factors, including cellular organelles and environmental conditions. Mitochondria play crucial roles in different types of cell death, including apoptosis, NETosis, paraptosis, parthanatos, and oxeiptosis216. For example, apoptosis is triggered by mitochondrial outer membrane permeabilization (MOMP), which leads to the release of cytochrome c and activation of the caspase cascade216,217. In cells undergoing NETosis, mitochondria produce mitochondrial ROS (mtROS), whereas in cells undergoing paraptosis, Ca2+ released from the ER causes mitochondrial Ca2+ overload and mitochondrial dilation218,219. Both parthanatos and oxeiptosis involve mitochondrial release of AIF, which is translocated from the mitochondria to the nucleus, resulting in cell death30,195.

Lysosomes play several roles in cell death. During lysosomal cell death, lysosomal membrane permeabilization results in the release of cathepsins, which activate apoptotic pathways83. During necrosis, lysosomal membrane permeabilization causes the release of lysosomal hydrolases and ROS, which cause cell damage and inflammation [183]. In cells undergoing autophagic death, lysosomes fuse with autophagosomes to degrade cellular components, leading to cell death220. Lysosomal exocytosis has been implicated in the induction of pyroptosis, a type of inflammatory cell death221. In addition, endothelial cells undergo lysosomal degradation182.

Similar to lysosomal factors, ROS trigger cell death in various ways. For example, ROS play a crucial role in activating NADPH oxidase, which is required for the degradation of azurophilic granules that trigger NETosis116. Moreover, ROS can cause lipid peroxidation, leading to ferroptosis27. Additionally, ROS can cause ER stress by inducing the accumulation of unfolded proteins, triggering paraptosis222. ROS production is also the primary cause of oxeiptosis initiation30. Furthermore, a rapid increase in the cytosolic pH vale can induce both lysosomal cell death and alkaliptosis17,29. Some types of cell death, such as paraptosis and methuosis, are caused by the formation of large vacuoles, highlighting the importance of organelle dysfunction in regulating cell death223.

Overall, the interconnectedness among the different types of cell death and their regulation via diverse signaling pathways and environmental factors highlight the complexity of cell death. Understanding the interplay among different signaling pathways and the impact of the cell context on the cell death modality is crucial for developing new therapeutic strategies that target cell death pathways for the treatment of various diseases. Further research is needed to fully characterize and differentiate among the various forms of cell death and their roles in health and disease.

PANoptosis: an emerging and complex form of cell death

In addition to the different types of cell death that share the same molecular pathways, it has recently been shown that different types of cell death are mediated simultaneously in a single cell. This phenomenon was first described by Kanneganti et al. in 2016 when they studied inflammasome activation by influenza virus224 and named it PANoptosis in 2019 (Fig. 18)225. PANoptosis is triggered by the formation of a protein complex called the PANoptosome, which is composed of several proteins, including RIPK1, RIPK3, caspase-8, NLRP3, and ASC226. This complex activates various cell death pathways, including pyroptosis, apoptosis, and necroptosis, resulting in an inflammatory cell death response226.

Fig. 18: Overview of PANoptosis.

PANoptosis is triggered by the formation of a protein complex called the PANoptosome, which includes several protein domains, namely, RIPK1, RIPK3, caspase-8, NLRP3, and ASC. This complex activates multiple types of cell death, including pyroptosis, apoptosis, and necroptosis, resulting in an inflammatory cell death response. During influenza A virus (IAV) infection, Z-DNA-binding protein (ZBP1) recognizes viral ribonucleoproteins and induces the formation of the ZBP1-dependent PANoptosome. TGF-β-activated kinase 1 (TAK1) is a crucial regulator of PANoptosis that negatively controls this process; however, bacterial infections can interrupt its suppression. Inhibition of TAK1 and activation of signaling through TLRs or death receptors promotes the formation of RIPK1-dependent PANoptosomes. During PANoptosis, the activation of caspase-1 or caspase-8 leads to the cleavage and activation of downstream effector proteins, such as gasdermin D and RIPK3, which drive pyroptosis and necroptosis, respectively. Activated caspase-8 subsequently cleaves and activates caspase-3, resulting in cell apoptosis.

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During influenza A virus (IAV) infection, Z-DNA-binding protein (ZBP1) plays a critical role in activating PANoptosis by recognizing viral ribonucleoproteins and inducing the formation of the ZBP1-dependent PANoptosome224,227. This complex consists of ZBP1 (the sensor), RIPK3, RIPK1, NLRP3, ASC, caspase-1, caspase-8, and scaffold caspase-6228. TGF-β-activated kinase 1 (TAK1) is a crucial regulator of PANoptosis that negatively controls its initiation. Notably, bacterial infections can interrupt PANoptosis suppression via the action of the Yersinia T3SS effector YopJ, leading to PANoptosome formation225. When TAK1 was inhibited and signaling through TLRs or death receptors was activated, RIPK1-dependent PANoptosomes were formed229.

During PANoptosis, the activation of caspase-1 or caspase-8 leads to the cleavage and activation of downstream effector proteins, such as gasdermin D and RIPK3, which drive pyroptosis and necroptosis, respectively226. In addition, activated caspase-8 can cleave and activate caspase-3, leading to apoptosis230. The pathophysiological functions and importance of phagocytosis in relation to viral infections have been extensively studied during the COVID-19 pandemic; however, clear evidence of a phagocytic protein complex has yet to be established. Further research is required to identify this complex or eliminate the possibility that a complex is formed.

Conclusion and future perspectives

In the preceding sections, we discussed the many types of cell death and history of their discovery. Understanding the diverse and complex processes underlying cell death is crucial for understanding diseases and may be beneficial for the development of new therapies. The classification of cell death based on morphological features is limited because it cannot accommodate newly discovered forms of cell death and may not reflect the underlying molecular pathways that determine a form of cell death. Therefore, recent guidelines proposed by the NCCD aim to establish a more comprehensive classification scheme based on genetic, biochemical, and functional criteria2. Moreover, several new forms of cell death have been discovered that are not included in the latest NCCD classification, and some scholars have disputed the usefulness of this classification. We hope that the next NCCD consensus will produce a new cell death classification system that addresses the aforementioned issues.

Researchers have made significant strides in characterizing and distinguishing various forms of cell death, thereby advancing our understanding of the roles of these modalities in health and disease. The complex mechanisms underlying cell death are underscored by the intricate interconnections among different types of cell death and the regulation of these mechanism through diverse signaling pathways and environmental factors. In addition, the importance of crosstalk among signaling pathways and the influence of the cellular context on cell death outcomes has become increasingly evident. These findings pave the way for the development of novel therapeutic strategies targeting cell death pathways for the treatment of diverse diseases. Further research is crucial to characterize and differentiate various forms of cell death, to gain a better understanding of their roles in disease progression, and to develop targeted therapeutic strategies (Table 2). Ultimately, a comprehensive understanding of the multifaceted nature of cell death will be indispensable for the development of innovative and more efficacious treatments for a broad spectrum of diseases.

Table 2 List of cell death-related diseases.

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As we gain a better understanding of new types of cell death and their complexities, the study of cell death is becoming increasingly difficult. In particular, different processes of cell death are linked by molecular mechanisms and, in some cases, are potentially coactivated. Because of these connections, the specificities of molecular markers used to distinguish among different types of cell death are becoming increasingly ambiguous. Furthermore, whether the agents used to inhibit specific cell death are sufficiently specific is an ongoing concern. Developing new inhibitors with greater specificity or modulating key genes may solve the problems associated with lack of specificity among inhibitors. However, the emergence of complex forms of cell death suggests that the inhibition of only one type of cell death may not be sufficient to achieve therapeutic results. Therefore, future studies on cell death may require an integrated view of different types of cell death.

A scientist studying death of a cell can be compared with a forensic physician investigating a crime scene. However, in contrast to forensic physicians who focus on identifying the cause of a murder, scientists focused on cell death are primarily interested in understanding the mechanisms and types of PCD, that is, cell suicide. From a forensic standpoint, some may question the need for such a detailed classification and identification of cell death. However, understanding the processes and types of cell death is important to fully comprehend the manner in which cells resolve internal disharmony and maintain balance. Therefore, scientists interested only in cell suicide will play an increasingly important role in the cellular universe, similar to forensic scientists investigating crime scenes in the macroscopic world.