Re: Lactate: the ugly duckling of energy metabolism

[문형철]

,영향력지수 19점 논문

Nat Metab. Author manuscript; available in PMC 2021 Jul 20.

Published in final edited form as:

Nat Metab. 2020 Jul; 2(7): 566–571.

Published online 2020 Jul 20. doi: 10.1038/s42255-020-0243-4

PMCID: PMC7983055

NIHMSID: NIHMS1680259

PMID: 32694798

Lactate: the ugly duckling of energy metabolism

Joshua D. Rabinowitz1,✉ and Sven Enerbäck2,✉

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The publisher's final edited version of this article is available at Nat Metab

Abstract

Lactate, perhaps the best-known metabolic waste product, was first isolated from sour milk, in which it is produced by lactobacilli. Whereas microbes also generate other fermentation products, such as ethanol or acetone, lactate dominates in mammals. Lactate production increases when the demand for ATP and oxygen exceeds supply, as occurs during intense exercise and ischaemia. The build-up of lactate in stressed muscle and ischaemic tissues has established lactate’s reputation as a deleterious waste product. In this Perspective, we summarize emerging evidence that, in mammals, lactate also serves as a major circulating carbohydrate fuel. By providing mammalian cells with both a convenient source and sink for three-carbon compounds, circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis. Lactate and pyruvate together serve as a circulating redox buffer that equilibrates the NADH/NAD ratio across cells and tissues. This reconceptualization of lactate as a fuel—analogous to how Hans Christian Andersen’s ugly duckling is actually a beautiful swan—has the potential to reshape the field of energy metabolism.

아마도 가장 잘 알려진 대사 폐기물인 젖산은 유산균에 의해 생성되는 신 우유에서 처음으로 분리되었습니다. 미생물은 에탄올이나 아세톤과 같은 다른 발효 산물도 생성하지만 포유류에서는 젖산염이 우세합니다. 격렬한 운동과 허혈 중에 발생하는 것처럼 ATP와 산소에 대한 수요가 공급을 초과할 때 젖산 생산이 증가합니다. 스트레스를 받은 근육과 허혈성 조직에 젖산이 축적되면서 젖산이 유해한 폐기물이라는 평판을 얻게 되었습니다. 이 관점에서 우리는 포유류에서 젖산이 주요 순환 탄수화물 연료 역할을 한다는 새로운 증거를 요약합니다. 포유동물 세포에 3탄소 화합물의 편리한 공급원과 흡수원을 제공함으로써 순환하는 젖산염은 해당과정에서 발생하는 탄수화물 구동 미토콘드리아 에너지의 분리를 가능하게 합니다. 젖산과 피루브산은 함께 세포와 조직에 걸쳐 NADH/NAD 비율을 평형화하는 순환 산화환원 완충제 역할을 합니다. 한스 크리스티안 안데르센(Hans Christian Andersen)의 미운 오리 새끼가 실제로 아름다운 백조인 것과 유사하게, 젖산을 연료로 재개념화하는 것은 에너지 대사 분야를 재편할 가능성이 있습니다.

Carbohydrates account for approximately half the caloric intake in humans. Most are eaten as starch, which is broken down into glucose in the small intestinal lumen. Glucose is then absorbed into the portal circulation and passed to the liver. The liver takes up a portion of dietary glucose and stores it as glycogen for future release during fasting. The remainder is distributed throughout the body for use as fuel. Some of this glucose is converted into lactate, and glucose and lactate are the two most abundant circulating carbon carriers in mammals.

탄수화물은 인간의 열량 섭취량의 약 절반을 차지합니다. 대부분은 전분으로 섭취되며 소장 내강에서 포도당으로 분해됩니다. 그런 다음 포도당은 문맥 순환으로 흡수되어 간으로 전달됩니다. 간은 식이 포도당의 일부를 흡수하고 공복 중에 향후 방출을 위해 글리코겐으로 저장합니다. 나머지는 연료로 사용하기 위해 몸 전체에 분배됩니다. 이 포도당의 일부는 젖산으로 전환되고 포도당과 젖산은 포유류에서 가장 풍부한 순환 탄소 운반체입니다.

The classic view: glucose as fuel, lactate as waste

Energy can be derived from glucose through two processes: fermentation and respiration. Both begin with catabolism of glucose via glycolysis into two molecules of pyruvate, with associated production of two ATP and two NADH molecules. The NADH is made at the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) step in the middle of glycolysis. During fermentation, the NADH is used to reduce pyruvate to lactate, which is then excreted. This process results in a net yield of two ATP and two lactate molecules per glucose, without consuming any oxygen.

In respiration, the NADH electrons and pyruvate generated by glycolysis are shuttled into the mitochondria, where they are consumed and subsequently produce copious usable energy (approximately 25 ATP molecules per glucose).

에너지는 발효와 호흡의 두 가지 과정을 통해 포도당에서 파생될 수 있습니다. 둘 다 2개의 ATP 및 2개의 NADH 분자의 관련 생산과 함께 2개의 피루브산 분자로의 해당과정을 통한 글루코스의 이화작용으로 시작합니다. NADH는 해당과정의 중간에 있는 GAPDH(glyceraldehyde-3-phosphate dehydrogenase) 단계에서 만들어집니다. 발효 과정에서 NADH는 피루브산을 젖산으로 환원시키는 데 사용되며, 이는 이후 배설됩니다. 이 과정은 산소를 소비하지 않고 포도당 당 2개의 ATP와 2개의 젖산 분자의 순 수율을 초래합니다. 

호흡에서 해당과정에 의해 생성된 NADH 전자와 피루브산은 미토콘드리아로 이동하여 미토콘드리아에서 소비되고 이어서 사용 가능한 풍부한 에너지(포도당 약 25개 ATP 분자)를 생성합니다.

The ability to ferment glucose into lactate reflects that two lactic acid molecules contain the same atoms as one glucose molecule (Fig. 1a). Thus, although the chemical bonds are rearranged, lactic acid is half of glucose.

포도당을 젖산으로 발효시키는 능력은 두 개의 젖산 분자가 하나의 포도당 분자와 동일한 원자를 포함하고 있음을 반영합니다(그림 1a). 따라서 화학 결합이 재배열되더라도 젖산은 포도당의 절반입니다.

Fig. 1 ∣

Lactate—waste and fuel.

a, Lactate is half of glucose, whereas pyruvate is more oxidized.

b, Lactate as waste. Glycolytic flux from glucose to pyruvate generates NADH from NAD at the GAPDH reaction. NADH’s electrons can be transported into mitochondria via the malate–aspartate or glycerol phosphate shuttles, regenerating cytosolic NAD. Alternatively, NADH can be used by LDH to reduce pyruvate to lactate, which is secreted as waste. 

c, Lactate as fuel. The reactions are the same, but the direction of LDH flux is reversed. The resulting extra NADH electrons are transported into mitochondria. GAP, glyceraldehyde 3-phosphate.

Pyruvate, in contrast, is more oxidized than either glucose or lactate. Specifically, each lactate molecule carries two more hydrogen atoms than pyruvate. These two hydrogen atoms consist of two protons and two electrons. To convert either glucose or lactate into pyruvate, these electrons must be disposed of, in a process that requires transporting the electrons, which are stored in NADH, into mitochondria. Although direct lactate import into the mitochondrial matrix is a possibility1, there are two better-established routes to transport the electrons: the malate–aspartate and glycerol phosphate shuttles2-4 (Fig. 1b).

When oxygen is available, NADH’s electrons can be quickly used by the electron-transport chain in the mitochondria, thereby yielding valuable energy. When oxygen is not available, however, mitochondria can no longer effectively clear electrons. Thus, under anaerobic conditions, fermentation is the only metabolic option. Even when oxygen is available, ATP production by oxidative phosphorylation can be limited by the oxygen uptake rate. Thus, under high-demand conditions, such as intense exercise, fermentation provides a way to accelerate energy generation. Accordingly, when muscle is pushed beyond the aerobic threshold, such as during a short sprint or toward the end of a long hard run, lactate is released as metabolic waste5 (Fig. 1b).

산소를 이용할 수 있을 때 NADH의 전자는 미토콘드리아의 전자 수송 사슬에서 빠르게 사용되어 귀중한 에너지를 생산할 수 있습니다. 그러나 산소를 사용할 수 없을 때 미토콘드리아는 더 이상 효과적으로 전자를 제거할 수 없습니다. 따라서 혐기성 조건에서 발효는 유일한 대사 옵션입니다. 산소를 이용할 수 있는 경우에도 산화적 인산화에 의한 ATP 생산은 산소 흡수율에 의해 제한될 수 있습니다. 따라서 격렬한 운동과 같은 수요가 많은 조건에서 발효는 에너지 생성을 가속화하는 방법을 제공합니다. 따라서 짧은 스프린트나 길고 힘든 달리기가 끝날 때와 같이 근육이 유산소 역치를 넘어서면 젖산이 대사 폐기물로 방출됩니다(그림 1b).

Lactate excretion by cultured cells

Lactate production does not occur in only oxygen-limited muscle. Most cultured mammalian cells produce copious lactate even when oxygen is abundant. Such aerobic glycolysis was initially noted by Warburg nearly a century ago, and rapid lactate production was the first molecular phenotype associated with cancer6. This observation led to the hypothesis that cancer is a disease of defective mitochondria7. But although mitochondrial defects occasionally occur in cancer, they are not a major cause8-10. Instead, fermentation is a common feature of mammalian cells in culture, including non-cancerous cells, such as proliferating T cells and even non-growing cells, such as quiescent fibroblasts11,12.

The reasons why cultured cells avidly ferment glucose remain incompletely understood, but media formulation plays a role. Classical tissue medium contains serum growth factors, supraphysiologic glucose and no lactate13. In such conditions, glucose is the only available carbohydrate fuel. Moreover, both glucose availability and lactate secretion are unconstrained, and glucose is refreshed and lactate is removed every time the culture medium is changed. These factors, together with growth-factor signals that trigger glucose uptake14, favour avid glucose fermentation. The release of lactate by both cells in vitro and stressed muscle in vivo supports the paradigm of glucose as fuel and lactate as waste.

An emerging possibility: glucose as specific fuel, lactate as universal fuel

Mammals evolved under different metabolic pressures from cells in culture, including a frequent risk of starvation. Because lactate is energy rich, mammals do not excrete it. Indeed, CO2 is the only carbonaceous waste that we excrete in substantial quantities. The full oxidation of dietary carbon to CO2 maximizes the extraction of usable energy from food.

How is this achieved?

The two most abundant circulating carbon metabolites are glucose (5 mM) and lactate (1 mM). Glucose and lactate can be interconverted by the processes of glycolysis and gluconeogenesis. One logical way to coordinate these processes is as follows: (1) most cells extract energy from carbohydrate by taking up glucose and fully oxidizing it to CO2; (2) cells facing particularly urgent energy needs take up extra glucose and release some lactate as waste—in addition, as shown by Gerty and Cori, fasting muscle releases glycogen stores as lactate15; and (3) the liver ‘cleans up’ this lactate, reconverting it to glucose. In this scenario, lactate is valuable only as a substrate for generating glucose.

The above strategy yields clear expectations regarding mammalian metabolic flux: tissue glucose consumption should far exceed lactate consumption, and the whole-body lactate production rate should approximately equal the lactate use by the liver and kidneys to support gluconeogenesis.

The relevant metabolic fluxes can be measured from two perspectives: arterial–venous differences in metabolite concentration and isotope tracing. Differences in arterial–venous metabolite concentrations reveal the net production or consumption of a metabolite across a vascular bed. In some cases, such as the renal artery and vein, the vascular bed aligns relatively neatly with a single organ (the kidney). In other cases, such as the femoral artery and vein, the vascular bed drains multiple tissue types (skin, adipose, bone and various types of muscle) whose activities may offset one another. With this caveat, such measurements generally conform to the above expectations regarding metabolic flux16,17.

Isotope-tracing measurements, however, paint a different picture. At pseudo–steady state, the total flux of a metabolite from tissues into the bloodstream is balanced with the total tissue consumption of the metabolite, thereby defining the metabolite’s ‘circulatory turnover flux’. For non-perturbative isotope infusions, circulatory turnover flux is synonymous with the ‘rate of appearance’, ‘rate of disappearance’ and, in the fasted state, the ‘endogenous production rate’. It can be measured by infusing an isotope-labelled metabolite and monitoring its dilution by endogenous production and the diet. Such measurements have commonly been made since the 1970s (refs. 18-21). The fasted circulatory turnover flux of lactate has consistently been shown, in both rodents and humans, to be approximately twice that of glucose on a molar basis, and thus is equivalent on a carbon-atom basis (because two lactates are equal to one glucose). The straightforward interpretation of these measurements is that pyruvate generated by glycolysis rarely flows within a cell directly into the tricarboxylic acid (TCA) cycle but instead is converted to lactate and released into the bloodstream. This process requires lactate dehydrogenase (LDH) and monocarboxylic transporter (MCT) activity.

Rapid production of circulating lactate must be offset by comparably rapid consumption (Fig. 1c). Recent work has examined the fate of infused 13C-labelled lactate, finding that it is a major fuel in the TCA cycle. Specifically, [13C]lactate labels TCA intermediates in every tissue of the body, even in tumors22,23. With the exception of the brain, tissue TCA labelling from lactate is typically greater than that from infused [13C]glucose.

A challenge in interpreting these isotope-tracer studies is that lactate can be converted into glucose, and glucose can be converted into lactate. Thus, infusion of either metabolite also labels the other. The relative contributions of circulating glucose and lactate to tissue TCA-cycle metabolism can be deconvoluted mathematically. Such analysis has shown that, in agreement with textbook knowledge, the brain directly oxidizes glucose as its primary fuel. Especially in the fasted state, however, the main route through which glucose labels the TCA cycle in the other major organs is via circulating lactate22.

How can these observations be reconciled with the arterial–venous measurements, which show modest net lactate consumption or production across most vascular beds? One possibility is that tissue pyruvate is rapidly exchanged for circulating lactate, but with only modest net flux of three-carbon (3C) units. This possibility is biochemically reasonable, because MCTs exchange one carboxylic acid for another more rapidly than they catalyse net excretion or uptake24

The more radical possibility is that, at the cellular level, glucose uptake may be dissociated from carbohydrate burning, and lactate may serve as a universal carbohydrate fuel.

Uncoupling of glycolysis and TCA

In the absence of lactate, glycolysis must operate in lockstep with the TCA cycle, such that every glycolysis-produced NADH and pyruvate is cleared by mitochondrial metabolism. Correspondingly, cells would need to break down glucose via glycolysis to generate energy from carbohydrate. Lactate’s fundamental role is to uncouple these pathways25 (Fig. 2). Interestingly, pancreatic alpha and beta cells, whose function is to secrete glucagon and insulin in response to circulating glucose levels, lack MCTs and therefore have tight glycolysis–TCA coupling26,27. Most mammalian cells, however, express both LDH and MCTs and therefore can independently run glycolysis and the TCA cycle.

Fig. 2 ∣

Redox buffering by circulating lactate and pyruvate.

a, Traditional perspective. Glycolytic flux exceeds pyruvate and lactate exchange between the cell and the circulation. Intracellular metabolic reactions (glycolytic flux and transport of NADH’s electrons into mitochondria) determine the cellular NADH/NAD ratio and thereby the cellular lactate/pyruvate ratio. b, Redox buffering perspective. Exchange in pyruvate and lactate between cells and the circulation is more rapid than glycolysis. These MCT-catalysed exchange reactions determine the cellular lactate/pyruvate ratio and thereby the cellular NADH/NAD ratio. In cases in which excessive NADH begins to build up, net uptake of pyruvate and excretion of lactate alleviates the redox imbalance. GLUT, glucose transporter.

How extensive is such uncoupling? Given the modest net lactate exchange across major vascular beds, this depends on the extent of lactate by exchange within vascular beds. Such exchange might occur between different tissues sharing the same vascular supply or between cell types within a tissue. For example, in the kidney, lactate uptake by the gluconeogenic cortex may be offset by lactate production by the glycolytic medulla28. Or, within the leg, a subset of highly glycolytic cells might rapidly ferment circulating glucose to circulating lactate, while other cells consume circulating lactate as their carbohydrate fuel. For example, adipocytes have been suggested to be highly glycolytic and to secrete copious lactate29-33.

In agreement with glucose use being relatively restricted, fluorodeoxyglucose positron emission tomography (PET) imaging studies show intense glucose uptake in the brain, tumours and areas of inflammation, but little uptake in many other parts of the body34. Although this finding partially reflects PET imaging studies being conducted in fasted resting individuals, the PET data align with glucose-transporter expression‎, which is strongest in the brain and activated immune cells.

In contrast to the restricted expression‎ of glucose transporters, which renders glucose uptake a key gating step in metabolism, the nearly universal expression‎ of MCTs makes lactate freely available to all cells of the body.

Use of lactate as the primary circulating carbohydrate energy source advantageously reserves glucose for particularly vital systems (such as the brain and immune system) and for biochemical functions that cannot be readily achieved by using other substrates (glycogen storage, glycosylation, NADPH and ribose generation by the pentose-phosphate pathway). By dissociating these processes from the housekeeping function of aerobic ATP generation from carbohydrate, glucose use can be regulated in tune with more advanced organismal needs. For example, in lymphocytes, glucose entry is coordinately regulated with activation and proliferation. Exclusion of glucose in the quiescent state may help prevent autoimmunity and cancer35.

In contrast, lactate rapidly exchanges throughout the body. This advantagenously tends to minimize local lactate build-up. When lactate does accumulate, this accumulation often reflects underlying pathology, such as acute inflammation or inadequate perfusion36,37. Such accumulation can be read out to drive proper physiological responses, such as inflammation resolution through favouring the development of regulatory T cells38, a propensity that can backfire in the case of cancer by suppressing anticancer immune responses39.

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Redox robustness

Both lactate and pyruvate circulate, and lactate is approximately 20 times more abundant in the bloodstream. MCTs can transport both lactate and pyruvate, and one can be exchanged for the other. Once inside cells, pyruvate and lactate are rapidly interconverted via the action of LDH. The direction of net LDH flux depends on the reaction quotient (Q) relative to the equilibrium constant (Keq) of LDH, as shown in the following equation:

Q=[lactate][NAD]∕[pyruvate][NADH]

with square brackets indicating concentration, and Q > Keq implying lactate consumption. Both lactate consumption and glycolysis require NAD as a substrate. Because GAPDH’s Michaelis constant for NAD is lower than LDH’s, glycolysis has priority for NAD40,41.

On the basis of the LDH reaction approaching equilibrium, the cellular lactate-to-pyruvate ratio has often been used as a proxy for the cytosolic NADH-to-NAD ratio42-44. If most cytosolic NADH, pyruvate and lactate were from glycolysis, then intracellular metabolic reactions would indeed control, via NADH, the balance between cellular lactate and pyruvate (Fig. 2a). Given the rapidity of the pyruvate–lactate exchange between cells and the circulation, however, causality may flow in the other direction. Specifically, the abundance of lactate and pyruvate in the circulation may determine their intracellular concentrations, which in turn may determine the cellular NADH-to-NAD ratio. In this case, the MCT–LDH reaction sequence would function to align every cell’s cytosolic NAD-to-NADH ratio to the systemic pyruvate-to-lactate ratio, thus effectively buffering NAD and NADH in each cell against the whole-body pyruvate–lactate pool (Fig. 2b).

Similar redox equilibration can also occur across compartments of a cell. Mitochondria are notable for lacking MCT transporters on their inner membranes, thereby excluding lactate, and instead using mitochondrial pyruvate carriers to import pyruvate. However, peroxisomes express MCT2, which may buffer their NAD and NADH pools with the cytosol45.

Redox buffering is based on cells (or compartments) with excess NADH taking in pyruvate and excreting lactate (Fig. 2b). Importantly, whereas glycolysis terminating in lactate is redox neutral, uptake of pyruvate and excretion of lactate results in a net dumping of electrons. Physiologically, the kidneys clear lactate electrons, releasing pyruvate and thereby helping to maintain an appropriately oxidized circulating lactate-to-pyruvate ratio17.

Direct support for the ability of circulating pyruvate and lactate to control tissue NADH-to-NAD ratio comes from the Mootha laboratory, which has recently developed an engineered enzyme that uses molecular oxygen to irreversibly convert circulating lactate to pyruvate. Administration of this enzyme to mice with lactate and NADH build-up due to genetic mitochondrial deficiency resulted, as desired, in a more oxidized circulating lactate-to-pyruvate ratio. Importantly, although the enzyme was localized to the bloodstream, both the brain and heart showed a decreased NADH-to-NAD ratio46. Thus, lactate–pyruvate exchange renders tissue redox maintenance robust by equilibrating redox status across the organism.

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Regulation of lactate homeostasis

Compared with some other important fuel molecules such as fatty acids, lactate is notable for tight homeostasis of its serum concentrations, and elevated serum lactate is a serious medical condition known as lactic acidosis. How are circulating lactate levels regulated? Lactate’s entry and exit from cells are governed by MCTs 1–4 (Slc16a1, Slc16a7, Slc16a3 and Slc16a4). Both the expression‎ and activity of these proteins can potentially be regulated to control lactate localization in the body. MCT flux, however, is fast, and therefore lactate is typically well mixed between tissues and the circulation. Accordingly, regulation of lactate concentration occurs substantially at the level of the whole-body lactate pool. Because lactate is always much more abundant in the circulation than pyruvate, lactate homeostasis depends on controlling the total pool size of these 3C carboxylic acids.

To maintain tight concentration homeostasis, overall production and consumption of lactate must be synchronized. The main route of 3C-compound production is glycolysis. The major consumption route is via the TCA cycle. Thus, whereas lactate decouples glycolysis and the TCA cycle at the cellular level, glycolysis and the TCA cycle must be balanced at the whole-body level (Fig. 3). TCA entry via pyruvate carboxylase generates a four-carbon compound, which can be reconverted into 3C compounds via malic enzyme or phosphoenolpyruvate carboxykinase47. In contrast, TCA entry via PDH generates a two-carbon unit in the form of acetyl-CoA, which in mammals cannot be reconverted into 3C units (Fig. 4). Thus, the PDH reaction irreversibly clears lactate. Therefore, the whole-body balance between glycolysis and PDH flux is likely to be the key determinant of lactate levels.

Fig. 3 ∣

Whole-body lactate homeostasis.

At the tissue level, lactate exchange with the circulation allows for independent operation of glycolysis and the TCA cycle. At the organismal level, however, lactate production (largely via glycolysis) and consumption (largely via the TCA cycle) must balance to maintain lactate homeostasis. Some tissues, such as kidney and muscle, both produce and consume circulating lactate.

Fig. 4 ∣

Production and consumption of 3C units.

At the organismal level, 3C-unit production (largely via glycolysis) and consumption (largely via PDH) must balance to maintain lactate homeostasis. Bidirectional connections indicate that the metabolites can interconvert (typically with energy input, for example, via glycolysis or gluconeogenesis).

PDH is a multimeric enzyme whose catalytic activity is regulated by the phosphorylation status of the E1a subunit and by NADH48,49. High phosphorylation, mediated by pyruvate dehydrogenase kinases (PDK 1–4), impairs mitochondrial pyruvate clearance and thereby promotes cellular lactate excretion and systemic 3C-compound accumulation. NADH activates PDK and thereby inhibits PDH, thus contributing to the elevated circulating lactate in patients with impaired mitochondrial activity or respiration.

Future perspectives

Given that 3C compounds are mainly produced by glycolysis (Fig. 4), mechanisms of lactate homeostasis may substantially overlap with those for glucose homeostasis. In insulin resistance, circulating lactate may play a critical role as an energy substrate in cells that are carbon limited because of deficient insulin-mediated glucose uptake. Whether interindividual differences in lactate handling contribute to diabetes pathogenesis or robustness to diabetic complications is an important topic for future study.

Control of lactate clearance ties into the well-studied regulatory biology of PDK. Despite PDK’s importance, manifested by the existence of four different kinase isozymes, its physiological purpose remains unclear. One likely role is redox homeostasis, promoting lactate export instead of catabolism when NADH builds up. Another possibility is that, during starvation, PDK serves to shut off PDH to preserve 3C units50. Conversion of these 3C units into glucose would then preserve the availability of glucose for the brain and immune system.

Given the particularly tight control of circulating lactate levels, a novel regulatory system for lactate homeostasis is likely to exist. Lactate can potentially be cleared by urinary excretion in addition to PDH. Renal lactate loss is typically prevented by urinary reabsorption via the sodium/lactate co-transporters Slc5a12 and Slc5A8 (ref. 51). Whether these enzymes are sometimes downregulated to release lactate is unclear. Circulating lactate can also enter the faeces and thereby feed the microbiome52. A quantitative understanding of the importance and regulation of microbiome-mediated lactate clearance merits further investigation.

Major metabolic enzymes and transporters, including glycolytic enzymes, MCTs, LDH, mitochondrial pyruvate carriers and PDH, are also potential targets for novel regulatory circuits controlling lactate homeostasis. Such circuits would presumably involve lactate sensors such as G-protein-coupled receptor 81 (ref. 53). Given the role of lactate as a universal fuel, the elucidation of such a system— for ensuring a beautiful but not overcrowded ‘pool of swans’—has the potential to reshape understanding of mammalian metabolism and disease treatment.

Acknowledgements

S.E. is supported by the Swedish Research Council (2019-00773, 2018-02537), The Knut and Alice Wallenberg Foundation, Sahlgrenska’s University Hospital (LUA-ALF) and Novo Nordisk Foundation. J.D.R. is supported by NIH Pioneer award 1DP1DK113643, Diabetes Research Center grant P30 DK019525 and Pfizer, Inc.

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Footnotes

Competing interests

J.D.R. is a cofounder and stockholder in VL54 and Raze Therapeutics, and an advisor and stockholder in Agios Pharmaceuticals, Kadmon Pharmaceuticals, Bantam Pharmaceuticals, Colorado Research Partners, Rafael Pharmaceuticals and L.E.A.F. Pharmaceuticals. S.E. declares no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations

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