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Cited by 535Cancer, Hypoxia, and MetabolismMitochondrial Function and PathologyBiochemical Acid Research Studies

Regulation and function of the mammalian tricarboxylic acid cycle

Open access
Arnold, Paige K., Finley, Lydia W.S.·2023·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2022.102838PMC PMC9871338
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Abstract

The tricarboxylic acid (TCA) cycle, otherwise known as the Krebs cycle, is a central metabolic pathway that performs the essential function of oxidizing nutrients to support cellular bioenergetics. More recently, it has become evident that TCA cycle behavior is dynamic, and products of the TCA cycle can be co-opted in cancer and other pathologic states. In this review, we revisit the TCA cycle, including its potential origins and the history of its discovery. We provide a detailed accounting of the requirements for sustained TCA cycle function and the critical regulatory nodes that can stimulate or constrain TCA cycle activity. We also discuss recent advances in our understanding of the flexibility of TCA cycle wiring and the increasingly appreciated heterogeneity in TCA cycle activity exhibited by mammalian cells. Deeper insight into how the TCA cycle can be differentially regulated and, consequently, configured in different contexts will shed light on how this pathway is primed to meet the requirements of distinct mammalian cell states.

AI snapshot

Written from the paper’s full text.

TL;DR

This review revisits the mammalian tricarboxylic acid (TCA) cycle, covering its evolutionary origins, historical discovery, biochemical wiring, regulation, and context-dependent heterogeneity. It argues that TCA cycle activity is dynamic and can be rewired or co-opted in cancer, immune cells, stem cells, and other mammalian cell states.

Key findings

  • Each complete turn of the TCA cycle oxidizes acetyl-CoA, releases two CO2 molecules, generates three NADH and one FADH2, and produces one GTP or ATP; oxaloacetate (OAA) is regenerated and acts catalytically. The cycle is amphibolic, supporting both catabolism and biosynthesis.
  • Sustained TCA cycle function requires continuous acetyl-CoA supply and anaplerosis to replace intermediates lost through cataplerosis. Acetyl-CoA sources include glucose/pyruvate, circulating lactate, fatty acids, amino acids, ketone bodies, and acetate; anaplerotic routes include glutamine oxidation, pyruvate carboxylase, propionyl-CoA/succinyl-CoA, and fumarate entry.
  • TCA cycle wiring is flexible: reductive carboxylation occurs under hypoxia or impaired respiration; reverse SDH reduces fumarate to succinate when ETC is inhibited; reverse citrate synthase can occur in SDH deficiency; and the citrate–malate shuttle can act as a noncanonical TCA cycle in cancer cells and embryonic stem cells.
  • Regulation occurs through allosteric control (NADH inhibits CS, IDH, and OGDH; ATP/ADP inhibits IDH; succinyl-CoA inhibits CS and OGDH; OAA inhibits SDH), covalent PDHC phosphorylation by PDKs/PDPs, and ion-mediated control (Ca2+ activates IDH, OGDH, and PDHC; iron affects aconitase). TCA metabolites also influence chromatin and cell fate, with oncometabolites succinate, fumarate, and 2HG inhibiting αKG-dependent dioxygenases. Reported examples include branched-chain amino acid catabolism accounting for almost a third of cellular acetyl-CoA pools in differentiated adipocytes, up to half of intramitochondrial acetyl-CoA derived from circulating acetate in glioblastoma tumors, and 2HG accumulating to millimolar levels in CD8+ T cells.

Methods

  • Narrative review; no primary experimental data are presented.
  • Synthesizes historical and recent literature on TCA cycle evolution, discovery, wiring, regulation, and heterogeneity across mammalian cell types and disease contexts.
  • Main analysis is conceptual and integrative, with figures summarizing the oxidative TCA cycle, reductive TCA cycle, inputs/outputs, electron shuttles, PDHC regulation, and chromatin regulation.

Limitations

  • The paper does not include a formal limitations section. It states many open questions and future directions, including how TCA cycle diversity is achieved, the extent to which cells transit between metabolic states, how intermediates are partitioned across compartments, what signals control anaplerotic fluxes, and whether core TCA cycle enzymes are regulated by phosphorylation.
  • Evident from the text: as a narrative review, it lacks systematic search criteria or quantitative synthesis, so its conclusions depend on the selected cited literature.
  • The authors declare a conflict of interest: they are authors on patent applications covering links between cellular metabolism and cell fate control.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jbc.2022.102838

Cites

213 of 214 references verified1 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 205 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Electron funneling through the ETC is coupled to generation of the mitochondrial membrane potential used to power ATP production via OXPHOS, with oxygen as terminal electron acceptor.

    “Electron funneling through the complexes of the ETC is coupled to generation of the mitochondrial membrane potential that is ultimately used to power the production of the cellular currency (ATP) in a process known as oxidative phosphorylation (OXPHOS), as oxygen serves as the terminal acceptor for electrons that transit through the ETC (Fig. 1) (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Ryan, 2020, Krebs cycle Reborn in macrophage immunometabolism, Annu. Rev. Immunol. source

      Not checked in the free run.

  • Interpretationreasoning

    These observations support the notion that the TCA cycle plays a significant role in sustaining mammalian tissue function.

    “These observations support the notion that the TCA cycle plays a significant role in sustaining mammalian tissue function.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In 1937, Hans Krebs showed that succinate could be synthesized by animal tissues in the presence of pyruvate.

    “In 1937, Hans Krebs (1, 32) showed that succinate could be synthesized by animal tissues in the presence of pyruvate, leading him to speculate that succinate may arise from citrate oxidation downstream of pyruvate.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Krebs, 1937, Metabolism of ketonic acids in animal tissues, Biochem. J. source

      Not checked in the free run.

    • cites [32] Kornberg, 2000, Krebs and his trinity of cycles, Nat. Rev. Mol. Cell Biol. source

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  • Premisecitation

    Several chemical intermediates of the TCA cycle serve as critical precursors for biosynthetic reactions.

    “However, several chemical intermediates of the TCA cycle also serve as critical precursors for biosynthetic reactions, which we will discuss in detail later (5, 6).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Inigo, 2021, Ins and outs of the TCA cycle: the central role of anaplerosis, Annu. Rev. Nutr. source

      Not checked in the free run.

    • cites [6] Pavlova, 2022, The hallmarks of cancer metabolism: still emerging, Cell Metab. source

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  • Premisecitation

    Stare and Baumann found that very small quantities of dicarboxylic acids were sufficient to cause an increase in oxygen consumption beyond what was necessary for oxidation of the quantities of substrate added.

    “Support for this idea came the following year when Stare (33) and Baumann found that very small quantities of dicarboxylic acids were sufficient to cause an increase in oxygen consumption and that this increase was beyond what was necessary for the oxidation of the quantities of substrate added.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Stare, 1936, The effect of fumarate on the respiration of liver and kidney tissue, Biochem. J. source

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  • Classified as probably not a substantial claim. 15
  • May combine two claims. 73

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Demonstration of the C-C bond forming reactions of the rTCA cycle has yet to be achieved efficiently and nonenzymatically under experimental conditions, raising the possibility that this portion of the pathway required organic catalysts and emerged later.

    “However, demonstration of the C-C bond forming reactions of the rTCA cycle has yet to be achieved efficiently and nonenzymatically under experimental conditions, raising the possibility that this portion of the pathway required organic catalysts and, thus, emerged later (21, 22).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Muchowska, 2020, Nonenzymatic metabolic reactions and life's origins, Chem. Rev. source

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    • cites [22] Yadav, 2022, Cyanide as a primordial reductant enables a protometabolic reductive glyoxylate pathway, Nat. Chem. source

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  • May combine two claims.

    Interpretationcitation

    These findings strengthen the notion that the rTCA cycle may represent both a vestige of prebiotic metabolism and an evolutionary precursor for the oxidative TCA cycle.

    “These findings strengthen the notion that the rTCA cycle may represent both a vestige of prebiotic metabolism and an evolutionary precursor for the oxidative TCA cycle (18, 27).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Buchanan, 1990, A reverse KREBS cycle in photosynthesis: consensus at last, Photosynth Res. source

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    • cites [27] Baldwin, 1981, The evolution of metabolic cycles, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxygenation of Earth's atmosphere increased availability of molecular oxygen, whose function as an electron acceptor facilitates oxidation of organic molecules derived from carbon assimilation.

    “The oxygenation of Earth’s atmosphere over time increased the availability of molecular oxygen, whose function as an electron acceptor facilitates oxidation of organic molecules derived from carbon assimilation (21, 28).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Muchowska, 2020, Nonenzymatic metabolic reactions and life's origins, Chem. Rev. source

      Not checked in the free run.

    • cites [28] Thannickal, 2009, Oxygen in the evolution of complex life and the price we pay, Am. J. Respir. Cell Mol. Biol. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Martius and Knoop found that αKG is a product of citrate oxidation and worked out the sequence of reactions from citrate to succinate.

    “A key finding in that same year came from Martius and Knoop (34), who found that αKG is a product of citrate oxidation and worked out the sequence of reactions from citrate to succinate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Martius, 1937, Physiological breakdown of citric acid, Prelim. Z. Physiol. Chem.

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The central function of the TCA cycle is to convert fuel sources into energy, and it is generally considered a catabolic process.

    “In this configuration, the central function of the TCA cycle is to convert fuel sources into energy, and therefore, the TCA cycle is generally considered a catabolic process.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The TCA cycle itself neither consumes molecular oxygen nor produces meaningful amounts of ATP; it removes electrons from inputs and transfers them to electron carriers that deposit electrons onto the ETC.

    “The TCA cycle itself neither consumes molecular oxygen nor produces meaningful amounts of ATP; rather, the TCA cycle removes electrons (reducing equivalents) from inputs (e.g., acetyl-CoA) and transfers them to electron carriers that deposit their electrons onto the electron transport chain (ETC).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Ryan, 2020, Krebs cycle Reborn in macrophage immunometabolism, Annu. Rev. Immunol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The TCA cycle is a broadly conserved metabolic pathway that harnesses high-energy electrons from fuel sources.

    “At the nexus of both catabolic and anabolic metabolism lies the tricarboxylic acid (TCA) cycle, a broadly conserved metabolic pathway consisting of a cyclic series of chemical reactions that harness high-energy electrons from fuel sources (1, 2, 3).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Krebs, 1937, Metabolism of ketonic acids in animal tissues, Biochem. J. source

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    • cites [2] Krebs, 1980, The role of citric acid in intermediate metabolism in animal tissues, FEBS Lett. source

      Not checked in the free run.

    • cites [3] Ryan, 2020, Krebs cycle Reborn in macrophage immunometabolism, Annu. Rev. Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stare and Baumann also found that added dicarboxylic acids were not used up and could still be detected in the medium, indicating they functioned catalytically.

    “Significantly, they also found that added dicarboxylic acids were not used up and could still be detected in the medium, indicating that these compounds were functioning in a catalytic capacity (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Stare, 1936, The effect of fumarate on the respiration of liver and kidney tissue, Biochem. J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 1935, Szent-Györgyi worked out the sequence of reactions from succinate to fumarate to malate to OAA and demonstrated rapid oxidation of these substances by pigeon muscle suspensions.

    “In 1935, Szent-Györgyi worked out the sequence of reactions from succinate to fumarate to malate to OAA and demonstrated the rapid oxidation of these substances by pigeon muscle suspensions (31, 32).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Annau, 1935, Über die Bedeutung der Fumarsäure für die tierische Gewebsatmung, Biol. Chem.

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    • cites [32] Kornberg, 2000, Krebs and his trinity of cycles, Nat. Rev. Mol. Cell Biol. source

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    Interpretationcitation

    Being able to fine-tune the function of metabolic pathways like the TCA cycle-in particular, to toggle between catabolic and anabolic activity-set the stage for early unicellular life forms to evolve into multicellular organisms.

    “Being able to fine-tune the function of metabolic pathways like the TCA cycle—in particular, to toggle between catabolic and anabolic activity—set the stage for early unicellular life forms to evolve into multicellular organisms, which require coordination of metabolic activity beyond that dictated by local nutrient availability (29, 30).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Fani, 2009, Origin and evolution of metabolic pathways, Phys. Life Rev. source

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    • cites [30] Intlekofer, 2019, Metabolic signatures of cancer cells and stem cells, Nat. Metab. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Given that prebiotic chemistry would have initially required production, not breakdown, of organic molecules, primordial metabolism likely centered on reductive CO2-fixing pathways.

    “However, given that prebiotic chemistry would necessarily have initially required the production, not the breakdown, of organic molecules, primordial metabolism likely centered on reductive CO2-fixing pathways.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    Because the TCA cycle functions in both catabolic and anabolic capacities, it is considered an amphibolic pathway.

    “Because the TCA cycle functions in both catabolic and anabolic capacities, it is considered an amphibolic pathway (7, 8).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Kornberg, 1965, Anaplerotic sequences in microbial metabolism, Angew. Chem. Int. Ed. Engl. source

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    • cites [8] Kornberg, 1966, Anapleroic sequences and their role in metabolism, Essays Biochem.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Krebs and Johnson discovered that citrate was readily oxidized by minced pigeon breast muscle and that citrate addition increased oxygen uptake beyond the amount necessary for complete oxidation of added citrate.

    “These crucial experiments teed up the findings of Hans Krebs and his colleague William Johnson (2) in Enzymologia in 1937, in which they discovered that citrate was readily oxidized by minced pigeon breast muscle and that citrate addition increased oxygen uptake beyond the amount necessary for the complete oxidation of the added citrate, indicating that citrate itself was stimulating consumption”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Krebs, 1980, The role of citric acid in intermediate metabolism in animal tissues, FEBS Lett. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This development likely enabled the emergence of the oxidative TCA cycle and its coupling with OXPHOS, allowing transfer of electrons from breakdown of carbon substrates onto molecular oxygen.

    “This development likely enabled the emergence of the oxidative TCA cycle and its coupling with OXPHOS, allowing the transfer of electrons derived from the breakdown of carbon substrates onto molecular oxygen.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cells addicted to glutamine become dependent on PC for growth when glutamine metabolism is suppressed; conversely, cells with high basal PC activity are generally more resistant to interruption of glutamine metabolism.

    “Likewise, cells that are addicted to glutamine become dependent on PC for growth when glutamine metabolism is suppressed; conversely, cells with high basal PC activity are generally more resistant to interruption of glutamine metabolism (87).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Cheng, 2011, Pyruvate carboxylase is required for glutamine-independent growth of tumor cells, Proc. Natl. Acad. Sci. U. S. A. source

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  • May combine two claims.

    Premisecitation

    Krebs determined that the two carbon atoms that condensed with OAA to form citrate were derived from pyruvate and that oxygen consumption in muscle increases when pyruvate is added.

    “In subsequent work, Krebs (4) determined that the two carbon atoms that condensed with OAA to form citrate were derived from pyruvate and that oxygen consumption in muscle increases when pyruvate is added.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Krebs, 1940, The oxidation of pyruvate in pigeon breast muscle, Biochem. J. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PC provides a critical backup when glutamine is not available or when nutrient status is high.

    “Thus, while glutamine anaplerosis efficiently allows cells both to capture reducing equivalents from substrate oxidation and maintain OAA production, PC provides a critical backup when glutamine is not available or when nutrient status is so high that the ATP-dependent circumventing of the oxidative TCA cycle mediated by PC may actually help cells cope with nutrient overload.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Supraphysiologic propionate administration increases TCA cycle metabolite pools in the liver and induces hepatic gluconeogenesis.

    “Supraphysiologic propionate administration increases TCA cycle metabolite pools in the liver and induces hepatic gluconeogenesis (96), but the degree to which cells can activate propionyl-CoA catabolism to sustain anaplerotic flux under physiologic conditions remains largely unknown.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Perry, 2016, Propionate increases hepatic pyruvate cycling and anaplerosis and alters mitochondrial metabolism, J. Biol. Chem. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    One study found that LDH can localize to the mitochondria, raising the possibility that lactate can be directly imported into the mitochondria for further oxidation.

    “Suggestively, one study found that LDH can localize to the mitochondria, raising the possibility that lactate can be directly imported into the mitochondria for further oxidation (61).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Chen, 2016, Lactate metabolism is associated with mammalian mitochondria, Nat. Chem. Biol. source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Cataplerosis of any TCA cycle intermediate requires compensatory input to sustain TCA cycle activity, a process termed anaplerosis.

    “Cataplerosis of any TCA cycle intermediate requires compensatory input to sustain TCA cycle activity, a process termed “anaplerosis” (37).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Owen, 2002, The key role of anaplerosis and cataplerosis for citric acid cycle function, J. Biol. Chem. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Recent work has found that different tissues in the body have distinct fuel preferences, raising the possibility that the source of acetyl-CoA generation is dependent on cell type and cell state.

    “While the mechanisms dictating a cell’s preferred source of acetyl-CoA are not well understood, recent work has found that different tissues in the body have distinct fuel preferences (44), raising the possibility that the source of acetyl-CoA generation is dependent on cell type and cell state.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Jang, 2019, Metabolite exchange between mammalian organs quantified in pigs, Cell Metab. source

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  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    Mitochondrial import and catabolism of lactate would prevent the buildup of cytosolic NADH while allowing for the mitochondrial capture of both carbon and reducing equivalents.

    “Mitochondrial import and catabolism of lactate would prevent the buildup of cytosolic NADH while allowing for the mitochondrial capture of both carbon and reducing equivalents (61).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Chen, 2016, Lactate metabolism is associated with mammalian mitochondria, Nat. Chem. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cultured cells, pyruvate is largely produced from glucose via glycolysis; in vivo, circulating lactate provides an additional major source of tissue pyruvate.

    “In cultured cells, pyruvate is largely produced from glucose via glycolysis; in vivo, circulating lactate provides an additional major source of tissue pyruvate (46, 47, 48).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Faubert, 2017, Lactate metabolism in human lung tumors, Cell source

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    • cites [47] Hui, 2017, Glucose feeds the TCA cycle via circulating lactate, Nature source

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    • cites [48] Kennedy, 2013, Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer, PLoS One source

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  • May combine two claims.

    Interpretationreasoning

    GOT2-driven glutamate metabolism offers benefits to proliferating cells: it circumvents physiological limitations on glutamate catabolism, preserves the amine nitrogen of glutamate for aspartate synthesis, and reduces production of toxic ammonia.

    “GOT2-driven glutamate metabolism thus offers several benefits to proliferating cells: GOT2 circumvents physiological limitations on glutamate catabolism, preserves the amine nitrogen of glutamate for aspartate synthesis, and reduces production of toxic ammonia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In most tissues and some tumors, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, supporting the idea that lactate is a fundamental TCA cycle substrate in living organisms.

    “In most tissues and some tumors, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, supporting the idea that lactate is a fundamental TCA cycle substrate in living organisms (46, 47).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [46] Faubert, 2017, Lactate metabolism in human lung tumors, Cell source

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    • cites [47] Hui, 2017, Glucose feeds the TCA cycle via circulating lactate, Nature source

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  • May combine two claims.

    Premisecitation

    Sensing of free fatty acid availability within the cell primarily occurs through peroxisome proliferator-activated receptors, which function as fatty acid-activated transcription factors that drive the expression of CPT1.

    “Sensing of free fatty acid availability within the cell primarily occurs through peroxisome proliferator–activated receptors, which function as fatty acid–activated transcription factors that drive the expression of CPT1 (64, 65).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [64] Chatelain, 1996, Cyclic AMP and fatty acids increase carnitine palmitoyltransferase I gene transcription in cultured fetal rat hepatocytes, Eur. J. Biochem. source

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    • cites [65] Mascaro, 1998, Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor, J. Biol. Chem. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Distinct isoforms of ACSS localize specifically to the cytosol and mitochondria, but how conversion of acetate to acetyl-CoA is coordinated between these two compartments remains poorly understood.

    “Distinct isoforms of ACSS localize specifically to the cytosol and mitochondria, but how conversion of acetate to acetyl-CoA is coordinated between these two compartments remains poorly understood (71).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Schug, 2016, The metabolic fate of acetate in cancer, Nat. Rev. Cancer source

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  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Interpretationreasoning

    As glucose uptake and usage are under growth factor control, this observation raises the possibility that a basal level of TCA cycle oxidation in cells can persist independent of exogenous growth factor stimulation.

    “As glucose uptake and usage are under growth factor control (58, 59, 60), this observation raises the possibility that a basal level of TCA cycle oxidation in cells can persist independent of exogenous growth factor stimulation.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [58] Christofk, 2008, Pyruvate kinase M2 is a phosphotyrosine-binding protein, Nature source

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    • cites [59] Thompson, 2011, Rethinking the regulation of cellular metabolism, Cold Spring Harb. Symp. Quant. Biol. source

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    • cites [60] Vander Heiden, 2001, Growth factors can influence cell growth and survival through effects on glucose metabolism, Mol. Cell Biol. source

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  • May combine two claims.

    Premisecitation

    PC is essential for growth of SDH-mutant cells, which exhibit a truncated TCA cycle and require an alternative source of OAA.

    “PC is essential for growth of succinate dehydrogenase (SDH)–mutant cells, which exhibit a truncated TCA cycle and thus require an alternative source of OAA to support TCA cycle function and sustain aspartate production for anabolic pathways (91, 92).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Cardaci, 2015, Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis, Nat. Cell Biol. source

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    • cites [92] Lussey-Lepoutre, 2015, Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism, Nat. Commun. source

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  • May combine two claims.

    Premisecitation

    The PDHC is allosterically inhibited by NADH, acetyl-CoA, and ATP, making it a potent sensor of TCA cycle activity and a critical node of TCA cycle regulation.

    “The PDHC is allosterically inhibited by NADH, acetyl-CoA, and ATP, making it a potent sensor of TCA cycle activity and thus a critical node of TCA cycle regulation (discussed further) (52).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Behal, 1993, Regulation of the pyruvate dehydrogenase multienzyme complex, Annu. Rev. Nutr. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The TCA cycle functions as a critical biosynthetic hub and is coupled with cellular energy production via OXPHOS, so cells have evolved multiple nodes of TCA cycle regulation.

    “Because the TCA cycle functions as a critical biosynthetic hub and is coupled with cellular energy production via OXPHOS, cells have evolved multiple nodes of TCA cycle regulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The PDHC generates acetyl-CoA, the starting molecule of the TCA cycle, and functions as a gatekeeper of TCA cycle activity.

    “While not technically part of the TCA cycle, the PDHC generates the starting molecule of the cycle, acetyl-CoA, thereby functioning as a gatekeeper of TCA cycle activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Low oxygen levels activate HIFs, which bind hypoxia-response elements in target genes including LDHA and PDK1, leading to suppression of PDHC activity and increased aerobic glycolysis.

    “For example, low oxygen levels activate the hypoxia-inducible transcription factors (HIFs), which bind to hypoxia-response elements within a number of target genes including LDH-A (LDHA) and PDK1, leading to suppression of PDHC activity with a concomitant increase in aerobic glycolysis (141).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Kim, 2006, HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia, Cell Metab. source

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  • May combine two claims.

    Interpretationcitation

    Cell proliferation can be impaired when demand for mitochondrial NAD+ exceeds that of ATP, which may explain why highly proliferative cells often engage in aerobic glycolysis over pyruvate oxidation and OXPHOS even with sufficient oxygen.

    “These results indicate that cell proliferation can be impaired when the demand for mitochondrial NAD+ exceeds that of ATP and may explain why highly proliferative cells often engage in aerobic glycolysis over pyruvate oxidation and OXPHOS, even in the presence of sufficient oxygen (138).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Luengo, 2021, Increased demand for NAD(+) relative to ATP drives aerobic glycolysis, Mol. Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Krebs found that GDH operates at close to equilibrium in vitro, and some evidence indicates GDH may be reversible in some tissues in vivo.

    “Krebs found that GDH operates at close to equilibrium in vitro, and some evidence indicates that GDH may be reversible in some tissues in vivo (112, 126).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [112] Williamson, 1967, The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver, Biochem. J. source

      Not checked in the free run.

    • cites [126] Treberg, 2010, On the reversibility of glutamate dehydrogenase and the source of hyperammonemia in the hyperinsulinism/hyperammonemia syndrome, Adv. Enzyme Regul. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    TCA cycle function is not "one size fits all"; components of the pathway are differentially and flexibly engaged in a context-specific fashion.

    “However, it has become increasingly appreciated that TCA cycle function is not “one size fits all,” and that components of the pathway are differentially and flexibly engaged in a context-specific fashion.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Electron shuttles facilitate oxidation of cytosolic NADH, which is required to support continued glycolysis and de novo synthesis of serine and lipids.

    “Beyond supporting net NADH “import” into the mitochondria, these shuttles also facilitate the oxidation of cytosolic NADH, which is required to support continued glycolysis and the de novo synthesis of serine and lipids (101, 102, 103).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [101] Baksh, 2020, Extracellular serine controls epidermal stem cell fate and tumour initiation, Nat. Cell Biol. source

      Not checked in the free run.

    • cites [102] Diehl, 2019, Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation, Nat. Metab. source

      Not checked in the free run.

    • cites [103] Li, 2022, Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited, Nat. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The glycerol 3-phosphate shuttle is not considered the major route of NADH shuttling in most mammalian cells but is particularly active in brown adipose tissue and may be implicated in thermoregulation.

    “The glycerol 3-phosphate shuttle is not considered the major route of NADH shuttling in most mammalian cells but has been shown to be particularly active in brown adipose tissue and may be implicated in thermoregulation (105, 106, 107).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [105] Koza, 1996, Sequence and tissue-dependent RNA expression of mouse FAD-linked glycerol-3-phosphate dehydrogenase, Arch. Biochem. Biophys. source

      Not checked in the free run.

    • cites [106] Ohkawa, 1969, Unusually high mitochondrial alpha glycerophosphate dehydrogenase activity in rat brown adipose tissue, J. Cell Biol. source

      Not checked in the free run.

    • cites [107] Safer, 1971, Control of the transport of reducing equivalents across the mitochondrial membrane in perfused rat heart, J. Mol. Cell Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CS, IDH, and OGDH catalyze rate-controlling steps in the TCA cycle and are considered regulatory enzymes.

    “Three enzymes in particular—CS, IDH, and oxoglutarate dehydrogenase (OGDH)—catalyze rate-controlling steps in the TCA cycle and are considered regulatory enzymes within the pathway (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Chandel, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Four PDKs (PDK1-4) catalyze phosphorylation of the serine residues, each with different site specificities, and PDPs reverse this phosphorylation.

    “Four pyruvate dehydrogenase kinases (PDKs; PDK1–4) catalyze phosphorylation of the serine residues, each with different site specificities (139).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Korotchkina, 2001, Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    NADH is not efficiently transported across the inner mitochondrial membrane, necessitating electron shuttle pathways that transport reducing equivalents from the cytoplasm into the mitochondrial matrix for oxidation in the ETC.

    “Notably, while NAD+ itself can be imported into mitochondria through SLC25A51–MCART1 (98, 99, 100), NADH is not efficiently transported.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [98] Girardi, 2020, Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import, Nat. Commun. source

      Not checked in the free run.

    • cites [99] Kory, 2020, MCART1/SLC25A51 is required for mitochondrial NAD transport, Sci. Adv. source

      Not checked in the free run.

    • cites [100] Luongo, 2020, SLC25A51 is a mammalian mitochondrial NAD(+) transporter, Nature source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Intramitochondrial Ca2+ regulates both carbon entry into and flux through the TCA cycle.

    “Thus, intramitochondrial Ca2+ regulates both carbon entry into and flux through the TCA cycle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The citrate-malate shuttle performs functions beyond electron shuttling and supports continuous citrate regeneration and TCA cycle intermediate homeostasis.

    “More recently, it was demonstrated that the citrate–malate shuttle performs functions beyond that of an electron shuttle and, in fact, supports continuous citrate regeneration and TCA cycle intermediate homeostasis (119, 121).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [119] Assmann, 2017, Srebp-controlled glucose metabolism is essential for NK cell functional responses, Nat. Immunol. source

      Not checked in the free run.

    • cites [121] Arnold, 2022, A non-canonical tricarboxylic acid cycle underlies cellular identity, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Breast cancer cells can engage in reductive amination, and GDH activity supports ammonia incorporation and tumor growth in mouse models of breast cancer.

    “Indeed, breast cancer cells can engage in reductive amination, and GDH activity supports ammonia incorporation and tumor growth in mouse models of breast cancer (128).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Spinelli, 2017, Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OGDH undergoes substrate inhibition by succinyl-CoA, which also allosterically inhibits CS.

    “OGDH undergoes substrate inhibition by succinyl-CoA, which also serves as an allosteric inhibitor of CS (134, 136).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [134] Martinez-Reyes, 2020, Mitochondrial TCA cycle metabolites control physiology and disease, Nat. Commun. source

      Not checked in the free run.

    • cites [136] LaNoue, 1972, Feedback interactions in the control of citric acid cycle activity in rat heart mitochondria, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As a result of the pseudohypoxic state, SDH- and FH-mutant tumors exhibit enhanced glycolytic metabolism and high ROS production.

    “As a result of this “pseudohypoxic” state, SDH- and FH-mutant tumors exhibit enhanced glycolytic metabolism and high ROS production (186).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Sullivan, 2013, The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling, Mol. Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PI3K-AKT signaling pathway mediates both the generation and cytosolic export of glucose-derived citrate, whereas AKT-mediated phosphorylation of ACL enhances its catalytic activity.

    “The PI3K–AKT signaling pathway mediates both the generation and cytosolic export of glucose-derived citrate, whereas AKT-mediated phosphorylation of ACL enhances its catalytic activity (190).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Berwick, 2002, The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depriving APC-mutant intestinal organoids of glutamine depletes intracellular αKG levels and promotes stem-like features and adenocarcinoma formation in vivo.

    “Depriving APC-mutant intestinal organoids of glutamine depletes intracellular αKG levels and promotes stem-like features and adenocarcinoma formation in vivo (162).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Tran, 2020, alpha-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer, Nat. Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    αKG supplementation rescues the effects of glutamine deprivation by driving DNA and histone demethylation, which facilitates upregulation of differentiation-associated genes and blunts tumor growth in vivo.

    “αKG supplementation rescues these effects by driving DNA and histone demethylation, which facilitates upregulation of differentiation-associated genes and blunts tumor growth in vivo (162).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Tran, 2020, alpha-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer, Nat. Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    αKG-dependent dioxygenases require αKG, ferrous iron, and oxygen as cosubstrates and are inhibited by high levels of succinate and fumarate.

    “These enzymes all require αKG, ferrous iron, and oxygen as cosubstrates and are inhibited by high levels of succinate and fumarate (161), thereby integrating multiple metabolic pathways in the control of gene expression programs and, ultimately, cell fate decisions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Baksh, 2021, Metabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases, Trends Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Succinate, fumarate, and 2HG are considered oncometabolites because they are linked to development of certain human cancers and because they act as competitive inhibitors of αKG-dependent dioxygenases.

    “Succinate, fumarate, and 2HG are all considered “oncometabolites” because they are linked to development of certain human cancers and because they affect cancer-relevant processes by virtue of their ability to act as competitive inhibitors of αKG-dependent dioxygenases (169) (Fig. 6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [169] DeBerardinis, 2016, Fundamentals of cancer metabolism, Sci. Adv. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    By blocking the enzymatic activity of histone and DNA demethylases, d-2HG can lock cells in a hypermethylated state that blocks differentiation and reinforces a malignant and stem cell-like phenotype.

    “By blocking the enzymatic activity of histone and DNA demethylases, d-2HG can function to lock cells in a hypermethylated state that blocks differentiation and reinforces a malignant and stem cell–like phenotype (30, 172, 173, 174).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30] Intlekofer, 2019, Metabolic signatures of cancer cells and stem cells, Nat. Metab. source

      Not checked in the free run.

    • cites [172] Figueroa, 2010, Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation, Cancer Cell source

      Not checked in the free run.

    • cites [173] Lu, 2012, IDH mutation impairs histone demethylation and results in a block to cell differentiation, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oncogenic activation of the PI3K-AKT signaling axis increases acetyl-CoA levels and promotes elevated histone acetylation both in vitro and in tumors.

    “Accordingly, oncogenic activation of the PI3K–AKT signaling axis increases acetyl-CoA levels and promotes elevated histone acetylation both in vitro and in tumors (188).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Lee, 2014, Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation, Cell Metab. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    As a central metabolic hub, the TCA cycle frequently undergoes significant remodeling during both normal and pathological changes in cell fate.

    “As a central metabolic hub, the TCA cycle frequently undergoes significant remodeling during both normal and pathological changes in cell fate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The effect of αKG on cell fate is likely context specific, as interventions that increase αKG levels in mouse ESCs favor self-renewal over differentiation.

    “However, the effect of αKG on cell fate is likely context specific as interventions that increase αKG levels in mouse ESCs favor self-renewal over differentiation (165, 166).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [165] Carey, 2015, Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells, Nature source

      Not checked in the free run.

    • cites [166] Hwang, 2016, Psat1-Dependent fluctuations in alpha-ketoglutarate affect the timing of ESC differentiation, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The 4Fe-4S cluster in ACO2 makes it susceptible to inactivation by ROS, contributing to TCA cycle deceleration upon ETC dysfunction.

    “Intriguingly, the 4Fe–4S cluster present within ACO2 makes it exquisitely susceptible to inactivation by ROS, serving as another example of TCA cycle deceleration upon ETC dysfunction (150).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Castro, 2019, Aconitases: non-redox iron-sulfur proteins sensitive to reactive species, Acc. Chem. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transcription factors are the ultimate controllers of cell fate, but their ability to act can be shaped by chemical modifications on DNA and histones that modulate DNA accessibility and cofactor recruitment.

    “While transcription factors are the ultimate controllers of cell fate, their ability to act can be shaped by chemical modifications on DNA and histones that can modulate DNA accessibility and cofactor recruitment (157).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Laugesen, 2014, Chromatin repressive complexes in stem cells, development, and cancer, Cell Stem Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Succinate and fumarate accumulation can inhibit αKG-dependent prolyl hydroxylases, leading to stabilization of HIF-1 and activation of the HIF/hypoxia transcriptional program.

    “In addition to affecting the activity of chromatin-associated αKG-dependent dioxygenases, succinate and fumarate accumulation can also inhibit αKG-dependent prolyl hydroxylases, leading to stabilization of HIF-1 and concomitant activation of the HIF/hypoxia transcriptional program (184, 185).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [184] Isaacs, 2005, HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability, Cancer Cell source

      Not checked in the free run.

    • cites [185] Selak, 2005, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    αKG-dependent dioxygenases include Jumonji C-domain-containing histone demethylases and ten-eleven translocation (TET) DNA methylcytosine dioxygenases, which remove repressive histone marks and 5-methylcytosine, respectively.

    “Succinate, fumarate, and αKG are all implicated in regulation of αKG-dependent dioxygenases, a family of enzymes that includes Jumonji C-domain–containing histone demethylases and ten–eleven translocation (TET) DNA methylcytosine dioxygenases, which remove repressive histone marks and 5-methylcytosine, respectively (Fig. 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Acetylation of histone tails alters chromatin dynamics and generally increases accessibility to transcription factors, leading to activation of gene transcription.

    “Acetylation of histone tails alters chromatin dynamics and generally increases accessibility to transcription factors, leading to activation of gene transcription (189) (Fig. 6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [189] Tessarz, 2014, Histone core modifications regulating nucleosome structure and dynamics, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High BCAT1 activity leads to a hypermethylated chromatin landscape that blunts normal myeloid differentiation; blocking BCAT1 triggers αKG accumulation and induces myeloid differentiation.

    “Accordingly, high BCAT1 activity leads to a hypermethylated chromatin landscape that blunts normal myeloid differentiation; reciprocally, blocking BCAT1 triggers αKG accumulation and induces myeloid differentiation (163).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Raffel, 2017, BCAT1 restricts alphaKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An increased αKG/succinate ratio in this system, whether driven by p53 reactivation or suppression of OGDH, enhances activity of αKG-dependent dioxygenases like the TETs and drives reacquisition of premalignant gene expression patterns associated with tumor differentiation.

    “An increased αKG/succinate ratio in this system, whether driven by p53 reactivation or suppression of OGDH, enhances activity of αKG-dependent dioxygenases like the TETs and drives reacquisition of premalignant gene expression patterns associated with tumor differentiation (164).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Morris, 2019, alpha-Ketoglutarate links p53 to cell fate during tumour suppression, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LDHA expression and activity are high in HFSCs relative to other cell types in the epidermis, and promoting lactate production via MPC deletion boosts their activation.

    “LDHA expression and activity are high in HFSCs relative to other cell types in the epidermis, and promoting lactate production via MPC deletion boosts their activation (208).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [208] Flores, 2017, Lactate dehydrogenase activity drives hair follicle stem cell activation, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Naïve ESCs primarily oxidize citrate in the traditional TCA cycle, and loss of ACO2 compromises acquisition of naïve pluripotency.

    “For example, we recently showed that naïve ESCs primarily oxidize citrate in the traditional TCA cycle, and, accordingly, loss of ACO2 compromises acquisition of naïve pluripotency (121).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Arnold, 2022, A non-canonical tricarboxylic acid cycle underlies cellular identity, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intracellular succinate accumulates rapidly upon cold temperature-mediated activation of thermogenesis in brown adipose tissue-in part because brown adipocytes begin sequestering circulating succinate more effectively.

    “For example, intracellular succinate accumulates rapidly upon cold temperature–mediated activation of thermogenesis in brown adipose tissue—in part because brown adipocytes begin sequestering circulating succinate more effectively (192).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Mills, 2018, Accumulation of succinate controls activation of adipose tissue thermogenesis, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Succinate pools are directly oxidized by SDH, resulting in ROS production that stimulates uncoupling protein 1 activity, which uncouples the mitochondrial proton gradient from respiration, thereby producing heat.

    “Succinate pools are directly oxidized by SDH, resulting in ROS production that stimulates uncoupling protein 1 activity, which in turn uncouples the mitochondrial proton gradient from respiration, thereby producing heat (192).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Mills, 2018, Accumulation of succinate controls activation of adipose tissue thermogenesis, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon lineage commitment and differentiation, cells increase their oxidation of pyruvate in the TCA cycle and display enhanced OXPHOS.

    “Upon lineage commitment and differentiation, however, cells increase their oxidation of pyruvate in the TCA cycle and display enhanced OXPHOS (203, 204, 205).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [203] Rodriguez-Colman, 2017, Interplay between metabolic identities in the intestinal crypt supports stem cell function, Nature source

      Not checked in the free run.

    • cites [204] Shapira, 2020, Metabolic regulation of tissue stem cells, Trends Cell Biol. source

      Not checked in the free run.

    • cites [205] Zheng, 2016, Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation, Elife source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The TCA cycle undergoes significant remodeling during immune cell activation and this remodeling supports distinct immune cell functions and fates.

    “Since this seminal finding, it has become increasingly appreciated that the TCA cycle also undergoes significant remodeling during immune cell activation and that this remodeling supports distinct immune cell functions and fates.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Pluripotency is a state that exists only transiently during early mammalian development, but it can be modeled indefinitely in vitro using ESCs derived from the inner cell mass of preimplantation blastocysts.

    “While pluripotency, or the ability to give rise to all embryonic germ layers, is a state that exists only transiently during early mammalian development, it can be modeled indefinitely in vitro using ESCs derived from the inner cell mass of preimplantation blastocysts (210).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [210] Weinberger, 2016, Dynamic stem cell states: Naive to primed pluripotency in rodents and humans, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

    • Rests on an assumption: Pluripotency is a state that exists only transiently during early mammalian development.

  • May combine two claims.

    Premisecitation

    Myogenic differentiation is coupled with increased pyruvate oxidation and OXPHOS, and this metabolic shift is likely driven, in part, by the significant energy demands of skeletal muscle.

    “Myogenic differentiation is also coupled with increased pyruvate oxidation and OXPHOS, and this metabolic shift is likely driven, in part, by the significant energy demands of skeletal muscle (121, 204, 209).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [121] Arnold, 2022, A non-canonical tricarboxylic acid cycle underlies cellular identity, Nature source

      Not checked in the free run.

    • cites [204] Shapira, 2020, Metabolic regulation of tissue stem cells, Trends Cell Biol. source

      Not checked in the free run.

    • cites [209] Leary, 1998, Interactions between bioenergetics and mitochondrial biogenesis, Biochim. Biophys. Acta source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TCA cycle activity varies with PSC identity in human ESCs, which display glutamine independence and increased mitochondrial respiration upon conversion to a more naïve state.

    “TCA cycle activity also varies with PSC identity in human ESCs, which display glutamine independence and increased mitochondrial respiration upon conversion to a more naïve state (215, 216).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [215] Bayerl, 2021, Principles of signaling pathway modulation for enhancing human naive pluripotency induction, Cell Stem Cell source

      Not checked in the free run.

    • cites [216] Takashima, 2015, Resetting transcription factor control circuitry toward ground-state pluripotency in human, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated macrophages accumulate high levels of succinate, which induces the proinflammatory cytokine interleukin 1β.

    “Activated macrophages have also been shown to accumulate high levels of succinate, which induces the proinflammatory cytokine interleukin 1β (201).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Itaconate displays anti-inflammatory properties, in part because it activates transcription factor Nrf2, which has antioxidant and anti-inflammatory activity.

    “Itaconate displays anti-inflammatory properties, in part because of its ability to activate the transcription factor Nrf2, which has antioxidant and anti-inflammatory activity (200).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Mills, 2018, Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In response to T-cell receptor stimulation, 2HG accumulates to millimolar levels in CD8+ T cells and enhances effector differentiation through a mechanism involving altered histone and DNA methylation.

    “In response to T-cell receptor stimulation, 2HG accumulates to millimolar levels in CD8+ T cells and enhances effector differentiation through a mechanism involving altered histone and DNA methylation (202).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Tyrakis, 2016, S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some cancer types, including liver and glioblastomas, readily take up acetate, which can be converted to acetyl-CoA by ACSS and undergo oxidation in the TCA cycle.

    “Some cancer types, including liver and glioblastomas, readily take up acetate, which can be converted to acetyl-CoA by ACSS and undergo oxidation in the TCA cycle (70, 195).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Mashimo, 2014, Acetate is a bioenergetic substrate for human glioblastoma and brain metastases, Cell source

      Not checked in the free run.

    • cites [195] Comerford, 2014, Acetate dependence of tumors, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clear cell renal carcinomas do not oxidize glucose-derived carbon in the TCA cycle and instead preferentially engage in aerobic glycolysis.

    “Clear cell renal carcinomas exhibit a tumor type–specific metabolic profile: these tumors do not oxidize glucose-derived carbon in the TCA cycle and instead preferentially engage in aerobic glycolysis (197).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Courtney, 2018, Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Naïve mouse ESCs accumulate pools of αKG and acetyl-CoA, which may reinforce the pluripotent state by stimulating more open chromatin.

    “Moreover, naïve mouse ESCs accumulate pools of αKG and acetyl-CoA, which may reinforce the pluripotent state by stimulating more open chromatin (165, 211, 212, 213, 214).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [165] Carey, 2015, Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells, Nature source

      Not checked in the free run.

    • cites [211] Leitch, 2013, Naive pluripotency is associated with global DNA hypomethylation, Nat. Struct. Mol. Biol. source

      Not checked in the free run.

    • cites [212] Moussaieff, 2015, Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intestinal stem cells express lower levels of MPC than their differentiated progeny, and blocking mitochondrial pyruvate entry via MPC inhibition drives increased ISC numbers and proliferative potential.

    “For example, intestinal stem cells (ISCs) express lower levels of MPC than their differentiated progeny, and blocking mitochondrial pyruvate entry via MPC inhibition drives increased ISC numbers and proliferative potential (206).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Schell, 2017, Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blocking the citrate-malate shuttle by disrupting ACL causes significant defects in TCA cycle metabolite homeostasis and prevents ESCs from exiting from the naïve pluripotent state.

    “Consequently, blocking the citrate–malate shuttle by disrupting ACL causes significant defects in TCA cycle metabolite homeostasis and prevents ESCs from exiting from the naïve pluripotent state (121).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Arnold, 2022, A non-canonical tricarboxylic acid cycle underlies cellular identity, Nature source

      Not checked in the free run.

79 of 79

  • The paper relies on this without support.

    Mutations that impair FH and SDH activity are associated with pathologic accumulation of fumarate and succinate, respectively.

    “Mutations that impair fumarate hydratase (FH) and SDH activity are associated with pathologic accumulation of substrates fumarate and succinate, respectively.”

  • The paper relies on this without support.

    Acetyl-CoA itself cannot transit across the mitochondrial membrane.

    “Acetyl-CoA itself cannot transit across the mitochondrial membrane.”

  • The paper relies on this without support.

    Most mammalian cells growing in culture rely on both glucose- and glutamine-derived carbon to fuel the TCA cycle.

    “Most mammalian cells growing in culture rely on both glucose- and glutamine-derived carbon to fuel the TCA cycle.”

  • The paper relies on this without support.

    Most cultured cell lines require glutamine supplementation to support cell survival and proliferation.

    “While most cultured cell lines require glutamine supplementation to support cell survival and proliferation, naïve mouse ESCs can grow in the absence of exogenous glutamine.”

  • The paper relies on this without support.

    Adult tissue stem cells maintain organ homeostasis by balancing self-renewal and differentiation into mature cell types.

    “Adult tissue stem cells maintain organ homeostasis by balancing self-renewal and differentiation into mature cell types.”

  • The paper relies on this without support.

    Pluripotency is a state that exists only transiently during early mammalian development.

    “While pluripotency, or the ability to give rise to all embryonic germ layers, is a state that exists only transiently during early mammalian development, it can be modeled indefinitely in vitro using ESCs derived from the inner cell mass of preimplantation blastocysts (210).”

  • The paper relies on this without support.

    Mouse and human ESCs can be cultured under conditions that drive a spectrum of pluripotent states.

    “Mouse and human ESCs can be cultured under conditions that drive a spectrum of pluripotent states, ranging from those that closely mimic the preimplantation state (otherwise known as the “naïve” state) to those that resemble the postimplantation epiblast.”

  • The paper relies on this without support.

    The TCA cycle provides another critical input to chromatin regulation in the form of acetyl-CoA.

    “The TCA cycle provides another critical input to chromatin regulation in the form of acetyl-CoA.”

  • The paper relies on this without support.

    TCA cycle metabolites can function as messengers facilitating interorgan crosstalk.

    “Beyond their intracellular roles, TCA cycle metabolites can also function as messengers facilitating interorgan crosstalk.”

  • The paper relies on this without support.

    Succinate represents the most established example of a TCA cycle intermediate that serves as a paracrine signal.

    “To date, succinate represents the most established example of a TCA cycle intermediate that serves as a paracrine signal.”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • NAD+ is a key factor in metabolism of all major biomolecules and in ATP synthesis by the electron transport chain.

    “It is a key factor in metabolism of all major biomolecules (lipids, carbohydrates, amino acids) as well as ATP synthesis by the electron transport chain [164, 165]”

    From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [164]

Cites

Flagged first, then by citations

1 of the 215 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. Kornberg, 1966, Anapleroic sequences and their role in metabolism, Essays Biochem., 2, 1
  2. Martius, 1937, Physiological breakdown of citric acid, Prelim. Z. Physiol. Chem., 246, 1
  3. Warburg, 1924, Ueber den stoffwechsel der tumoren, Biochem. Z., 152, 319

Cited by

Sorted by citations

Related

Authors
Arnold, P. K., & Finley, L. W. S.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Finley, Lydia W.S.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2023-02
Volume
299
Issue
2
Pages
102838
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2022.102838
PMC
PMC9871338
OpenAlex
W4312221298
Cited by
535
References
215
Citations by year
2026: 172 · 2025: 209 · 2024: 120 · 2023: 33 · 2022: 1
FWCI
11.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (P30CA008748, R37CA252305)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (F31HD098824)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
Keywords
TCA cycle, cellular bioenergetics, nutrient oxidation, cancer metabolism, mammalian cells, cell state heterogeneity
MeSH terms
Animals, Citric Acid Cycle, Energy Metabolism, Mammals

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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