Regulation and function of the mammalian tricarboxylic acid cycle

In the paper

“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).”

What the sources say

• Not checked yetcites [21] Muchowska, 2020, Nonenzymatic metabolic reactions and life's origins, Chem. Rev. source
• Supported

  In “O2 AND METAZOAN EVOLUTION” (page not provided), the paper reports a substantial rise in atmospheric O2 and says that O2 serves as an electron acceptor in the oxidation of carbon-based fuels. This supports the citing sentence’s account of increased oxygen availability and its metabolic role; the reference to organic molecules derived from carbon assimilation is a paraphrase of those carbon-based fuels. (LLM, conf=0.90)

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

In the paper

“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).”

What the sources say

• Supported

  The “Acetyl-CoA synthetases” section identifies ACSS1 as mitochondrial and ACSS2 as nucleocytosolic. The “Acetate contribution to fatty acid synthesis” section describes a route between the compartments but says the interplay of ACSS1, ACSS2 and ACLY in controlling acetyl-CoA metabolism remains an area for future research. Page numbers are unavailable in our copy. (LLM, conf=0.89)

  cites [71] Schug, 2016, The metabolic fate of acetate in cancer, Nat. Rev. Cancer source

In the paper

“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).”

What the sources say

• Partly supported

  In the section comparing the glutamate- and β-hydroxybutyrate-dehydrogenase systems (page unavailable), the paper presents evidence that glutamate dehydrogenase is in equilibrium in rat liver in vivo. It does not report that the authors found GDH operating close to equilibrium in vitro; its separately measured equilibrium constant is not such a finding. (LLM, conf=0.85)

  cites [112] Williamson, 1967, The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver, Biochem. J. sourceExperimental — accuracy not yet measured
• Not checked yetcites [126] Treberg, 2010, On the reversibility of glutamate dehydrogenase and the source of hyperammonemia in the hyperinsulinism/hyperammonemia syndrome, Adv. Enzyme Regul. source

In the paper

“Notably, while NAD+ itself can be imported into mitochondria through SLC25A51–MCART1 (98, 99, 100), NADH is not efficiently transported.”

What the sources say

• Supported

  The citation in the printed sentence attaches to NAD+ import, not to the subsequent statement about NADH. The Discussion identifies SLC25A51 as required for mitochondrial NAD+ uptake in human cells, while noting that direct transport assays are still needed to establish its mechanism definitively. (LLM, conf=0.90)

  cites [98] Girardi, 2020, Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import, Nat. Commun. source
• Supported

  The citation is attached to the statement that NAD+ can be imported into mitochondria through SLC25A51/MCART1. The Discussion identifies MCART1 as a putative mitochondrial NAD importer in humans, and the Results report MCART1-dependent NAD+ uptake. The sentence's separate statement about inefficient NADH transport is not the part attributed to this citation. (LLM, conf=0.93)

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

  In the printed sentence, the citations attach to the claim that NAD+ enters mitochondria through SLC25A51, rather than to the subsequent statement about NADH. The paper’s “SLC25A51 drives mitochondrial NAD+ uptake” section reports SLC25A51-dependent uptake of NAD+ into the mitochondrial matrix. The paper does not establish the additional electron-shuttle explanation in the supplied claim. (LLM, conf=0.91)

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

In the paper

“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).”

What the sources say

• Supported

  The Results section on MPC expression reports that MPC1 is nearly absent at the crypt base, where LGR5+ intestinal stem cells reside, but strongly expressed in the upper crypt and villus; the Discussion says MPC expression increases upon differentiation. The Drosophila Results report approximately twice as many stem cells and increased proliferation after MPC disruption, while the organoid Results report enhanced stem-cell function and markers after MPC inhibition. (LLM, conf=0.92)

  cites [206] Schell, 2017, Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism, Nat. Cell Biol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [21] Muchowska, 2020, Nonenzymatic metabolic reactions and life's origins, Chem. Rev. source
• Not checked yetcites [22] Yadav, 2022, Cyanide as a primordial reductant enables a protometabolic reductive glyoxylate pathway, Nat. Chem. source

In the paper

“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).”

What the sources say

• Not checked yetcites [18] Buchanan, 1990, A reverse KREBS cycle in photosynthesis: consensus at last, Photosynth Res. source
• Not checked yetcites [27] Baldwin, 1981, The evolution of metabolic cycles, Nature source

In the paper

“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.”

What the sources say

• Not checked yetcites [34] Martius, 1937, Physiological breakdown of citric acid, Prelim. Z. Physiol. Chem.

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [3] Ryan, 2020, Krebs cycle Reborn in macrophage immunometabolism, Annu. Rev. Immunol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [1] Krebs, 1937, Metabolism of ketonic acids in animal tissues, Biochem. J. source
• Not checked yetcites [2] Krebs, 1980, The role of citric acid in intermediate metabolism in animal tissues, FEBS Lett. source
• Not checked yetcites [3] Ryan, 2020, Krebs cycle Reborn in macrophage immunometabolism, Annu. Rev. Immunol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [33] Stare, 1936, The effect of fumarate on the respiration of liver and kidney tissue, Biochem. J. source

In the paper

“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).”

What the sources say

• Not checked yetcites [31] Annau, 1935, Über die Bedeutung der Fumarsäure für die tierische Gewebsatmung, Biol. Chem.
• Not checked yetcites [32] Kornberg, 2000, Krebs and his trinity of cycles, Nat. Rev. Mol. Cell Biol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [29] Fani, 2009, Origin and evolution of metabolic pathways, Phys. Life Rev. source
• Not checked yetcites [30] Intlekofer, 2019, Metabolic signatures of cancer cells and stem cells, Nat. Metab. source

In the paper

“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.”

In the paper

“Because the TCA cycle functions in both catabolic and anabolic capacities, it is considered an amphibolic pathway (7, 8).”

What the sources say

• Not checked yetcites [7] Kornberg, 1965, Anaplerotic sequences in microbial metabolism, Angew. Chem. Int. Ed. Engl. source
• Not checked yetcites [8] Kornberg, 1966, Anapleroic sequences and their role in metabolism, Essays Biochem.

In the paper

“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”

What the sources say

• Not checked yetcites [2] Krebs, 1980, The role of citric acid in intermediate metabolism in animal tissues, FEBS Lett. source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [87] Cheng, 2011, Pyruvate carboxylase is required for glutamine-independent growth of tumor cells, Proc. Natl. Acad. Sci. U. S. A. source

In the paper

“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.”

What the sources say

• Not checked yetcites [4] Krebs, 1940, The oxidation of pyruvate in pigeon breast muscle, Biochem. J. source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [96] Perry, 2016, Propionate increases hepatic pyruvate cycling and anaplerosis and alters mitochondrial metabolism, J. Biol. Chem. source

In the paper

“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).”

What the sources say

• Not checked yetcites [61] Chen, 2016, Lactate metabolism is associated with mammalian mitochondria, Nat. Chem. Biol. source

In the paper

“Cataplerosis of any TCA cycle intermediate requires compensatory input to sustain TCA cycle activity, a process termed “anaplerosis” (37).”

What the sources say

• Not checked yetcites [37] Owen, 2002, The key role of anaplerosis and cataplerosis for citric acid cycle function, J. Biol. Chem. source

In the paper

“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.”

What the sources say

• Not checked yetcites [44] Jang, 2019, Metabolite exchange between mammalian organs quantified in pigs, Cell Metab. source

In the paper

“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).”

What the sources say

• Not checked yetcites [61] Chen, 2016, Lactate metabolism is associated with mammalian mitochondria, Nat. Chem. Biol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [46] Faubert, 2017, Lactate metabolism in human lung tumors, Cell source
• Not checked yetcites [47] Hui, 2017, Glucose feeds the TCA cycle via circulating lactate, Nature source
• Not checked yetcites [48] Kennedy, 2013, Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer, PLoS One source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [46] Faubert, 2017, Lactate metabolism in human lung tumors, Cell source
• Not checked yetcites [47] Hui, 2017, Glucose feeds the TCA cycle via circulating lactate, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [64] Chatelain, 1996, Cyclic AMP and fatty acids increase carnitine palmitoyltransferase I gene transcription in cultured fetal rat hepatocytes, Eur. J. Biochem. source
• Not checked yetcites [65] Mascaro, 1998, Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor, J. Biol. Chem. source

In the paper

“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.”

What the sources say

• Not checked yetcites [58] Christofk, 2008, Pyruvate kinase M2 is a phosphotyrosine-binding protein, Nature source
• Not checked yetcites [59] Thompson, 2011, Rethinking the regulation of cellular metabolism, Cold Spring Harb. Symp. Quant. Biol. source
• Not checked yetcites [60] Vander Heiden, 2001, Growth factors can influence cell growth and survival through effects on glucose metabolism, Mol. Cell Biol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [91] Cardaci, 2015, Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis, Nat. Cell Biol. source
• Not checked yetcites [92] Lussey-Lepoutre, 2015, Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism, Nat. Commun. source

In the paper

“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).”

What the sources say

• Not checked yetcites [52] Behal, 1993, Regulation of the pyruvate dehydrogenase multienzyme complex, Annu. Rev. Nutr. source

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [141] Kim, 2006, HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia, Cell Metab. source

In the paper

“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).”

What the sources say

• Not checked yetcites [138] Luengo, 2021, Increased demand for NAD(+) relative to ATP drives aerobic glycolysis, Mol. Cell source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [101] Baksh, 2020, Extracellular serine controls epidermal stem cell fate and tumour initiation, Nat. Cell Biol. source
• Not checked yetcites [102] Diehl, 2019, Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation, Nat. Metab. source
• Not checked yetcites [103] Li, 2022, Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited, Nat. Metab. source

In the paper

“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).”

What the sources say

• Not checked yetcites [105] Koza, 1996, Sequence and tissue-dependent RNA expression of mouse FAD-linked glycerol-3-phosphate dehydrogenase, Arch. Biochem. Biophys. source
• Not checked yetcites [106] Ohkawa, 1969, Unusually high mitochondrial alpha glycerophosphate dehydrogenase activity in rat brown adipose tissue, J. Cell Biol. source
• Not checked yetcites [107] Safer, 1971, Control of the transport of reducing equivalents across the mitochondrial membrane in perfused rat heart, J. Mol. Cell Cardiol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [41] Chandel, 2015

In the paper

“Four pyruvate dehydrogenase kinases (PDKs; PDK1–4) catalyze phosphorylation of the serine residues, each with different site specificities (139).”

What the sources say

• Not checked yetcites [139] Korotchkina, 2001, Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase, J. Biol. Chem. source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [119] Assmann, 2017, Srebp-controlled glucose metabolism is essential for NK cell functional responses, Nat. Immunol. source
• Not checked yetcites [121] Arnold, 2022, A non-canonical tricarboxylic acid cycle underlies cellular identity, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [128] Spinelli, 2017, Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass, Science source

In the paper

“OGDH undergoes substrate inhibition by succinyl-CoA, which also serves as an allosteric inhibitor of CS (134, 136).”

What the sources say

• Not checked yetcites [134] Martinez-Reyes, 2020, Mitochondrial TCA cycle metabolites control physiology and disease, Nat. Commun. source
• Not checked yetcites [136] LaNoue, 1972, Feedback interactions in the control of citric acid cycle activity in rat heart mitochondria, J. Biol. Chem. source

In the paper

“As a result of this “pseudohypoxic” state, SDH- and FH-mutant tumors exhibit enhanced glycolytic metabolism and high ROS production (186).”

What the sources say

• Not checked yetcites [186] Sullivan, 2013, The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling, Mol. Cell source

In the paper

“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).”

What the sources say

• Not checked yetcites [190] Berwick, 2002, The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes, J. Biol. Chem. source

In the paper

“Depriving APC-mutant intestinal organoids of glutamine depletes intracellular αKG levels and promotes stem-like features and adenocarcinoma formation in vivo (162).”

What the sources say

• Not checked yetcites [162] Tran, 2020, alpha-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer, Nat. Cancer source

In the paper

“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).”

What the sources say

• Not checked yetcites [162] Tran, 2020, alpha-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer, Nat. Cancer source

In the paper

“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.”

What the sources say

• Not checked yetcites [161] Baksh, 2021, Metabolic coordination of cell fate by α-ketoglutarate-dependent dioxygenases, Trends Cell Biol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [169] DeBerardinis, 2016, Fundamentals of cancer metabolism, Sci. Adv. source

In the paper

“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).”

What the sources say

• Not checked yetcites [30] Intlekofer, 2019, Metabolic signatures of cancer cells and stem cells, Nat. Metab. source
• Not checked yetcites [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 yetcites [173] Lu, 2012, IDH mutation impairs histone demethylation and results in a block to cell differentiation, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [188] Lee, 2014, Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation, Cell Metab. source

In the paper

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

In the paper

“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).”

What the sources say

• Not checked yetcites [165] Carey, 2015, Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells, Nature source
• Not checked yetcites [166] Hwang, 2016, Psat1-Dependent fluctuations in alpha-ketoglutarate affect the timing of ESC differentiation, Cell Metab. source

In the paper

“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).”

What the sources say

• Not checked yetcites [150] Castro, 2019, Aconitases: non-redox iron-sulfur proteins sensitive to reactive species, Acc. Chem. Res. source

In the paper

“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).”

What the sources say

• Not checked yetcites [157] Laugesen, 2014, Chromatin repressive complexes in stem cells, development, and cancer, Cell Stem Cell source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [185] Selak, 2005, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase, Cancer Cell source

In the paper

“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).”

In the paper

“Acetylation of histone tails alters chromatin dynamics and generally increases accessibility to transcription factors, leading to activation of gene transcription (189) (Fig. 6).”

What the sources say

• Not checked yetcites [189] Tessarz, 2014, Histone core modifications regulating nucleosome structure and dynamics, Nat. Rev. Mol. Cell Biol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [163] Raffel, 2017, BCAT1 restricts alphaKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [164] Morris, 2019, alpha-Ketoglutarate links p53 to cell fate during tumour suppression, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [208] Flores, 2017, Lactate dehydrogenase activity drives hair follicle stem cell activation, Nat. Cell Biol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [121] Arnold, 2022, A non-canonical tricarboxylic acid cycle underlies cellular identity, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [192] Mills, 2018, Accumulation of succinate controls activation of adipose tissue thermogenesis, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [192] Mills, 2018, Accumulation of succinate controls activation of adipose tissue thermogenesis, Nature source

In the paper

“Upon lineage commitment and differentiation, however, cells increase their oxidation of pyruvate in the TCA cycle and display enhanced OXPHOS (203, 204, 205).”

What the sources say

• Not checked yetcites [203] Rodriguez-Colman, 2017, Interplay between metabolic identities in the intestinal crypt supports stem cell function, Nature source
• Not checked yetcites [204] Shapira, 2020, Metabolic regulation of tissue stem cells, Trends Cell Biol. source
• Not checked yetcites [205] Zheng, 2016, Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation, Elife source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [210] Weinberger, 2016, Dynamic stem cell states: Naive to primed pluripotency in rodents and humans, Nat. Rev. Mol. Cell Biol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [121] Arnold, 2022, A non-canonical tricarboxylic acid cycle underlies cellular identity, Nature source
• Not checked yetcites [204] Shapira, 2020, Metabolic regulation of tissue stem cells, Trends Cell Biol. source
• Not checked yetcites [209] Leary, 1998, Interactions between bioenergetics and mitochondrial biogenesis, Biochim. Biophys. Acta source

In the paper

“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).”

What the sources say

• Not checked yetcites [215] Bayerl, 2021, Principles of signaling pathway modulation for enhancing human naive pluripotency induction, Cell Stem Cell source
• Not checked yetcites [216] Takashima, 2015, Resetting transcription factor control circuitry toward ground-state pluripotency in human, Cell source

In the paper

“Activated macrophages have also been shown to accumulate high levels of succinate, which induces the proinflammatory cytokine interleukin 1β (201).”

What the sources say

• Not checked yetcites [201] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [200] Mills, 2018, Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [202] Tyrakis, 2016, S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [70] Mashimo, 2014, Acetate is a bioenergetic substrate for human glioblastoma and brain metastases, Cell source
• Not checked yetcites [195] Comerford, 2014, Acetate dependence of tumors, Cell source

In the paper

“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).”

What the sources say

• Not checked yetcites [197] Courtney, 2018, Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo, Cell Metab. source

In the paper

“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).”

What the sources say

• Not checked yetcites [165] Carey, 2015, Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells, Nature source
• Not checked yetcites [211] Leitch, 2013, Naive pluripotency is associated with global DNA hypomethylation, Nat. Struct. Mol. Biol. source
• Not checked yetcites [212] Moussaieff, 2015, Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells, Cell Metab. source

In the paper

“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).”

What the sources say

• Not checked yetcites [121] Arnold, 2022, A non-canonical tricarboxylic acid cycle underlies cellular identity, Nature source