Regulation and function of the mammalian tricarboxylic acid cycle

In the paper

“The preferred anaplerotic substrate in most proliferating cells growing in culture is glutamine, the most abundant circulating amino acid in mammals (30, 72, 73, 74).”

What the sources say

• Partly supported

  The section ‘Glucose and glutamine are fundamental substrates for mammalian cells growing in culture’ describes glutamine as central to cultured-cell proliferation, and ‘Beyond glucose and glutamine: alternative metabolic strategies’ calls glutamine oxidation nearly ubiquitous in cultured cancer cells. Neither passage establishes that glutamine is the preferred anaplerotic substrate in most proliferating cultured cells; the latter addresses cancer cells specifically. Page numbers were not provided in our copy. (LLM, conf=0.82)

  cites [30] Intlekofer, 2019, Metabolic signatures of cancer cells and stem cells, Nat. Metab. sourceExperimental — accuracy not yet measured
• Not checked yetcites [72] DeBerardinis, 2008, The biology of cancer: metabolic reprogramming fuels cell growth and proliferation, Cell Metab. source
• Partly supported

  The Discussion reports that most oxaloacetate in the studied proliferating glioblastoma cells was derived from glutamine. It says this may reflect a general phenomenon during rapid cell growth, but does not establish that glutamine is the preferred anaplerotic substrate in most proliferating cells grown in culture. (LLM, conf=0.88)

  cites [73] DeBerardinis, 2007, Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis, Proc. Natl. Acad. Sci. U. S. A. sourceExperimental — accuracy not yet measured

In the paper

“For example, liver tumors with aberrant overexpression of MYC display enhanced glutamine oxidation and sensitivity to therapies that target glutamine catabolism relative to liver tumors driven by overexpression of MET (196).”

What the sources say

• Partly supported

  The Results section, “MYC and MET Differently Affect Glutamine Metabolism in the Liver” (page unavailable), reports increased glutamine catabolism in MYC-induced liver tumors, whereas MET-induced tumors produce glutamine rather than catabolize it. The Results section, “MYC Sensitizes Cells to Inhibition of Glutaminase” (page unavailable), shows greater sensitivity to GLS1 inhibition in MYC-overexpressing cell lines, but does not demonstrate greater treatment sensitivity in MYC-driven liver tumors than in MET-driven liver tumors. (LLM, conf=0.88)

  cites [196] Yuneva, 2012, The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type, Cell Metab. sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [1] Krebs, 1937, Metabolism of ketonic acids in animal tissues, Biochem. J. source
• Not checked yetcites [32] Kornberg, 2000, Krebs and his trinity of cycles, Nat. Rev. Mol. Cell Biol. source

In the paper

“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).”

What the sources say

• Not checked yetcites [5] Inigo, 2021, Ins and outs of the TCA cycle: the central role of anaplerosis, Annu. Rev. Nutr. source
• Not checked yetcites [6] Pavlova, 2022, The hallmarks of cancer metabolism: still emerging, Cell Metab. source

In the paper

“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.”

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

“Multiple metabolic signals control both TCA cycle inputs and directionality, and increasing work demonstrates the importance of such TCA cycle flexibility for optimizing cellular fitness both under physiological conditions and in the context of disease.”

In the paper

“Given the central role of the TCA cycle in both provisioning key anabolic substrates and in maintaining energy production, it is not surprising that TCA cycle activity is under tight physiologic regulation.”

In the paper

“By adding malonate, an inhibitor of succinate oxidation, they found that succinate accumulated when OAA was added to muscle, implying that this series of reactions was cyclical in nature (2, 32).”

What the sources say

• Not checked yetcites [2] Krebs, 1980, The role of citric acid in intermediate metabolism in animal tissues, FEBS Lett. source
• Not checked yetcites [32] Kornberg, 2000, Krebs and his trinity of cycles, Nat. Rev. Mol. Cell Biol. source

In the paper

“Moreover, they found that citrate did not disappear during this process, indicating that it was being continuously reformed (2, 32).”

What the sources say

• Not checked yetcites [2] Krebs, 1980, The role of citric acid in intermediate metabolism in animal tissues, FEBS Lett. source
• Not checked yetcites [32] Kornberg, 2000, Krebs and his trinity of cycles, Nat. Rev. Mol. Cell Biol. source

In the paper

“The rTCA cycle is an appealing candidate for early prebiotic metabolism because, similar to the oxidative TCA cycle, it produces the five universal precursors to biological metabolism (12, 14, 18).”

What the sources say

• Not checked yetcites [12] Muchowska, 2017, Metals promote sequences of the reverse Krebs cycle, Nat. Ecol. Evol. source
• Not checked yetcites [14] Muchowska, 2019, Synthesis and breakdown of universal metabolic precursors promoted by iron, Nature source
• Not checked yetcites [18] Buchanan, 1990, A reverse KREBS cycle in photosynthesis: consensus at last, Photosynth Res. source

In the paper

“Multiple metabolic signals control both TCA cycle inputs and directionality, and increasing work demonstrates the importance of such TCA cycle flexibility for optimizing cellular fitness both under physiological conditions and in the context of disease.”

In the paper

“Human patients who present with mutations in TCA cycle–associated genes display neonatal symptoms, developmental defects, and failure to thrive (9, 10).”

What the sources say

• Not checked yetcites [9] Erez, 2015, Metabolic dysregulation in monogenic disorders and cancer - finding method in madness, Nat. Rev. Cancer source
• Not checked yetcites [10] Rustin, 1997, Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human, Biochim. Biophys. Acta source

In the paper

“In mammals, the consequences of disrupting TCA cycle function can be found in a group of disorders known as inborn errors of metabolism, which are caused by inherited mutations in genes encoding metabolic enzymes.”

What the sources say

• Not checked yetcites [9] Erez, 2015, Metabolic dysregulation in monogenic disorders and cancer - finding method in madness, Nat. Rev. Cancer source
• Not checked yetcites [10] Rustin, 1997, Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human, Biochim. Biophys. Acta source

In the paper

“The TCA cycle is thus linked to oxygen consumption, as the oxidized electron carriers required to continue to turn the cycle are regenerated by the ETC, and the concerted activity of these two pathways allows for the generation of significant amounts of ATP.”

In the paper

“Proliferating cells thus must balance use of pyruvate toward oxidation in the TCA cycle with demand for cytosolic NAD+ regeneration to support continued glycolytic flux.”

In the paper

“Pyruvate functions as a significant source of acetyl-CoA for the TCA cycle in most mammalian cells (45).”

What the sources say

• Not checked yetcites [45] Moffett, 2020, Acetate revisited: a key biomolecule at the nexus of metabolism, epigenetics, and oncogenesis - Part 2: acetate and ACSS2 in health and disease, Front. Physiol.

In the paper

“While glutamine can be synthesized directly by most mammalian cells, it has been recognized for several decades that glutamine supplementation is necessary for the growth and viability of many cultured cell lines, particularly cancer cell lines (72, 75, 76).”

What the sources say

• Not checked yetcites [72] DeBerardinis, 2008, The biology of cancer: metabolic reprogramming fuels cell growth and proliferation, Cell Metab. source
• Not checked yetcites [75] Eagle, 1955, Nutrition needs of mammalian cells in tissue culture, Science source
• Not checked yetcites [76] Eagle, 1956, The growth response of mammalian cells in tissue culture to L-glutamine and L-glutamic acid, J. Biol. Chem. source

In the paper

“However, under normal and glucose-replete conditions, transamination is the dominant reaction that drives glutamine anaplerosis in cultured cells (79, 80, 81, 82).”

What the sources say

• Not checked yetcites [79] Yang, 2014, Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport, Mol. Cell source
• Not checked yetcites [80] Borst, 1962, The pathway of glutamate oxidation by mitochondria isolated from different tissues, Biochim. Biophys. Acta source
• Not checked yetcites [81] Son, 2013, Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway, Nature source

In the paper

“In differentiated adipocytes, catabolism of branched-chain amino acids accounts for almost a third of cellular acetyl-CoA pools (68).”

What the sources say

• Not checked yetcites [68] Green, 2016, Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis, Nat. Chem. Biol. source

In the paper

“Later work by Lipmann et al. (35, 36) elucidated that the two-carbon molecule required for citrate synthesis was, in fact, acetyl coenzyme A or acetyl-CoA.”

What the sources say

• Not checked yetcites [35] Novelli, 1950, The catalytic function of coenzyme A in citric acid synthesis, J. Biol. Chem. source
• Not checked yetcites [36] Stern, 1950, Synthesis and breakdown of citric acid with crystalline condensing enzyme, Nature source

In the paper

“The relevance of acetate as a potential fuel source has also been observed in vivo: in glioblastoma tumors resected from patients, up to half of the intramitochondrial acetyl-CoA pool is derived from circulating acetate (70).”

What the sources say

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

In the paper

“The process of breaking down fatty acids to produce acetyl-CoA, known as β-oxidation, supplies the majority of acetyl-CoA for TCA cycle oxidation in certain tissues such as the heart (62).”

What the sources say

• Not checked yetcites [62] Murashige, 2020, Comprehensive quantification of fuel use by the failing and nonfailing human heart, Science source

In the paper

“However, recent studies in vivo have demonstrated that cells import lactate from the circulation via monocarboxylate transporter 1 and subsequently oxidize lactate to form pyruvate, resulting in a large fraction of pyruvate and downstream TCA cycle intermediates being derived from circulating lactate (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

“To prevent the futile cycle of simultaneous fatty acid synthesis and oxidation, the rate-limiting enzyme of fatty acid oxidation—CPT1—is regulated in both a transcriptional and an allosteric manner.”

In the paper

“Rather, propionyl-CoA is converted to the TCA cycle intermediate succinyl-CoA through a pathway involving propionyl-CoA carboxylase and methylmalonyl-CoA mutase (5).”

What the sources say

• Not checked yetcites [5] Inigo, 2021, Ins and outs of the TCA cycle: the central role of anaplerosis, Annu. Rev. Nutr. source

In the paper

“By converting the glycolytic product pyruvate into a substrate for TCA cycle oxidation, the PDHC functions as a gatekeeping enzyme that links glycolysis to the TCA cycle and mitochondrial respiration.”

In the paper

“As a result, most cultured cells are exquisitely dependent upon glutamine to support anaplerosis.”

In the paper

“In cancer cells, citrate becomes labeled following supplementation of cells with isotopically labeled acetate ([13C]acetate), indicating that acetate can undergo oxidation in the TCA cycle in cultured cell lines (69).”

What the sources say

• Not checked yetcites [69] Schug, 2015, Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress, Cancer Cell source

In the paper

“While the field continues to debate the underlying benefits of engaging in aerobic glycolysis, one clear advantage to the process is that it allows cells to robustly regenerate NAD+ in the cytosol (57).”

What the sources say

• Not checked yetcites [57] Wang, 2022, Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells, Mol. Cell source

In the paper

“CPT1 itself is allosterically inhibited by the fatty acid synthesis intermediate malonyl-CoA (41, 63).”

What the sources say

• Not checked yetcites [41] Chandel, 2015
• Not checked yetcites [63] Houten, 2010, A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation, J. Inherit. Metab. Dis. source

In the paper

“Pyruvate, derived from glucose, lactate, and amino acid sources, can function as a major anaplerotic source of OAA through the activity of the mitochondrial enzyme pyruvate carboxylase (PC) (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

“As low mitochondrial NAD+/NADH inhibits production of acetyl-CoA by PDH, reductive carboxylation provides a critical alternative mechanism to generate citrate required to sustain cytosolic acetyl-CoA supply for de novo lipid synthesis even during reducing conditions.”

In the paper

“Collectively, the PDKs and PDPs provide cells with the ability to fine-tune PDHC activity through multiple signaling inputs.”

In the paper

“Once inside the mitochondria, Ca2+ ions directly activate IDH and OGDH enzymes.”

What the sources say

• Not checked yetcites [148] Gherardi, 2020, The mitochondrial Ca(2+) uptake and the fine-tuning of aerobic metabolism, Front. Physiol. source

In the paper

“Given that the mitochondrial membrane is impermeable to acetyl-CoA, it was appreciated early on that cleavage of cytosolic citrate by ACL provides a route for delivering acetyl-CoA into the cytosol and, thus, supporting fatty acid synthesis (117).”

What the sources say

• Not checked yetcites [117] Watson, 1970, Citrate and the conversion of carbohydrate into fat. Fatty acid synthesis by a combination of cytoplasm and mitochondria, J. Biol. Chem. source

In the paper

“Increasing flux through OXPHOS by increasing ATP consumption reverses the growth inhibitory effects of PDHC activation (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

“By siphoning electrons onto fumarate, reverse SDH activity allows the ETC to continue to accept electrons from other oxidation reactions, such as that catalyzed by dihydroorotate dehydrogenase, which is critical for nucleotide biosynthesis (129).”

What the sources say

• Not checked yetcites [129] Spinelli, 2021, Fumarate is a terminal electron acceptor in the mammalian electron transport chain, Science source

In the paper

“While both shuttles rely on MDH1 and MDH2, the citrate–malate shuttle is coupled with an energy-expending reaction to favor cytosolic NADH oxidation (104, 116).”

What the sources say

• Not checked yetcites [104] Borst, 2020, The malate-aspartate shuttle (Borst cycle): how it started and developed into a major metabolic pathway, IUBMB Life source
• Not checked yetcites [116] Borst, 1963, Hydrogen transport and transport metabolites

In the paper

“Through shared metabolic intermediates and enzymes, the malate–aspartate shuttle and TCA cycle are functionally coupled (115).”

What the sources say

• Not checked yetcites [115] LaNoue, 1971, Interrelationships between malate-aspartate shuttle and citric acid cycle in rat heart mitochondria, Metabolism source

In the paper

“High NADH thus serves as a key signal of ETC overloading to shutdown TCA cycle flux and prevent delivery of excess electrons to the ETC that can generate potentially dangerous reactive oxygen species (ROS).”

In the paper

“Upon ETC dysfunction, the cytosolic steps of the malate–aspartate shuttle can reverse to produce, rather than consume, cytosolic aspartate (42, 43).”

What the sources say

• Not checked yetcites [42] Birsoy, 2015, An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis, Cell source
• Not checked yetcites [43] Sullivan, 2015, Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells, Cell source

In the paper

“All three enzymes undergo allosteric inhibition by high levels of NADH (41, 133).”

What the sources say

• Not checked yetcites [41] Chandel, 2015
• Not checked yetcites [133] Liu, 2018, Insights into the inhibitory mechanisms of NADH on the alphagamma heterodimer of human NAD-dependent isocitrate dehydrogenase, Sci. Rep. source

In the paper

“Apart from the three regulatory enzymes, SDH undergoes allosteric inhibition by OAA, slowing the cycle down upon insufficient acetyl-CoA availability (137).”

What the sources say

• Not checked yetcites [137] Fink, 2018, Oxaloacetic acid mediates ADP-dependent inhibition of mitochondrial complex II-driven respiration, J. Biol. Chem. source

In the paper

“OXPHOS activity also signals to the TCA cycle at the level of ATP: high ATP/ADP ratios allosterically inhibit IDH, resulting in a deceleration of the cycle upon excess energy supply (135).”

What the sources say

• Not checked yetcites [135] Gabriel, 1986, Activity of purified NAD-specific isocitrate dehydrogenase at modulator and substrate concentrations approximating conditions in mitochondria, Metabolism source

In the paper

“The coupling of aspartate efflux to proton import feature makes the malate–aspartate shuttle largely unidirectional toward glutamate import and aspartate efflux in most contexts (104).”

What the sources say

• Not checked yetcites [104] Borst, 2020, The malate-aspartate shuttle (Borst cycle): how it started and developed into a major metabolic pathway, IUBMB Life source

In the paper

“A similar alternative entry point for amino acids into the TCA cycle is direct conversion of phenylalanine and tyrosine to fumarate by fumarylacetoacetate hydratase (5).”

What the sources say

• Not checked yetcites [5] Inigo, 2021, Ins and outs of the TCA cycle: the central role of anaplerosis, Annu. Rev. Nutr. source

In the paper

“For example, under conditions of hypoxia or impaired mitochondrial respiration, certain reactions of the TCA cycle reverse to support glutamine-dependent reductive carboxylation (92, 122, 123).”

What the sources say

• Not checked yetcites [92] Lussey-Lepoutre, 2015, Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism, Nat. Commun. source
• Not checked yetcites [122] Metallo, 2011, Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia, Nature source
• Not checked yetcites [123] Mullen, 2011, Reductive carboxylation supports growth in tumour cells with defective mitochondria, Nature source

In the paper

“Even CS may reverse: CS reversibility, which occurs in prokaryotes under high CO2 conditions (see aforementioned), has been observed in mammalian cells in the context of SDH deficiency in which reductive glutamine metabolism produces citrate and, strikingly, citrate-derived OAA that can be used to sustain biosynthesis (132).”

What the sources say

• Not checked yetcites [132] Lee, 2019, Spatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells, Nat. Commun. source

In the paper

“The activity of the mammalian complex is regulated by the phosphorylation status of three serine residues on the pyruvate dehydrogenase E1 alpha subunit (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

“For example, ETC inhibition, which prevents cells from using molecular oxygen as a terminal electron acceptor, can force the SDH complex to operate in reverse, reducing fumarate to produce succinate (129).”

What the sources say

• Not checked yetcites [129] Spinelli, 2021, Fumarate is a terminal electron acceptor in the mammalian electron transport chain, Science source

In the paper

“The malate–aspartate shuttle uses the complementary reactions of glutamic-oxaloacetic transaminase 1 and GOT2 transaminases paired with MDH1 and MDH2 to oxidize NADH in the cytosol and reduce NAD+ in the mitochondria (Fig. 4B).”

What the sources say

• Not checked yetcites Fig. 4B

In the paper

“Iron also plays a significant role in modulating the TCA cycle by regulating both the activity and expression of ACO.”

In the paper

“To preferentially engage aerobic glycolysis, cancer cells frequently co-opt several pathways, including the HIF/hypoxia transcriptional program, to enhance PDK1 expression and achieve PDHC repression (142).”

What the sources say

• Not checked yetcites [142] Kim, 2007, Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1, Mol. Cell Biol. source

In the paper

“IDH1/2 mutations have been identified in a range of tumor types, including solid tumors (e.g., gliomas and chondrosarcomas) and blood cancers like acute myelogenous leukemia (169, 170, 171).”

What the sources say

• Not checked yetcites [169] DeBerardinis, 2016, Fundamentals of cancer metabolism, Sci. Adv. source
• Not checked yetcites [170] Mardis, 2009, Recurring mutations found by sequencing an acute myeloid leukemia genome, N. Engl. J. Med. source
• Not checked yetcites [171] Yan, 2009, IDH1 and IDH2 mutations in gliomas, N. Engl. J. Med. source

In the paper

“However, citrate export to the cytosol and subsequent cleavage by ACL provides a major source of cytosolic acetyl-CoA that is the obligate substrate for both de novo lipid synthesis and protein acetylation reactions (39, 187, 188).”

What the sources say

• Not checked yetcites [39] Wellen, 2009, ATP-citrate lyase links cellular metabolism to histone acetylation, Science source
• Not checked yetcites [187] Cai, 2011, Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes, Mol. Cell source
• Not checked yetcites [188] Lee, 2014, Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation, Cell Metab. source

In the paper

“Consistently, heterozygous germline mutations in genes encoding the TCA cycle enzymes involved in the breakdown of these metabolites—SDH and FH—have been shown to facilitate the pathogenesis of certain rare cancers (e.g., paragangliomas) and inherited cancer-predisposition syndromes (181, 182, 183).”

What the sources say

• Not checked yetcites [181] Baysal, 2000, Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma, Science source
• Not checked yetcites [182] Hao, 2009, SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma, Science source
• Not checked yetcites [183] Tomlinson, 2002, Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer, Nat. Genet. source

In the paper

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

In the paper

“the branched-chain amino acid transaminase 1 (BCAT1) enzyme, which transaminates αKG to initiate catabolism of valine, leucine, and isoleucine, constrains αKG pools in acute myelogenous leukemia.”

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

“Oncogenic mutations in genes encoding IDH1/2 result in neomorphic enzyme activity that favors reduction of αKG to d-2-hydroxyglutarate (D-2HG) (167, 168).”

What the sources say

• Not checked yetcites [167] Dang, 2009, Cancer-associated IDH1 mutations produce 2-hydroxyglutarate, Nature source
• Not checked yetcites [168] Ward, 2010, The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate, Cancer Cell source

In the paper

“Notably, both mouse and human muscle cells selectively release succinate during physical activity (191).”

What the sources say

• Not checked yetcites [191] Reddy, 2020, pH-gated succinate secretion regulates muscle remodeling in response to exercise, Cell source

In the paper

“thereby integrating multiple metabolic pathways in the control of gene expression programs and, ultimately, cell fate decisions.”

In the paper

“Notably, steady-state levels of TCA cycle metabolites can affect the activity of chromatin-modifying enzymes, including αKG-dependent dioxygenases and histone acetyltransferases (Fig. 6).”

In the paper

“The enantiomer of d-2HG, l-2HG, can be produced in the absence of mutant IDH1/2 via the promiscuous enzymatic activity of MDH1, MDH2, or LDHA (169).”

What the sources say

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

In the paper

“Circulating succinate binds its receptor SUCNR1 in nonmyofibrillar cells in muscle tissue to initiate transcriptional programs that support tissue remodeling in response to exercise (191).”

What the sources say

• Not checked yetcites [191] Reddy, 2020, pH-gated succinate secretion regulates muscle remodeling in response to exercise, Cell source

In the paper

“These tumors provide examples of how tumors can exploit TCA cycle metabolism to promote epigenetic and transcriptional remodeling that facilitates tumorigenesis.”

In the paper

“This release occurs in a pH-dependent manner via monocarboxylate transporter 1 and is facilitated by transient protonation of succinate upon muscle cell acidification (191).”

What the sources say

• Not checked yetcites [191] Reddy, 2020, pH-gated succinate secretion regulates muscle remodeling in response to exercise, Cell source

In the paper

“Alterations in intracellular αKG levels have been shown to modulate cell fate in cancer and stem cells in a variety of model systems.”

In the paper

“Thus, regulation of cytosolic acetyl-CoA generation can modulate transcriptional outputs by altering global histone acetylation (187).”

What the sources say

• Not checked yetcites [187] Cai, 2011, Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes, Mol. Cell source

In the paper

“These findings suggest that activation of signaling pathways stimulates transcriptional remodeling in part by altering levels of TCA cycle metabolites.”

In the paper

“The 5′ end of ACO2 contains a conserved IRE, which is likely responsible for the reduction in ACO2 protein expression observed in mice maintained on a low iron diet (152).”

What the sources say

• Not checked yetcites [152] Kim, 1996, Identification of a conserved and functional iron-responsive element in the 5'-untranslated region of mammalian mitochondrial aconitase, J. Biol. Chem. source

In the paper

“In cell lines derived from mouse models of pancreatic ductal adenocarcinoma driven by mutant Kras and reversible silencing of the tumor suppressor p53, restoring p53 function rewires TCA cycle metabolism and drives accumulation of αKG relative to succinate (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

“Like 2HG accumulation, increased levels of succinate and fumarate can inhibit Jumonji C-domain–containing histone demethylases and TET enzymes, driving a widespread hypermethylation phenotype that disrupts normal cell differentiation (179, 180).”

What the sources say

• Not checked yetcites [179] Cervera, 2009, Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells, Mol. Cancer source
• Not checked yetcites [180] Xiao, 2012, Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors, Genes Dev. source

In the paper

“By co-opting the production and localization of select TCA cycle metabolites, cells can modulate the activity of chromatin-modifying enzymes and exert control over gene expression and cell fate (158, 159, 160).”

What the sources say

• Not checked yetcites [158] Reid, 2017, The impact of cellular metabolism on chromatin dynamics and epigenetics, Nat. Cell Biol. source
• Not checked yetcites [159] Schvartzman, 2018, Metabolic regulation of chromatin modifications and gene expression, J. Cell Biol. source
• Not checked yetcites [160] Trefely, 2020, Compartmentalised acyl-CoA metabolism and roles in chromatin regulation, Mol. Metab. source

In the paper

“Together, these studies provide examples of how αKG accumulation—whether enabled by changes in TCA cycle wiring or upstream pathways—can function in a tumor suppressive capacity by stimulating chromatin remodeling that drives a more differentiated and less aggressive cancer phenotype.”

In the paper

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

In the paper

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

In the paper

“Pluripotent cell-state transitions can be accompanied by large-scale changes in TCA cycle configuration.”

In the paper

“In multiple tissue contexts, adult stem cells have been found to primarily engage in aerobic glycolysis.”

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

“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.”

In the paper

“For example, activated macrophages increase expression of the enzyme aconitate decarboxylase 1 (previously known as IRG1), which produces itaconate from the decarboxylation of TCA cycle–derived aconitate, an intermediate in the conversion of citrate to isocitrate (199).”

What the sources say

• Not checked yetcites [199] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U. S. A. source

In the paper

“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.”

What the sources say

• Not checked yetcites [165] Carey, 2015, Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells, Nature source

In the paper

“indicating that environmental context can drive fuel preferences”

In the paper

“Collectively, these studies illustrate that TCA cycle substrate preference and behavior can vary within the same lineage in adult stem cells.”

In the paper

“The field of immunometabolism was ignited following the discovery that activated T-cells significantly upregulate glucose uptake and glycolysis to support the energetic and biosynthetic demands of T-cell expansion (198).”

What the sources say

• Not checked yetcites [198] Frauwirth, 2002, The CD28 signaling pathway regulates glucose metabolism, Immunity source

In the paper

“The glutamine-independent phenotype exhibited by naïve mouse ESCs is coupled with a reduction in the contribution of glutamine-derived carbons to TCA cycle intermediates (165).”

What the sources say

• Not checked yetcites [165] Carey, 2015, Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells, Nature source

In the paper

“Recent tracing studies have also revealed that TCA cycle metabolism in vivo is fueled by substrates beyond glucose and glutamine.”

In the paper

“Unlike ISCs, hair follicle stem cells (HFSCs) are not continuously proliferative and instead remain dormant unless induced to divide during a new hair cycle (207).”

What the sources say

• Not checked yetcites [207] Wei, 2018, The force is strong with this one: metabolism (Over)powers stem cell fate, Trends Cell Biol. source

In the paper

“Conversely, deleting LDHA prevents HFSC activation and the initiation of a new hair cycle (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

“Increasing work is identifying metabolic alterations that correlate with developmental stages in both mouse and human, including variability in preferred substrate for oxidation in the TCA cycle and changes in steady-state levels of TCA cycle metabolites.”

In the paper

“Beyond inherent flexibility in reactions of the TCA cycle, different cell states and contexts also display variability in overall TCA cycle behavior, including preferred substrates for oxidation.”

In the paper

“However, isotope tracing studies in both lung and glioblastoma tumors suggest that glutamine is a relatively minor source of TCA cycle carbon in some cancer cells growing in vivo, indicating that environmental context can drive fuel preferences (193, 194).”

What the sources say

• Not checked yetcites [193] Davidson, 2016, Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer, Cell Metab. source
• Not checked yetcites [194] Marin-Valencia, 2012, Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo, Cell Metab. source

In the paper

“In this system, two metabolic shifts—namely exercise-mediated acidification of muscle cells and succinate accumulation—coordinate to initiate a paracrine signaling cascade during physical activity.”

In the paper

“Beyond being driven by environmental differences between in vitro versus in vivo growth, TCA cycle substrate preferences are also determined by cancer tissue type and driver genetic mutations.”

In the paper

“As described previously, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose in most tissues and tumors (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

“Conversely, cells undergoing exit from the naïve pluripotent state shift toward cytosolic TCA cycle metabolism via the citrate–malate shuttle.”

What the sources say

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

In the paper

“Diverse cell culture model systems and in vivo isotope tracing approaches have combined to illuminate notable heterogeneity in TCA cycle substrate preference and wiring in both normal development and pathological conditions.”

In the paper

“These findings reveal that variability in TCA cycle wiring may drive the metabolic heterogeneity observed across ESCs and other mammalian cell types.”