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Cited by 1,935Mitochondrial Function and PathologyAutophagy in Disease and TherapyMetabolism, Diabetes, and Cancer

The multifaceted contributions of mitochondria to cellular metabolism

Open access
Spinelli, Jessica B., Haigis, Marcia C.·2018·Nature Cell Biology
DOI 10.1038/s41556-018-0124-1PMC PMC6541229
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Abstract

Although classically appreciated for their role as the powerhouse of the cell, the metabolic functions of mitochondria reach far beyond bioenergetics. In this Review, we discuss how mitochondria catabolize nutrients for energy, generate biosynthetic precursors for macromolecules, compartmentalize metabolites for the maintenance of redox homeostasis and function as hubs for metabolic waste management. We address the importance of these roles in both normal physiology and in disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that mitochondria contribute to cellular metabolism well beyond ATP production, serving as bioenergetic powerhouses, biosynthetic hubs, balancers of redox equivalents, and waste-management centres. It synthesizes how metabolic compartmentalization enables these roles in normal physiology and disease, and highlights unresolved questions about metabolite transport and in vitro/in vivo discrepancies.

Key findings

  • Mitochondria catabolize diverse fuels — pyruvate (via MPC, then PDC or PC), glutamine (via GLS/GDH), branched-chain amino acids, and fatty acids (via CPT1/CPT2) — to supply both ATP and TCA cycle intermediates, with compartmentalization determining pyruvate's fate between oxidation and lactate production.
  • Mitochondria are biosynthetic hubs for nucleotides (1C metabolism via SHMT2/MTHFD2, pyrimidines via DHODH), citrate (exported by SLC25A1 for FAS, cholesterol, ketone bodies), amino acids, gluconeogenesis (initiated by PC), and heme (ALAS through FECH).
  • Redox balance depends on shuttles: the malate-aspartate shuttle, citrate-malate shuttle, and α-glycerophosphate shuttle, plus 1C metabolism as a major NADPH source; the cytosolic NAD+/NADH ratio is reported as 60–700 versus approximately 7–8 in mitochondria.
  • Mitochondria manage waste products — ammonia (urea cycle, GS, GDH), ROS (SOD2, Prx3/Prx5, Trx2, TRXR2), and H2S (SQR, SO) — and these by-products also serve signaling roles (e.g., ROS in proliferation and immune activation).

Methods

  • Narrative review; no primary experimental data, sample, or statistical analysis is reported.
  • The authors synthesize published literature across bioenergetics, biosynthesis, redox biology, and waste metabolism, organized around four functional themes with supporting figures (Figures 1–4).
  • No systematic search strategy, inclusion criteria, or quantitative synthesis is described.

Limitations

  • The paper states no formal limitations of its own; it repeatedly flags open questions, including uncharacterized mitochondrial transporters for glutamine, BCAAs, and glutathione, unknown mechanisms of carbamoyl phosphate export, and uncertainty about which transporter dominates malate export in gluconeogenesis.
  • The authors explicitly caution that in vitro and in vivo metabolic dependencies often diverge (e.g., glutaminase inhibitor sensitivity depends on extracellular cystine), and that mitochondrial metabolite concentrations differ from whole-cell concentrations — limitations of the underlying literature rather than of the review itself.
  • Evident from the text: as a narrative review, it offers no new data, and several claims are explicitly speculative (e.g., the authors "speculate" on links between heme metabolism and ROS-sensitive signaling).

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

Integrity signals

Registry

Crossref · 10.1038/s41556-018-0124-1

Cites

164 of 164 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 71 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    PDC deficiency is sufficient to rewire energy metabolism towards aerobic glycolysis despite the potential adaptive node for TCA cycle anaplerosis mediated by PC.

    “PDC deficiency is sufficient to rewire energy metabolism towards aerobic glycolysis despite the potential adaptive node for TCA cycle anaplerosis (a process to replenish TCA cycle intermediates), mediated by PC.28”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Patel, K. P., O’Brien, T. W., Subramony, S. H., Shuster, J. & Stacpoole, P. W. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol. Genet. Metab. 105, 34–43 (2012). source

      Not checked in the free run.

  • Premisenone given

    In mitochondria, glutaminase converts glutamine into glutamate and ammonia.

    “In mitochondria, glutaminase (GLS) converts glutamine into glutamate and ammonia.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The tissue of origin dictates dependency on BCAA catabolism in normal physiology and in cancer.

    “The tissue of origin dictates dependency on BCAA catabolism in normal physiology and in cancer.45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Mayers, J. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016). source

      Not checked in the free run.

  • Premisenone given

    Mitochondrial fatty acid import is a rate-determining step for fatty acid oxidation.

    “Mitochondrial FA import is a rate-determining step for fatty acid oxidation (FAO) and demonstrates how metabolic compartmentalization adapts to cellular state.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Glutamine anaplerosis is critical for meeting the energetic requirements of proliferative cells, such as T cells during the transition from quiescent naïve T cells to effector cells, and in cancers, particularly with MYC elevation.

    “Glutamine anaplerosis is critical for meeting the energetic requirements of proliferative cells, such as T cells during the transition from quiescent naïve T cells to effector cells, and in cancers, particularly with MYC elevation.32,36,37”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [32] DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007). source

      Not checked in the free run.

    • cites [36] Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011). source

      Not checked in the free run.

    • cites [37] Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. 105, 18782–18787 (2008). source

      Not checked in the free run.

  • May combine two claims. 29
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisecitation

    The catabolism of glutamine often starts in the mitochondria and its carbon and nitrogen atoms are distributed into macromolecules throughout the cell, including TCA cycle intermediates, amino acids, nucleotides, glutathione, and lipids.

    “The catabolism of glutamine, the most abundant amino acid, often starts in the mitochondria and its carbon and nitrogen atoms are distributed into macromolecules throughout the cell, including TCA cycle intermediates (important in bioenergetics), amino acids, nucleotides, glutathione, and lipids.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] DeBerardinis, R. J. & Cheng, T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313–324 (2010). source

      Not checked in the free run.

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    Premisecitation

    Pharmacological inhibition of MPC represses mitochondrial pyruvate uptake, shifting reliance to glycolysis for ATP production.

    “Pharmacological inhibition of MPC represses mitochondrial pyruvate uptake, shifting reliance to glycolysis for ATP production.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Herzig, S. et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science 337, 93–96 (2012). source

      Not checked in the free run.

    • cites [16] Bricker, D. K. et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337, 96–100 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The role of MPC is context-dependent and sensitive to mitochondrial respiratory capacity and/or nutrient availability.

    “suggesting that the role of MPC is context-dependent and sensitive to mitochondrial respiratory capacity and/or nutrient availability.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Mitochondria produce metabolic precursors for macromolecules such as lipids, proteins, DNA and RNA.

    “In addition to ATP, mitochondria produce metabolic precursors for macromolecules such as lipids, proteins, DNA and RNA.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Mitochondrial reactions are required components of metabolic pathways because cellular metabolism is compartmentalized.

    “This integral relationship is demonstrated by the compartmentalized nature of cellular metabolism, in which mitochondrial reactions are required components of metabolic pathways.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Cancer cells rewire glucose metabolism for lactate synthesis even in normoxia, known as the Warburg Effect.

    “Otto Warburg observed that cancer cells rewire glucose metabolism for lactate synthesis even in normoxia, known as the Warburg Effect.14,21”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009). source

      Not checked in the free run.

    • cites [21] Diaz-Ruiz, R., Rigoulet, M. & Devin, A. The Warburg and Crabtree effects: on the origin of cancer cell energy metabolism and of yeast glucose repression. Biochim. Biophys. acta 1807, 568–576 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In normoxia, pyruvate is generated via glycolysis and transported across the IMM through the Mitochondrial Pyruvate Carrier, then catabolized inside mitochondria through the TCA cycle.

    “In normoxia, pyruvate is generated via glycolysis and transported across the IMM through the Mitochondrial Pyruvate Carrier (MPC).15,16 Pyruvate is further catabolized inside mitochondria through the TCA cycle.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Herzig, S. et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science 337, 93–96 (2012). source

      Not checked in the free run.

    • cites [16] Bricker, D. K. et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337, 96–100 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BCAA catabolism is repressed in maple syrup urine disease, which is caused by mutations to branched-chain keto acid dehydrogenase and causes dysfunction of immune cells, skeletal muscle and the central nervous system.

    “BCAA catabolism is repressed in maple syrup urine disease, which is caused by mutations to branched-chain keto acid dehydrogenase (BCKDH) and causes dysfunction of immune cells, skeletal muscle and the central nervous system.48”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Blackburn, P. R. et al. Maple syrup urine disease: mechanisms and management. Appl. Clin. Genet. 10, 57–66 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Mitochondria catabolize nutrients for energy, generate biosynthetic precursors for macromolecules, compartmentalize metabolites for redox homeostasis, and function as hubs for metabolic waste management.

    “Mitochondria catabolize nutrients for energy, generate biosynthetic precursors for macromolecules, compartmentalize metabolites for the maintenance of redox homeostasis, and function as hubs for metabolic waste management.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    During hypoxia, mitochondrial respiration is repressed, causing cells to adaptively sink electrons onto pyruvate through lactate dehydrogenase, generating lactate in the cytosol.

    “During hypoxia, mitochondrial respiration is repressed, causing cells to adaptively sink electrons onto pyruvate through lactate dehydrogenase (LDH), generating lactate in the cytosol.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cancer cells repress MPC1 to promote the Warburg Effect, and myocytes of diabetic mice elevate glucose consumption in response to MPC inhibition.

    “This shift is evident in cancer cells, which repress MPC1 to promote the Warburg Effect, and in myocytes of diabetic mice, which elevate glucose consumption in response to MPC inhibition22,23”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Schell, J. C. et al. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol. Cell 56, 400–413 (2014). source

      Not checked in the free run.

    • cites [23] Divakaruni, A. S. et al. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Proc. Natl Acad. Sci. USA 110, 5422–5427 (2013). source

      Not checked in the free run.

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

    Premisenone given

    Mitochondria generate metabolic by-products such as ROS and ammonia and possess mechanisms to clear or utilize waste products.

    “Mitochondria also generate metabolic by-products, such as reactive oxygen species (ROS) and ammonia, and possess mechanisms to clear or utilize waste products.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CPT1 forms acylcarnitines from fatty acyl CoAs; acylcarnitines are shuttled into mitochondria through SLC25A20; CPT2 liberates fatty acid from carnitine, initiating FAO.

    “The outer mitochondrial membrane (OMM) enzyme carnitine palmitoyl transferase 1 (CPT1) forms acylcarnitines from fatty acyl CoAs.50 Acylcarnitines are shuttled into mitochondria through the carnitine–acylcarnitine translocase (SLC25A20) in the IMM. CPT2 liberates FA from carnitine, initiating FAO.51”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] McGarry, J. D. & Brown, N. F. The mitochondrial carnitine palmitoyltransferase system from concept to molecular analysis. Eur. J. Biochem. 244, 1–14 (1997). source

      Not checked in the free run.

    • cites [51] Houten, S. M. & Wanders, R. J. A. A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation. J. Inherit. Metab. Dis. 33, 469–477 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sensitivity to GLS inhibition in vitro is not always consistent in vivo and is dependent on extracellular cystine levels.

    “However, sensitivity to GLS inhibition in vitro is not always consistent in vivo, and is dependent on extracellular cystine levels.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Muir, A. et al. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. eLife 6, e27713 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In normal physiology, myocytes and adipocytes activate mitochondrial BCAA catabolic enzymes to support ATP production during exercise or fasting and differentiation, respectively.

    “In normal physiology, myocytes and adipocytes activate mitochondrial BCAA catabolic enzymes to support ATP production during exercise or fasting and differentiation, respectively.46,47”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Shimomura, Y., Murakami, T., Nakai, N., Nagasaki, M. & Harris, R. A. Exercise promotes BCAA catabolism: effects of BCAA supplementation on skeletal muscle during exercise. J. Nutr. 134, 1583–1587 (2004). source

      Not checked in the free run.

    • cites [47] Green, C. R. et al. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat. Chem. Biol. 12, 15–21 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PDC and PC both catalyze the flux of pyruvate into the TCA cycle, but their metabolic roles do not appear to be interchangeable.

    “Although PDC and PC both catalyze the flux of pyruvate into the TCA cycle, their enzymatic activities can be distinguished by stable isotope tracing26,27, and their metabolic roles do not appear to be interchangeable.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Metallo, C. M., Walther, J. L. & Stephanopoulos, G. Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells. J. Biotech. 144, 167–174 (2009). source

      Not checked in the free run.

    • cites [27] Sellers, K. et al. Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J. Clin. Invest. 125, 687–698 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MTHFD2 expression is regulated by mTORC1 and is critical for growth and proliferation.

    “MTHFD2 expression is regulated by mTORC1, and is critical for growth and proliferation.70”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M. & Manning, B. D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351, 728–733 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SHMT2 favors production of glycine and 5,10 methylene-THF, and cells deficient in mitochondrial 1C metabolism are glycine auxotrophs.

    “SHMT2 favors production of glycine and 5,10 methylene-THF, and cells deficient in mitochondrial 1C metabolism are glycine auxotrophs.68”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Chasin, L. A., Feldman, A., Konstam, M. & Urlaub, G. Reversion of a chinese hamster cell auxotrophic mutant. Proc. Natl Acad. Sci. USA 71, 718–722 (1974). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acetyl CoA from FAO is used for the TCA cycle as well as for aspartate and nucleotide synthesis.

    “Acetyl CoA from FAO is used for the TCA cycle as well as for aspartate and nucleotide synthesis.52”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192–197 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACC2 is hydroxylated by PHD3, and hydroxylation promotes ACC2 activity in nutrient abundance.

    “ACC2 is also hydroxylated by the dioxygenase prolyl hydroxylase 3 (PHD3).55 Hydroxylation promotes ACC2 activity in nutrient abundance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] German, N. J. et al. PHD3 loss in cancer enables metabolic reliance on fatty acid oxidation via deactivation of ACC2. Mol. Cell 63, 1006–1020 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DHODH is targeted in autoimmune disorders and inhibition suppresses myeloid differentiation of AML cells.

    “DHODH is targeted in autoimmune disorders and inhibition suppresses myeloid differentiation of AML cells.75”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Sykes, D. B. et al. Inhibition of dihydroorotate dehydrogenase overcomes differentiation blockade in acute myeloid leukemia. Cell 167, 171–186 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Citrate is generated by citrate synthase or through the reduction of α-ketoglutarate by isocitrate dehydrogenase.

    “Citrate is generated by citrate synthase (CS) or through the reduction of α-ketoglutarate by isocitrate dehydrogenase (IDH).79–81”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [79] Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012). source

      Not checked in the free run.

    • cites [80] Mullen, A. R. et al. Reductive carboxilation supports growth in tumor cells with defective mitochondria. Nature 481, 385–388 (2012). source

      Not checked in the free run.

    • cites [81] Jiang, L. et al. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255–258 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FAO is fundamental for the survival and function of memory CD8+ T cells, unlike effector cells that rely on glycolysis and glutaminolysis for energy.

    “FAO is fundamental for the survival and function of memory CD8+ T cells, unlike effector cells that rely on glycolysis and glutaminolysis for energy.60,61”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009). source

      Not checked in the free run.

    • cites [61] O’Sullivan, D. et al. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41, 75–88 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Malonyl CoA represses CPT1 to inhibit acylcarnitine import, and its levels dictate the balance of fat synthesis or oxidation within a cell.

    “Malonyl CoA, generated by the enzyme acetyl CoA carboxylase (ACC), represses CPT1 to inhibit acylcarnitine import.53 Malonyl CoA is the initiating metabolite for FAS, and its levels dictate the balance of fat synthesis or oxidation within a cell.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Ruderman, N. & Prentki, M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat. Rev. Drug Discov. 3, 340–351 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The 1C metabolic pathway generates and transfers activated one carbon units for de novo nucleotide synthesis, compartmentalizes amino acids, and contributes to redox homeostasis.

    “The 1C metabolic pathway involves a set of reactions that generate and transfer activated one carbon (1C) units for de novo nucleotide synthesis, compartmentalize amino acids, and contribute to redox homeostasis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In low energy conditions, AMPK phosphorylates and inhibits ACC, decreasing malonyl CoA and increasing CPT1 activity.

    “In low energy conditions, AMP-activated protein kinase (AMPK) phosphorylates and inhibits ACC, decreasing malonyl CoA and increasing CPT1 activity.54”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Munday, M. R. Regulation of mammalian acetyl-CoA carboxylase. Biochem. Soc. Trans. 30, 1059–1063 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SLC25A1 is sensitive to membrane rigidity, and high levels of cholesterol or acidic phospholipids in the IMM repress mitochondrial citrate export.

    “SLC25A1 is sensitive to membrane rigidity, and high levels of cholesterol or acidic phospholipids in the IMM repress mitochondrial citrate export.84”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Glerum, D. M., Claeys, D., Mertens, W. SpringerAmpamp; Azzi, A. The tricarboxylate carrier from rat liver mitochondria. Euro. J. Biochem. 194, 681–684 (1990). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FAO is activated in insulin resistance, in which free fatty acids provide a compensatory fuel for repressed glucose uptake.

    “Likewise, FAO is activated in insulin resistance, in which free fatty acids provide a compensatory fuel for repressed glucose uptake.62,63”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] Stern, J. H., Rutkowski, J. M. & Scherer, P. E. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab. 23, 770–784 (2016). source

      Not checked in the free run.

    • cites [63] Serra, D., Mera, P., Malandrino, M. I., Mir, J. F. & Herrero, L. Mitochondrial fatty acid oxidation in obesity. Antioxid. Redox Sign. 19, 269–284 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Activated THF molecules are generated through an oxidative/reductive cycle that catabolizes serine in the mitochondria and synthesizes serine in the cytosol.

    “Activated THF molecules are generated through an oxidative/reductive cycle that catabolizes serine (to generate glycine) in the mitochondria and synthesizes serine in the cytosol.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mitochondrial citrate controls anabolic reactions by directly acting as the carbon source for fatty acids, cholesterol and ketone bodies through ATP citrate lyase, and by allosteric modulation.

    “Mitochondrial citrate controls anabolic reactions by directly acting as the carbon source for FAs, cholesterol and ketone bodies through ATP citrate lyase (ACLY),78 and by allosteric modulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PHD3 is suppressed in cancers that rely on FAO, such as AML and prostate cancer, and elevated in cancers that rely on FAS such as breast and non-small-lung-cell cancer.

    “PHD3 is suppressed in cancers that rely on FAO, such as AML and prostate cancer, and elevated in cancers that rely on FAS such as breast and non-small-lung-cell cancer.55–57”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [55] German, N. J. et al. PHD3 loss in cancer enables metabolic reliance on fatty acid oxidation via deactivation of ACC2. Mol. Cell 63, 1006–1020 (2016). source

      Not checked in the free run.

    • cites [56] Currie, E., Schulze, A., Zechner, R., Walther, T. C. & Farese, R. V. Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 18, 153–161 (2013). source

      Not checked in the free run.

    • cites [57] Svensson, R. U. et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat. Med. 22, 1108–1119 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondria participate in the biosynthesis of nucleotides, fatty acids, cholesterol, amino acids, glucose, and heme.

    “Mitochondria participate in the biosynthesis of nucleotides, FAs, cholesterol, amino acids, glucose, and heme (Figure 2).64”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Ahn, C. S. & Metallo, C. M. Mitochondria as biosynthetic factories for cancer proliferation. Cancer Metab. 3, 1 (2015). source

      Not checked in the free run.

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Research works printed but not linked: 1

  1. Nelson, D. L. & Cox, M. M. Lehninger Principles of Biochemistry. (W.H. Freeman and company, New York, 2005).

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Authors
Spinelli, J. B., & Haigis, M. C.
Affiliations
Harvard University (US)
Corresponding author
Haigis, Marcia C.
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2018-06-27
Volume
20
Issue
7
Pages
745-754
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/s41556-018-0124-1
PMC
PMC6541229
OpenAlex
W2809281987
Semantic Scholar
34ccb7994b9f5158a07c5aebd168839ff3256cea
Cited by
1,935
References
164
Citations by year
2026: 317 · 2025: 346 · 2024: 331 · 2023: 309 · 2022: 228 · 2021: 222 · 2020: 131 · 2019: 43 · 2018: 7
FWCI
9.89
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA213062)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
mitochondria, cellular metabolism, energy metabolism, biosynthetic precursors, redox homeostasis, mitochondrial disease
MeSH terms
Animals, Biological Transport, Cell Survival, Energy Metabolism, Homeostasis, Humans, Mitochondria, Oxidation-Reduction, Signal Transduction, Reactive Oxygen Species, Oxidative Stress

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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