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Cited by 398Cancer, Hypoxia, and MetabolismImmune cells in cancerCancer Immunotherapy and Biomarkers

Coupling Krebs cycle metabolites to signalling in immunity and cancer

Open access
Ryan, Dylan G., Murphy, Michael P., Frezza, Christian, Prag, Hiran A., Chouchani, Edward T., O’Neill, Luke A., Mills, Evanna L.·2018·Nature Metabolism
DOI 10.1038/s42255-018-0014-7PMC PMC6485344
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Abstract

Metabolic reprogramming has become a key focus for both immunologists and cancer biologists, with exciting advances providing new insights into the mechanisms underlying disease. There is now extensive evidence that intermediates and derivatives of the mitochondrial Krebs cycle—metabolites traditionally associated with bioenergetics or biosynthesis—also possess ‘non-metabolic’ signalling functions. In this review, we summarize the non-metabolic signalling mechanisms of succinate, fumarate, itaconate, 2-hydroxyglutarate isomers (d-2-hydroxyglutarate and l-2-hydroxyglutarate) and acetyl-CoA, with a specific focus on how such signalling pathways alter immune cell and transformed cell function. We believe that the insights gained from immune and cancer cells that are summarized here will also be useful for understanding and treating a range of other diseases. Intermediate metabolites of the Krebs cycle serve bioenergetic and biosynthetic needs but have recently also been linked to signalling. The authors of this Review summarize such non-metabolic signalling functions of succinate, fumarate, itaconate, 2-hydroxyglutarate isomers and acetyl-CoA in both immune cells and cancer cells.

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Written from the paper’s full text.

TL;DR

This review argues that Krebs cycle intermediates—succinate, itaconate, fumarate, 2-HG, and acetyl-CoA—act as signalling molecules in immune cells and cancer beyond bioenergetics. It synthesizes mechanisms by which these metabolites alter inflammation, epigenetics, and tumorigenesis, and discusses therapeutic implications.

Key findings

  • Succinate accumulates in LPS/IFN-γ-treated macrophages and promotes inflammation via SUCNR1, HIF-1α stabilization, mtROS/RET at complex I, succinylation, and epigenetic regulation; SDH inhibition by DMM/malonate reduces LPS-induced HIF-1α, IL-1β, and ROS and boosts IL-10/IL-1RA.
  • Itaconate, produced by IRG1/CAD from cis-aconitate, is anti-inflammatory: it inhibits SDH, induces Nrf2 via KEAP1 cysteine alkylation (e.g., C151), and can regulate the IκBζ–ATF3 axis; 4-OI was protective in LPS lethality. In peritoneal tumours, tumour-infiltrating macrophage-derived itaconate boosted OXPHOS/mtROS/MAPK and tumour growth.
  • Fumarate acts as an oncometabolite and immunomodulator: FH mutations cause HLRCC; fumarate succinates KEAP1, GAPDH, ACO2, and Fe-S proteins, inhibits α-KGDDs/TETs/JMJDs, drives pseudohypoxia and EMT; in β-glucan-trained monocytes fumarate accumulation is required for trained immunity and H3K4me3 at Tnf/Il6.
  • 2-HG enantiomers regulate immunity/cancer: D-2-HG from mutant IDH1/2 inhibits α-KGDDs (KDM IC50 24–106 μM; FIH 1.5 mM; PHD2 7.3 mM) and accumulates up to 35 mM in IDH-mutant glioma; L-2-HG rises up to 1.5 mM in TCR-triggered mouse CD8+ T cells and enhances anti-tumour capacity. Acetyl-CoA from citrate via ACLY supports histone acetylation and immune/tumour gene expression.

Methods

  • Narrative review; no primary experimental design, sample, or dataset is reported.
  • Synthesizes published literature on succinate, itaconate, fumarate, 2-HG, and acetyl-CoA in immunity and cancer; no systematic search strategy, inclusion criteria, or meta-analysis is described.
  • Main analysis is conceptual/mechanistic synthesis with figures and therapeutic discussion.

Limitations

  • Stated: limited human and in vivo data; rapid steady-state metabolism makes accurate in vivo snapshots challenging; human immune cell studies are limited.
  • Stated: many open questions remain about metabolite ratios/compartments, unidentified GPCRs/transporters, and whether metabolites are biomarkers or drivers; oncometabolite findings often come from rare cancer syndromes.
  • Evident: as a narrative review, it does not systematically assess evidence quality or quantify bias; many mechanistic claims rely on mouse/cell-line studies and cited primary papers.

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

Integrity signals

Registry

Crossref · 10.1038/s42255-018-0014-7

Cites

205 of 205 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    A selective SUCNR1 antagonist is protective in hypertension, a disease in which succinate is elevated.

    “A selective antagonist for human and rat has been shown to be protective in hypertension, a disease in which succinate is elevated11.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Hollander, A. P., Corke, K. P., Freemont, A. J. & Lewis, C. E. Expression of hypoxia-inducible factor 1α by macrophages in the rheumatoid synovium: implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum. 44, 1540–1544 (2001). source

      Not checked in the free run.

  • Premisereasoning

    LPS can stabilize HIF-1α indirectly by increasing succinate levels.

    “LPS can also stabilize HIF-1α indirectly, by increasing succinate levels.”
    Quote in the paperSubstantial claim
  • Premisecitation

    HIF-1 transcriptionally directs a switch in metabolism from oxidative phosphorylation to glycolysis, allowing rapid ATP production without oxygen.

    “It transcriptionally directs a switch in metabolism from oxidative phosphorylation to glycolysis, which allows rapid ATP production without the need for oxygen15.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Lewis, G. D. et al. Metabolic signatures of exercise in human plasma. Sci. Transl. Med. 2, 33ra37 (2010). source

      Not checked in the free run.

  • Premisenone given

    HIF-1α is regulated by prolyl hydroxylases, α-KG-dependent dioxygenases that convert α-KG to succinate and use molecular oxygen to hydroxylate HIF-1α.

    “HIF-1α is tightly regulated by prolyl hydroxylases (PHD), a class of α-ketoglutarate (α-KG)-dependent dioxygenases (α-KGDDs) that convert α-KG to succinate and use molecular oxygen to hydroxylate HIF-1α.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Priming of DCs with succinate and antigen simultaneously elevates antigen-specific T cell activation, increasing TNFα and IFN-γ production.

    “Priming of DCs with succinate and antigen simultaneously, elevates antigen-specific T cell activation, increasing TNFα and IFN-γproduction from these cells4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Chouchani, E. T. et al. A unifying mechanism for mitochondrial superoxide production during ischemia–reperfusion injury. Cell. Metab. 23, 254–263 (2016). source

      Not checked in the free run.

  • May combine two claims. 98
  • Classified as probably not a substantial claim. 7

  • May combine two claims.

    Premisecitation

    HIF-1 binds hypoxia response elements in target genes and increases expression of glycolytic enzymes and glucose transporters GLUT1 and GLUT3.

    “HIF-1 binds to hypoxia response elements (HREs) in target genes and increases the expression of numerous glycolytic enzymes and the glucose transporters (GLUT)1 and GLUT3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LPS-induced succinate inhibits PHD activity in macrophages directly and indirectly via ROS, resulting in stabilization of HIF-1α.

    “Analogous to tumours, LPS-induced succinate was shown to both directly and indirectly (via ROS) inhibit PHD activity in macrophages resulting in stabilization of HIF-1α2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TRAP1 is highly expressed in many tumors and decreases SDH activity, causing succinate accumulation.

    “An additional mechanism by which succinate accumulates tumors involves the mitochondrial chaperone, tumor necrosis factor receptor-associated protein 1 (TRAP1) which is highly expressed in many tumors22. TRAP1 decreases SDH activity and succinate accumulates as a result.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Epstein, A. C. R. et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43–54 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the presence of oxygen, conserved proline residues in HIF-1α are hydroxylated by PHD 1, 2 and 3, providing a recognition site for VHL E3 ubiquitin ligase, which ubiquitinates HIF-1α and targets it for proteasomal degradation.

    “In the presence of oxygen, conserved proline residues in the HIF-1α subunit are hydroxylated by PHD 1, 2 and 3 16. Hydroxylation provides a recognition site for the binding of Von Hippel-Lindau (VHL) E3 ubiquitin ligase, which ubiquitinates HIF-1α and subsequently targets it for proteasomal degradation17.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Peruzzotti-Jametti, L. et al. Macrophage-derived extracellular succinate licenses neural stem cells to suppress chronic neuroinflammation. Cell Stem Cell 22, 355–368.e13 (2018). source

      Not checked in the free run.

    • cites [17] Bhuniya, D. et al. Discovery of a potent and selective small molecule hGPR91 antagonist. Bioorg. Med. Chem. Lett. 21, 3596–3602 (2011). source

      Not checked in the free run.

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    Premisecitation

    SUCNR1 is highly expressed in mouse kidney, liver, spleen, small intestine, and on dendritic cells, and ligand binding induces Gi and Gq signalling cascades.

    “SUCNR1 is highly expressed in mouse kidney, liver, spleen, small intestine3, and on dendritic cells (DCs) 4 and ligand binding induces Gi and Gq signalling cascades3.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] He, W. et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193 (2004). source

      Not checked in the free run.

    • cites [4] Chouchani, E. T. et al. A unifying mechanism for mitochondrial superoxide production during ischemia–reperfusion injury. Cell. Metab. 23, 254–263 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Extracellular succinate acts in synergy with TLR ligands to increase TNFα and IL-1β expression and increases the capacity of DCs to act as antigen presenting cells.

    “Extracellular succinate addition also acts in synergy with TLR ligands to increase TNFα and IL-1β expression4 and increases the capacity of DCs to act as antigen presenting cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Chouchani, E. T. et al. A unifying mechanism for mitochondrial superoxide production during ischemia–reperfusion injury. Cell. Metab. 23, 254–263 (2016). source

      Not checked in the free run.

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

    Premisecitation

    Succinate is elevated in plasma after acute exercise and in marathon runners.

    “Specifically, succinate is elevated in plasma after acute exercise and in marathon runners175.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Sivanand, S. et al. Nuclear acetyl-CoA production by ACLY promotes homologous recombination. Mol. Cell 67, 252–265.e56 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Succinate acts through direct generation of mitochondrial ROS, activation of HIF-1α, and ligation of SUCNR1 to exert inflammatory effects.

    “succinate has been shown to act through several pathways to exert its inflammatory effects: through direct generation of mitochondrial ROS (mtROS), by activation of hypoxia-inducible factor-1alpha (HIF-1α; discussed below), and by through ligation of the G-protein coupled receptor succinate receptor 1 (SUCNR1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a mouse model of multiple sclerosis, transplantation of neural stem cells reduces succinate levels in the cerebrospinal fluid and decreases infiltration of damaging macrophages and microglial cells.

    “In a mouse model of multiple sclerosis (MS) transplantation of neural stem cells (NSCs) reduced succinate levels in the cerebrospinal fluid and thereby decreased infiltration of damaging macrophages and microglial cells10.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Kim, S. et al. Global metabolite profiling of synovial fluid for the specific diagnosis of rheumatoid arthritis from other inflammatory arthritis. PLoS One 9, e97501 (2014). source

      Not checked in the free run.

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    Premisecitation

    Succinate and α-KG act as ligands for the orphan G-protein coupled receptors GPR91 (now SUCNR1) and GPR99 (now OXGR1), respectively.

    “He and colleagues made an important discovery when they found that the Krebs cycle-derived metabolites, succinate and α-KG, acted as ligands for the orphan G-protein coupled receptors GPR91 (now known as SUCNR1) and GPR99 (now known as OXRG1), respectively3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] He, W. et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193 (2004). source

      Not checked in the free run.

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    Premisecitation

    In limited oxygen, HIF-1α degradation is prevented, allowing translocation to the nucleus, dimerization with HIF-1β and binding of target genes.

    “This degradation is prevented in conditions of limited oxygen, allowing for HIF-1α translocation to the nucleus, dimerization with HIF-1β and binding of target genes13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] van Diepen, J. A. et al. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. Diabetologia 60, 1304–1313 (2017). source

      Not checked in the free run.

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    Premisecitation

    Succinate acts as a hypertensive agent, modulating the renin-angiotensin system via SUCNR1 signalling, independent of its role in bioenergetics.

    “The authors demonstrated that succinate acted as an important hypertensive agent, modulating the renin-angiotensin system via SUCNR1 signalling, independent of its role in bioenergetics3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] He, W. et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS impair the activity of FIH, which hydroxylates an asparagine residue in HIF-1α and decreases transcriptional activity.

    “ROS also impair the activity of Factor Inhibiting HIF (FIH), another member of the α-KGDD family25, which hydroxylates an asparagine residue in the carboxy terminal of HIF-1α resulting in a decrease in transcriptional activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Frede, S., Stockmann, C., Freitag, P. & Fandrey, J. Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB. Biochem. J. 396, 517–527 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Succinate is a pro-inflammatory metabolite that accumulates in LPS/IFN-γ-treated macrophages.

    “Recent data indicate that succinate is a pro-inflammatory metabolite that accumulates in LPS/IFN-γ-treated macrophages1,2.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015). source

      Not checked in the free run.

    • cites [2] Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ligation of SUCNR1 on neural stem cells upregulates the dicarboxylate co-transporter Slc13a3/5, correlating with increased succinate uptake by the NSCs.

    “Mechanistically, ligation of SUCNR1 on the surface of NSCs upregulates the expression of the dicarboxylate co-transporter Slc13a3/5, which correlates with increased uptake by the NSCs thereby scavenging succinate away from pro-inflammatory immune cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Kim, S. et al. Global metabolite profiling of synovial fluid for the specific diagnosis of rheumatoid arthritis from other inflammatory arthritis. PLoS One 9, e97501 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS stabilize HIF-1α by inducing non-enzymatic decarboxylation of α-KG and by oxidizing Fe2+ to Fe3+.

    “ROS-can stabilize HIF-1α by inducing non-enzymatic decarboxylation of α-KG24 and by oxidizing iron (Fe2+) to Fe3+, two required PHD co-factors25.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643 (2013). source

      Not checked in the free run.

    • cites [25] Frede, S., Stockmann, C., Freitag, P. & Fandrey, J. Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-κB. Biochem. J. 396, 517–527 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In the absence of SUCNR1, a reduction in absolute numbers of macrophages, but not inflammatory signalling, is observed and this improves adipose tissue inflammation and glucose tolerance in mice following high-fat diet feeding.

    “In the absence of SUCNR1 a reduction in absolute numbers of macrophages, but not inflammatory signalling, was observed and this resulted in an improvement in adipose tissue inflammation and improved glucose tolerance in mice following high-fat diet feeding.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Succinate inhibits the PHDs via product inhibition and stabilizes HIF-1α.

    “The PHDs generate succinate from α-KG, and importantly succinate (acting via product inhibition) will inhibit the PHDs and stabilize HIF-1α21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Semenza, G. L. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda) 24, 97–106 (2009).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following LPS treatment, both intracellular succinate levels and cell surface expression of SUCNR1 are increased.

    “Following LPS treatment both intracellular succinate levels and the cell surface expression of SUCNR1 are increased.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Rubic, T. et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat. Immunol. 9, 1261–1269 (2008). source

      Not checked in the free run.

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    Premisecitation

    Lysine succinylation is caused by accumulation of succinyl-CoA, which can result from SDH inhibition and succinate accumulation.

    “This modification is caused by the accumulation of succinyl-CoA, which can result from SDH inhibition and succinate accumulation38.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Jin, Z., Wei, W., Yang, M., Du, Y. & Wan, Y. Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell. Metab. 20, 483–498 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Complex I of the electron transport chain is an important site of ROS production in macrophages and such ROS production may depend on reverse electron transport.

    “These data suggest that complex I of the ETC is an important site of ROS production in macrophages and such ROS production may depend on RET.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Succinate can have profound impacts on cellular function acting intracellularly via ROS and HIF-1α, succinylation and histone and DNA modification and extracellularly via SUCNR1.

    “These data demonstrate that succinate can have profound impacts on cellular function acting both intracellularly via ROS and HIF-1α, succinylation and histone and DNA modification and extracellularly via SUCNR1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Training with β-glucan is protective against Staphylococcus aureus infection and this effect is abrogated in HIF-1α-deficient mice.

    “Training with β-glucan was shown to be protective against Staphylococcus aureus infection and this effect was abrogated in HIF-1α-deficient mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] El-Khoury, R. et al. Engineering the alternative oxidase gene to better understand and counteract mitochondrial defects: state of the art and perspectives. Br. J. Pharmacol. 171, 2243–2249 (2014). source

      Not checked in the free run.

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    Premisecitation

    SIRT5 desuccinylates and activates PKM2 and limits IL-1β production.

    “The authors demonstrate that SIRT5 desuccinylates and activates PKM2 and this limits IL-1β production.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Zhang, Z. et al. Identification of lysine succinylation as a new post-translational modification. Nat. Chem. Biol. 7, 58–63 (2011). source

      Not checked in the free run.

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    Premisecitation

    DI potently induces Nrf2 and several Nrf2 target genes in control and LPS-activated BMDMs.

    “DI was first employed as an experimental tool and was shown to potently induce Nrf2 and several Nrf2 target genes in control and LPS-activated BMDMs59.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

      Not checked in the free run.

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    Premisecitation

    Itaconate modulates inflammation by competitively inhibiting SDH and succinate oxidation.

    “Lampropoulou and colleagues (2016) suggested that mechanistically the ability of itaconate to modulate inflammation arose from its ability to competitively inhibit SDH and succinate oxidation50.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell. Proteomics 11, 100–107 (2012). source

      Not checked in the free run.

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    Premisecitation

    This potentiation requires both succinate oxidation by SDH and an increase in mitochondrial membrane potential.

    “This requires both succinate oxidation by the enzyme succinate dehydrogenase (SDH) and an increase in mitochondrial membrane potential.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). source

      Not checked in the free run.

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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Itaconate is an important immunomodulatory metabolite that negatively regulates the inflammatory response and cytokine production.

    “Since 2016, several key studies have uncovered a role for itaconate as a crucial anti-inflammatory metabolite that negatively regulates the inflammatory response and cytokine production50,59–61, as shown in Figure 3.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [50] Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell. Proteomics 11, 100–107 (2012). source

      Not checked in the free run.

    • cites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

      Not checked in the free run.

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  • May combine two claims.

    Premisecitation

    Irg1-deficient BMDMs exhibit a significant increase in production of IL-12, IL-6, NO, and under NLRP3 inflammasome-activating conditions, increased IL-1β and IL-18.

    “Furthermore, Irg1-deficient BMDMs, whereby genetic deletion of Irg1 completely abolished itaconate synthesis, exhibited a significant increase in the production of IL-12, IL-6, NO, and under conditions that activate the NLRP3 inflammasome, increased IL-1β and IL-1850.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell. Proteomics 11, 100–107 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LPS-induced HIF-1α not only promotes glycolysis but is also directly pro-inflammatory.

    “LPS-induced HIF-1α not only promotes glycolysis but is also directly pro-inflammatory.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Sustained induction of IL-1β in response to LPS requires HIF-1α and occurs under normoxia.

    “The sustained induction of IL-1β in response to LPS was shown to require HIF-1α and to occur under normoxia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SirT5 has potent desuccinylase and demalonylase activity.

    “SirT5, which was previously thought to function primarily as a deacetylase has been shown to have potent desuccinylase activity 44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Cheng, S. C. et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Limiting succinate oxidation with dimethylmalonate represses LPS-induced HIF-1α, IL-1β and ROS and boosts IL-10 and IL-1RA.

    “Limiting succinate oxidation with the pro-drug dimethylmalonate (DMM), which releases malonate that inhibits SDH function, profoundly represses LPS-induced HIF-1α, IL-1β and ROS and boosts IL-10 and IL-1RA.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Succinylation is evolutionarily conserved and its substrates are numerous, including proteins involved in cellular metabolism.

    “Western blot analysis of whole cell lysates revealed that this modification is evolutionarily conserved and that substrates are numerous39 and include proteins involved in cellular metabolism38.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Jin, Z., Wei, W., Yang, M., Du, Y. & Wan, Y. Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell. Metab. 20, 483–498 (2014). source

      Not checked in the free run.

    • cites [39] Murphy, M. P. How mitochondria produce reactive oxygen species. Biochem. J. 417, 1–13 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Itaconate is an α,β-unsaturated carbonyl compound and a potential Michael acceptor that could undergo nucleophilic attack by the thiolate ion of protein cysteine residues.

    “It is also important to note that itaconate is an α,β-unsaturated carbonyl compound, making it a potential Michael acceptor that could undergo nucleophilic attack by the thiolate ion of protein cysteine residues, as such the methyl esterification of the proximal carboxyl group conjugated to the alkene would be predicted to increase the electrophilicity of itaconate63.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Michelucci, A. et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc. Natl. Acad. Sci. USA. 110, 7820–7825 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Training with β-glucan induces epigenetic upregulation of glycolytic genes including HIF-1α, hexokinase and pyruvate kinase and increases succinate levels.

    “Interestingly, in addition to potentiating cytokine production in response to LPS, training with β-glucan induced epigenetic upregulation of genes involved in glycolysis such as HIF-1α, Hexokinase (HK) and pyruvate kinase and increased succinate levels37.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] El-Khoury, R. et al. Engineering the alternative oxidase gene to better understand and counteract mitochondrial defects: state of the art and perspectives. Br. J. Pharmacol. 171, 2243–2249 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of HIF-1α in macrophages decreases TNF-α, IL-1β and IL-1α production but does not affect production of IL-4 or IL-10.

    “The loss of HIF-1α in macrophages decreased TNF-α, IL-1β and IL-1α production, but did not affect production of the anti-inflammatory cytokines IL-4 or IL-10 29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Mu, X. et al. Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation. Oncotarget 8, 13174–13185 (2017). source

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  • May combine two claims.

    Premisecitation

    Inhibition of IκBξ by DI is mediated by activation of ATF3 and occurs at the level of Nfkbiz translation, as assessed by eIF2α phosphorylation, in a Nrf2-independent manner.

    “inhibition of IκBξ by DI was shown to be mediated by activation of the transcription factor ATF3 and occur at the level of Nfkbiz translation, as assessed by eIF2α phosphorylation, in a Nrf2-independent manner60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Supplementation of ROS in Irg1-deficient BMDMs increases A20 expression and abolishes the break of endotoxin tolerance.

    “Supplementation of ROS in Irg1-deficient BMDMs increased A20 expression and abolished the break of endotoxin tolerance67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBξ–ATF3 inflammatory axis. Nature 556, 501–504 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DI selectively inhibits LPS-induced IL-6 while TNF-α levels remain unaffected.

    “DI is reported to selectively inhibit LPS-induced IL-6 while TNF-α levels remain unaffected”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    4-OI is protective in an LPS lethality model in vivo, prolonging survival, improving body temperature regulation and decreasing pro-inflammatory cytokine production.

    “4-OI was also shown to be protective in an LPS lethality model in vivo, prolonging survival, improving body temperature regulation and decreasing pro-inflammatory cytokine production59.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Elevated fumarate levels may act as an endogenous anti-inflammatory signal to limit inflammation.

    “Intriguingly, endogenous fumarate was also found to succinate GAPDH in both mouse and human macrophages, suggesting that elevated fumarate levels may act as an endogenous anti-inflammatory signal to limit inflammation, however, the precise role of fumarate accumulation remains an open question to be explored.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Fumarate accumulation inhibits the KDM5 family of histone demethylases, increasing H3K4me3 at the promoters of Tnf and Il6.

    “The authors proposed that fumarate accumulation acted to inhibit the KDM5 family of histone demethylases, which subsequently increased the levels of H3K4me3, a marker of active gene transcription, at the promoters of both Tnf and Il6, thus providing the first link between Krebs cycle rewiring and epigenetic regulation in an inflammatory context97.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Rustin, P. et al. Inborn errors of the Krebs cycle: a group of unusual mitochondrial diseases in human. Biochim. Biophys. Acta 1361, 185–197 (1997). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fumarate binds glutathione, forming succinic-glutathione, and depletes this antioxidant molecule leading to unscheduled oxidative stress.

    “Later, it was also shown that fumarate binds glutathione (forming succinic-glutathione (succinicGSH)), and thereby depletes this antioxidant molecule leading to unscheduled oxidative stress83,84.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] Shi, H. Z., Wang, D., Sun, X. N. & Sheng, L. MicroRNA-378 acts as a prognosis marker and inhibits cell migration, invasion and epithelial-mesenchymal transition in human glioma by targeting IRG1. Eur. Rev. Med. Pharmacol. Sci. 22, 3837–3846 (2018).

      Not checked in the free run.

    • cites [84] Pan, J. et al. Immune responsive gene 1, a novel oncogene, increases the growth and tumorigenicity of glioma. Oncol. Rep. 32, 1957–1966 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased IRG1 in glioma is associated with a decrease in miR-378, which targets Irg1, and poorer overall survival and clinicopathological parameters.

    “This was associated with a decrease in the microRNA miR-378, which targets Irg1 as well as poorer overall survival and clinicopathological parameters.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Li, Y. et al. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J. Biol. Chem. 288, 16225–16234 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HLRCC is characterised by benign tumours of smooth muscle of skin and uterus and a very aggressive form of renal cancer.

    “However, in 2002 it was shown that mutations of FH are the cause of Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a cancer predisposition syndrome characterised by benign tumours of the smooth muscle of skin and uterus, and a very aggressive form of renal cancer78.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Cheon, Y. P., Xu, X., Bagchi, M. K. & Bagchi, I. C. Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. Endocrinology 144, 5623–5630 (2003). source

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  • May combine two claims.

    Premisecitation

    DMF and MMF modify and irreversibly inhibit GAPDH enzymatic activity and aerobic glycolysis in PBMCs from mice and MS patients treated with DMF.

    “This suggestion arose from the observation that the cell-permeable fumaric esters, DMF and MMF, modify and irreversibly inhibit GAPDH enzymatic activity and aerobic glycolysis in peripheral blood mononuclear cells (PBMCs) from mice and MS patients treated with DMF99.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Blatnik, M., Thorpe, S. R. & Baynes, J. W. Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. Ann. NY Acad. Sci. 1126, 272–275 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    There are two mechanisms for itaconate-induced Nrf2 activation: directly via KEAP1 2,3-dicarboxypropylation and indirectly via ROS production.

    “suggesting there are two mechanisms for itaconate-induced Nrf2 activation; directly via KEAP1 2,3-dicarboxypropylation and indirectly via ROS production (which would then modify KEAP1)75.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    DMF blocks the association of PKCθ with CD28 and T cell activation.

    “Mechanistically, DMF blocked the association of PKCθ with the costimulatory receptor CD28 and T cell activation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] He, D. et al. Global proteome analyses of lysine acetylation and succinylation reveal the widespread involvement of both modification in metabolism in the embryo of germinating rice seed. J. Proteome Res. 15, 879–890 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The argininosuccinate shunt accounts for elevated fumarate levels observed in macrophages.

    “As Asl cleaves argininosuccinate into arginine and fumarate, the authors proposed that this metabolic pathway accounted for the elevated fumarate levels observed in macrophages1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015). source

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  • May combine two claims.

    Premisecitation

    DMF but not MMF inhibits activation of human and mouse T cells.

    “Blewett and colleagues (2016) demonstrated that dimethyl fumarate (DMF), a potent electrophile which is currently used to treat psoriasis and relapse-remitting MS, but not MMF inhibited the activation of human and mouse T cells 49.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] He, D. et al. Global proteome analyses of lysine acetylation and succinylation reveal the widespread involvement of both modification in metabolism in the embryo of germinating rice seed. J. Proteome Res. 15, 879–890 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Elevated fumarate levels negatively regulate glycolysis via succination of the active site cysteine residue C152 in GAPDH.

    “More recently, Kornberg and colleagues (2018) suggested that a potential consequence of elevated fumarate levels is to negatively regulate glycolysis via succination of the active site cysteine residue (C152) in GAPDH99,100.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [99] Blatnik, M., Thorpe, S. R. & Baynes, J. W. Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. Ann. NY Acad. Sci. 1126, 272–275 (2008). source

      Not checked in the free run.

    • cites [100] Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IRG1 is essential for OXPHOS-driven mtROS production and bactericidal killing in zebrafish macrophages.

    “The effect of itaconate on ROS production is consistent with a previous study in zebrafish macrophages, which demonstrated that IRG1 was essential for OXPHOS-driven mtROS production and bactericidal killing172.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell. Metab. 20, 306–319 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of miR-378 suppresses glioma tumour growth in vitro and in vivo, EMT and metastasis.

    “Overexpression of miR-378 suppressed glioma tumour growth both in vitro and in vivo, the epithelial-mesenchymal transition (EMT) and metastasis75.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Li, Y. et al. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J. Biol. Chem. 288, 16225–16234 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fumarate acts as a powerful inhibitor of the TET family of DNA demethylases and of a series of histone demethylases.

    “Recent data demonstrated that fumarate acts as a powerful inhibitor of the TET family of DNA demethylases and of a series of histone demethylases91,92.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Angiari, S. & O’Neill, L. A. Dimethyl fumarate: targeting glycolysis to treat MS. Cell Res. 28, 613–615 (2018). source

      Not checked in the free run.

    • cites [92] Kornberg, M. D. et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449–453 (2018). source

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  • May combine two claims.

    Premisecitation

    Inhibition of GOT1 by AOAA decreases D-2-HG levels and promotes Foxp3 expression and differentiation of TH17 cells to iTregs.

    “Inhibition of GOT1 by aminooxyacetic acid (AOAA), which decreases D-2-HG levels, promoted expression Foxp3 and the differentiation of TH17 cells to iTregs143.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Germline mutations in L2HGDH and D2HGDH cause L-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria.

    “The cause of these so-called 2-hydroxyglutaric acidurias (2HGAs) was attributed to germline mutations in L-2-HG dehydrogenase (L2HGDH) and D-2-HG dehydrogenase (D2HGDH), the mitochondrial enzymes responsible for the conversion of 2-HG to α-KG and thus its breakdown107-109.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [107] Bardella, C. et al. Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J. Pathol. 225, 4–11 (2011). source

      Not checked in the free run.

    • cites [108] Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016). source

      Not checked in the free run.

    • cites [109] Salminen, A., Kauppinen, A. & Kaarniranta, K. 2-Oxoglutarate-dependent dioxygenases are sensors of energy metabolism, oxygen availability, and iron homeostasis: potential role in the regulation of aging process. Cell. Mol. Life Sci. 72, 3897–3914 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Fumarate accumulation promotes genomic alterations that could give rise to cancer formation in HLRCC patients, cooperating with other oncogenic signals.

    “Overall, these lines of evidence provide a potential model for how fumarate accumulation promotes genomic alterations that could give rise to cancer formation in HLRCC patients, cooperating with the other above-described oncogenic signals it elicits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CD8+ T cells are highly dependent on activation of HIF-1α and glycolysis, which mediates trafficking into hypoxic tumour environments and inflamed tissue.

    “Like TH17 cells, CD8+ T cells are highly dependent on the activation of HIF-1α and glycolysis, which is responsible for mediating trafficking into hypoxic tumour environments and inflamed tissue147,148.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [147] Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012). source

      Not checked in the free run.

    • cites [148] Wang, P. et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 32, 3091–3100 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nuclear FH generates fumarate via its reverse activity, which inhibits KDM2B and facilitates binding of DNA repair proteins.

    “Here, via its reverse activity, it generates fumarate that inhibits histone lysine demethylase KDM2B, which in turn facilitates the binding of proteins involved in DNA repair177.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Valls-Lacalle, L. et al. Selective inhibition of succinate dehydrogenase in reperfused myocardium with intracoronary malonate reduces infarct size. Sci. Rep. 8, 2442 (2018). source

      Not checked in the free run.

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

    Premisecitation

    In D2HGA, about 50% of patients present with D2HGDH mutations, while the remaining half possess mutations in IDH2.

    “In the case of D2HGA, about 50% of patients present with D2HGDH mutations, while the remaining half possess mutations in the Krebs cycle enzyme isocitrate dehydrogenase 2 (IDH2), which converts isocitrate to α-KG110.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 8, 143–153 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TH17 cells rely heavily on a switch from OXPHOS to glycolysis, requiring activation of HIF-1α and induction of RORγt.

    “T-helper 17 (TH17) cells, derived from naïve CD4+ T cells, are one such subset that rely heavily on a switch from OXPHOS to glycolysis, a process that requires the activation of HIF-1α and induction of RORγt143,146.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [143] Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009). source

      Not checked in the free run.

    • cites [146] Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 17, 510–522 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CDKN2A (P16) is hypermethylated and suppressed in tumours of HLRCC patients.

    “Consistent with an important role of senescence bypass for the development of tumorigenesis, recent data in HLRCC patients showed that CDKN2A (also known as P16), a key player in senescence, is hypermethylated and suppressed in tumours85.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Frezza, C. Mitochondrial metabolites: undercover signalling molecules. Interface Focus 7, 20160100 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated D-2-HG is associated with increased DNA methylation at the Foxp3 locus, resulting in its repression.

    “The elevated levels of D-2-HG was associated with increased DNA methylation levels at the Foxp3 locus, the master transcription factor driving iTreg differentiation, resulting in its repression143.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TH17 cell differentiation can be initiated by exogenous addition of D-2-HG to naïve CD4+ T cells or by genetic silencing of TET1 and TET2.

    “Furthermore, TH17 cell differentiation could be initiated by exogenous addition of D-2-HG to naïve CD4+ T cells or by genetic silencing of TET1 and TET2, established targets of 2-HG143-145.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [143] Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009). source

      Not checked in the free run.

    • cites [144] Chowdhury, R. et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463 (2011). source

      Not checked in the free run.

    • cites [145] Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 19, 17–30 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon DNA damage, FH localises in the nucleus where it is phosphorylated by DNA-PKcs.

    “Upon DNA damage, FH localises in the nucleus, where it is phosphorylated by the catalytic subunit of DNA-PK (DNA-PKcs)177.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [177] Valls-Lacalle, L. et al. Selective inhibition of succinate dehydrogenase in reperfused myocardium with intracoronary malonate reduces infarct size. Sci. Rep. 8, 2442 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aberrant accumulation of fumarate in HLRCC correlates with increased endogenous damage, lower DNA repair efficiency and increased sensitivity to PARP inhibitors.

    “In support of this unexpected function of fumarate, it was recently shown that the aberrant accumulation of this metabolite in HLRCC correlates with increased endogenous damage, lower DNA repair efficiency and increased sensitivity to poly-ADP ribose polymerase (PARP) inhibitors178.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [178] Kohlhauer, M. et al. Metabolomic profiling in acute ST-segment-elevation myocardial infarction identifies succinate as an early marker of human ischemia-reperfusion injury. J. Am. Heart Assoc. 7, e007546 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    D-2-HG inhibits FIH and PHD2 with IC50 values of 1.5 and 7.3 mM, respectively.

    “Although the IC50 of D-2-HG toward KDM family members is in the low micromolar range (24-106 μM), it can also inhibit FIH and PHD2, with IC50 values of 1.5 and 7.3 mM, respectively121.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Duran, M., Kamerling, J. P., Bakker, H. D., van Gennip, A. H. & Wadman, S. K. l-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J. Inherit. Metab. Dis. 3, 109–112 (1980). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HIF-1α stabilisation induces LDHA expression and activity, which converts glutamine-derived α-KG to L-2-HG.

    “Mechanistically, HIF-1α stabilisation induced LDHA expression and activity, which promiscuously converted glutamine-derived α-KG to L-2-HG149.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    D-2-HG occupies the active site of histone demethylases, increasing histone methylation in primary gliomas.

    “D-2-HG produced by mIDH1/2 has been shown to drive a CpG island methylator phenotype (G-CIMP) in both glioma and ICC tumours to promote tumorigenesis, and has also been found to occupy the active site of histone demethylases thereby increasing histone methylation in primary gliomas121,123-125.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [121] Duran, M., Kamerling, J. P., Bakker, H. D., van Gennip, A. H. & Wadman, S. K. l-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J. Inherit. Metab. Dis. 3, 109–112 (1980). source

      Not checked in the free run.

    • cites [123] Rzem, R. et al. A gene encoding a putative FAD-dependent l-2-hydroxyglutarate dehydrogenase is mutated in l-2-hydroxyglutaric aciduria. Proc. Natl. Acad. Sci. USA 101, 16849–16854 (2004). source

      Not checked in the free run.

    • cites [124] Struys, E. A. et al. Mutations in the d-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am. J. Hum. Genet. 76, 358–360 (2005). source

      Not checked in the free run.

    • cites [125] Topçu, M. et al. l-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum. Mol. Genet. 13, 2803–2811 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L-2HG production under hypoxia is independent of IDH1 and 2 and primarily mediated by LDHA and MDH via promiscuous reduction of αKG, enhanced by acidic pH.

    “The authors demonstrate that this is independent of IDH1 and 2 and primarily mediated by LDHA and malate dehydrogenase (MDH) via “promiscuous” reduction of αKG and this is enhanced by acidic pH52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Wang, Y. et al. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature 552, 273–277 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    D-2-HG-induced metabolic rewiring decreases NAAG, and NAAG levels are significantly lower in IDH-mutant human glioma tissue.

    “This metabolic rewiring resulted in a decrease in a common dipeptide found in the brain N-acetyl-aspartyl-glutamate (NAAG), and NAAG levels were found to be significantly lower in IDH-mutant human glioma tissue134.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 18, 553–567 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    mIDH-derived D-2-HG accumulation is directly linked to DNA damage, genetic instability and carcinogenesis.

    “As such, these findings directly link mIDH-derived D-2-HG accumulation to DNA damage, genetic instability and carcinogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    D-2-HG accumulation in IDH-mutant glioma inhibits PHD hydroxylase and stabilises HIF-1α.

    “Indeed, D-2-HG accumulation in IDH-mutant glioma has been found to inhibit PHD hydroxylase and stabilise HIF-1α126 and HIF-1αstabilisation has been shown to occur in IDH1-mutant brain tissue127.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Kranendijk, M. et al. IDH2 mutations in patients with d-2-hydroxyglutaric aciduria. Science 330, 336 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Somatic mutations in IDH1 and IDH2 are among the first genetic events in tumorigenesis in human glioma and AML and initiate pathogenesis by a common mechanism.

    “Genomic studies have established that somatic mutations in IDH1 and IDH2 are perhaps the first genetic events to occur during tumorigenesis in human glioma and AML, and appear to initiate pathogenesis by a common mechanism103,115-117.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [103] Linehan, W. M. et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N. Engl. J. Med. 374, 135–145 (2016). source

      Not checked in the free run.

    • cites [115] Yogev, O. et al. Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response. PLoS Biol. 8, e1000328 (2010). source

      Not checked in the free run.

    • cites [116] Jiang, Y. et al. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat. Cell Biol. 17, 1158–1168 (2015). source

      Not checked in the free run.

    • cites [117] Sulkowski, P. L. et al. Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat. Genet. 50, 1086–1092 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under acidic conditions, αKG is protonated, promoting binding to LDHA and L-2HG production.

    “Under acidic conditions αKG is protonated and this promotes binding to LDHA and L-2HG production.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Wang, Y. et al. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature 552, 273–277 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IDH-mutant cells display reduced DNA repair kinetics, accumulate DNA double stranded breaks, and are sensitized to alkylating agents.

    “Indeed, IDH-mutant cells display reduced DNA repair kinetics, accumulate DNA double stranded breaks (DSBs) and are sensitized to alkylating agents131,174.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [131] MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013). source

      Not checked in the free run.

    • cites [174] Mi, W. et al. YEATS2 links histone acetylation to tumorigenesis of non-small cell lung cancer. Nat. Commun. 8, 1088 (2017). source

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  • May combine two claims.

    Interpretationcitation

    D-2-HG accumulation under pathogenic conditions may contribute to tumorigenicity by stabilizing HIF-1α and impairing collagen biogenesis.

    “the concentrations at which it accumulates under pathogenic conditions suggests HIF-1α stabilisation and impaired collagen biogenesis may contribute to tumorigenicity126-130.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [126] Kranendijk, M. et al. IDH2 mutations in patients with d-2-hydroxyglutaric aciduria. Science 330, 336 (2010). source

      Not checked in the free run.

    • cites [127] Nota, B. et al. Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined d-2- and l-2-hydroxyglutaric aciduria. Am. J. Hum. Genet. 92, 627–631 (2013). source

      Not checked in the free run.

    • cites [128] Dang, L. & Su, S. M. Isocitrate dehydrogenase mutation and R-2-hydroxyglutarate: from basic discovery to therapeutics development. Annu. Rev. Biochem. 86, 305–331 (2017). source

      Not checked in the free run.

    • cites [129] Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009). source

      Not checked in the free run.

    • cites [130] Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The increase in L-2-HG in CD8+ T cells occurs under normoxic conditions and is dependent on HIF-1α stabilisation.

    “This increase occurred under normoxic conditions and was dependent on HIF-1α stabilisation149.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L-2HG is sufficient to alter histone methylation, in particular H3K9me3, and can promote HIF-1α stabilization in normoxia.

    “Functionally, L-2HG is both sufficient to try histone methylation, in particular histone 3 lysine 9 (H3K9me3), and can also promote HIF-1α stabilization in normoxia and therefore may assist with hypoxic adaptation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Du, J. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Almost all IDH1/2 mutations occur in a few unique locations in the active site, resulting in neomorphic activity converting α-KG to D-2-HG.

    “Remarkably, almost all IDH1/2 mutations occur in a few unique locations in the active site of the enzymes, which results in the acquirement of a neomorphic enzymatic activity converting α-KG to the oncometabolite D-2-HG118-120.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [118] Johnson, T. I., Costa, A. S. H., Ferguson, A. N. & Frezza, C. Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation. Cell Death Dis. 9, 913 (2018). source

      Not checked in the free run.

    • cites [119] Ye, D., Guan, K. L. & Xiong, Y. Metabolism, activity, and targeting of d- and l-2-Hydroxyglutarates. Trends Cancer 4, 151–165 (2018). source

      Not checked in the free run.

    • cites [120] Chalmers, R. A. et al. d-2-hydroxyglutaric aciduria: case report and biochemical studies. J. Inherit. Metab. Dis. 3, 11–15 (1980). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACLY is required to enhance histone acetylation levels and induce expression of cell cycle regulating genes in response to IL-2.

    “The authors demonstrate that ACLY is required to enhance histone acetylation levels and induce the expression of cell cycle regulating genes in response to IL-2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Meiser, J. et al. Pro-inflammatory macrophages sustain pyruvate oxidation through pyruvate dehydrogenase for the synthesis of itaconate and to enable cytokine expression. J. Biol. Chem. 291, 3932–3946 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Citrate acts as a source of acetyl-CoA to drive histone acetylation, with impacts on tumor and immune cell function.

    “Citrate, a component of the TCA cycle has been shown to act as a source of acetyl-CoA to drive histone acetylation and this process can have profound impacts on both tumor and immune cell function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Gibson, G. E. et al. α-ketoglutarate dehydrogenase complex–dependent succinylation of proteins in neurons and neuronal cell lines. J. Neurochem. 134, 86–96 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    D-2-HG binds DNA methyltransferase DNMT1, which represses RIP3.

    “D-2-HG has also been found to bind the DNA methyltransferase DNMT1, which subsequently represses receptor-interacting protein kinase 3 (RIP3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [140] Watanabe, T., Nobusawa, S., Kleihues, P. & Ohgaki, H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am. J. Pathol. 174, 1149–1153 (2009). source

      Not checked in the free run.

    • cites [141] Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LDHA-deficient T cells show decreased acetyl-CoA levels and decreased H3K9Ac on the Ifng promoter.

    “Mechanistically LDHA-deficient T cells showed decreased acetyl-CoA levels and decreased histone H3 acetylation at the lysine 9 residue (H3K9Ac), a histone mark associated with active transcription, on the Ifng promoter.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACL is required for response to growth factor stimulation and during differentiation, including differentiation of murine 3T3-L1 pre-adipocytes into adipocytes.

    “One of the earliest studies to identify a role for ACL in histone acetylation demonstrated a requirement for this gene in response to growth factor stimulation and during differentiation, for example the differentiation of murine 3T3- L1 pre-adipocytes into adipocytes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Wang, F. et al. SIRT5 desuccinylates and activates pyruvate kinase M2 to block macrophage IL-1β production and to prevent dss-induced colitis in mice. Cell Rep. 19, 2331–2344 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    D-2-HG impairs necroptosis and the small GTPase Cdc42, leading to suppression of MLK3-mediated apoptosis.

    “Finally, D-2HG also impairs necroptosis and the small GTPase Cdc42, leading to suppression of mixed lineage kinase 3 (MLK3)-mediated apoptosis140,141.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [140] Watanabe, T., Nobusawa, S., Kleihues, P. & Ohgaki, H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am. J. Pathol. 174, 1149–1153 (2009). source

      Not checked in the free run.

    • cites [141] Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Artificial acetyl-CoA reduction through ACLY inhibition decreases IFN-γ expression, and acetate supplementation corrects H3K9Ac marks and IFN-γ expression in LDHA-deficient T cells.

    “Furthermore, artificial acetyl-CoA reduction, through inhibition of ACLY, decreased IFN-γ expression and acetate supplementation, which augmented acetyl-CoA production, corrected H3K9Ac marks and IFN-γ expression in LDHA-deficient T cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Histone acetylation in mammalian cells is dependent on ACL, and ACL silencing decreases histone acetylation.

    “It has been demonstrated in mammalian cells that histone acetylation is dependent on ACL, the enzyme that converts citrate into acetyl-CoA, a required co-factor for acetylation,54 with ACL silencing decreasing the degree of histone acetylation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Wang, F. et al. SIRT5 desuccinylates and activates pyruvate kinase M2 to block macrophage IL-1β production and to prevent dss-induced colitis in mice. Cell Rep. 19, 2331–2344 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACLY deficiency results in impaired BRCA1 recruitment to DSBs and suppression of homologous recombination.

    “ACLY deficiency results in impaired BRCA1 recruitment to sites of DSBs and suppression of homologous recombination.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACLY is phosphorylated downstream of AKT activation following DNA damage and facilitates histone acetylation at DSB sites, enabling BRCA1 recruitment and DNA repair by homologous recombination.

    “ACLY is phosphorylated downstream of AKT activation, following DNA damage and this facilitates histone acetylation at double strand break (DSB) sites, enabling breast cancer early onset 1 (BRCA1) recruitment and DNA repair by homologous recombination.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Succinate production is enhanced during inflammation, acting as a signal from mitochondria to cytosol to activate pro-inflammatory gene expression and generating ROS as a pro-inflammatory redox signal.

    “The production of succinate is also enhanced during inflammation13, acting as a signal from mitochondria to the cytosol to activate pro-inflammatory gene expression while also generating ROS as a further pro-inflammatory redox signal28.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] van Diepen, J. A. et al. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. Diabetologia 60, 1304–1313 (2017). source

      Not checked in the free run.

    • cites [28] Rasola, A., Neckers, L. & Picard, D. Mitochondrial oxidative phosphorylation TRAP(1)ped in tumor cells. Trends Cell Biol. 24, 455–463 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice with T cell-specific LDHA deficiency produce less IFN-γ and are protected from immunopathology.

    “Mice with an T cell-specific LDHA deficiency produced less IFN-γ and were protected from immunopathology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    D-2-HG is a competitive inhibitor of SDH, resulting in succinate accumulation, impaired mitochondrial oxygen consumption, and increased protein succinylation.

    “D-2-HG has also been found to be a competitive inhibitor of SDH, a key metabolic enzyme and tumour suppressor as previously discussed, resulting in the accumulation of succinate, impaired mitochondrial oxygen consumption and increased protein succinylation139.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Suzuki, H. et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat. Genet. 47, 458–468 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    D-2-HG activates NF-κB in bone marrow stromal cells in an IκB kinase-independent fashion, generating a stromal niche for IDH mutant AML development.

    “D-2-HG activates NF-κB in bone marrow stromal cells in an IκB kinase-independent fashion, thus generating a stromal niche for IDH mutant AML development138.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Finlay, D. K. et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209, 2441–2453 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High levels of succinate or 2-HG inhibit α-KGDDs, including PHDs, TET DNA demethylases, and JMJDs.

    “High levels of succinate or 2-HG inhibit α-KGDDs. These include the PHDs, the TET DNA demethylases, and the JMJDs154-156”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [60] Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995). source

      Not checked in the free run.

    • cites [61] Shin, J. H. et al. 1H NMR-based metabolomic profiling in mice infected with Mycobacterium tuberculosis. J. Proteome Res. 10, 2238–2247 (2011). source

      Not checked in the free run.

    • cites [62] Sugimoto, M. S. H. Y. et al. Non-targeted metabolite profiling in activated macrophage secretion. Metabolomics 8, 624–633 (2011). source

      Not checked in the free run.

    • cites [154] Sasaki, M. et al. d-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 26, 2038–2049 (2012). source

      Not checked in the free run.

    • cites [155] Tarhonskaya, H. et al. Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases. Nat. Commun. 5, 3423 (2014). source

      Not checked in the free run.

    • cites [156] Wang, P. et al. Oncometabolite d-2-hydroxyglutarate inhibits ALKBH DNA repair enzymes and sensitizes IDH mutant cells to alkylating agents. Cell Rep. 13, 2353–2361 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibitors of α-KGDDs are often non-specific, hitting multiple isoforms or α-KGDD family members, such as DMOG acting on TETs but also PHDs.

    “Inhibitors of α-KGDDs are often non-specific, either hitting multiple isoforms or a-KGDD family members, such as dimethyloxaloylglycine (DMOG) acting on TETs but also PHDs [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Nadjsombati, M. S. et al. Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit. Immunity 49, 33–41.e7 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Specific PHD inhibitors such as Vadadustat have shown promise in chronic kidney disease, increasing erythropoiesis and providing a means of attenuating HIF in other pathologies.

    “However, specific PHD inhibitors have been developed, such as Vadadustat, and have shown promise in chronic kidney disease, increasing erythropoiesis and providing a means of attenuating HIF in other pathologies [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Kim, S. et al. Global metabolite profiling of synovial fluid for the specific diagnosis of rheumatoid arthritis from other inflammatory arthritis. PLoS One 9, e97501 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Enasidenib binds the mutated but not wild-type form of IDH2 to prevent D-2-HG production.

    “a drug Enasidenib has been developed for AML, which binds to the mutated, but not the wild-type, form of IDH2 only to prevent D-2-HG production163.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Chen, J. Y. et al. The oncometabolite R-2-hydroxyglutarate activates NF-κB-dependent tumor-promoting stromal niche for acute myeloid leukemia cells. Sci. Rep. 6, 1 (2016). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Limited human and in vivo data exist on metabolite signalling.

    “One critical point to consider is the limited human and in vivo data existing to date.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Studies in human immune cells are currently very limited.

    “Studies in human immune cells are also currently very limited.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Succinate promotes a potentially tumour-fighting, pro-inflammatory state but also drives HIF-1α activation in tumours associated with cancer progression.

    “succinate, which promotes a potentially tumour-fighting, pro-inflammatory state also drives HIF-1α activation in tumours which is associated with cancer progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    4-OI is an itaconate mimic that is protective in a mouse model of sepsis, decreasing cytokine production and increasing survival.

    “4-OI is an itaconate mimic that was protective in a mouse model of sepsis, decreasing cytokine production and increasing survival59.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Okabe, M., Lies, D., Kanamasa, S. & Park, E. Y. Biotechnological production of itaconic acid and its biosynthesis in Aspergillus terreus. Appl. Microbiol. Biotechnol. 84, 597–606 (2009). source

      Not checked in the free run.

103 of 103

Claims other papers make about this one

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

  • The nervous system coordinates whole-body metabolism by producing neurohormones that act locally and by direct innervation of target tissues.

    “Alternatively, the nervous system coordinates whole‐body metabolism not only by the production of neurohormones that act locally, but also by direct innervation of the target tissues 2, 3, 4, 5.”

    From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [2]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The fifth Krebs-cycle step is assigned to the wrong enzyme

    Minor

    The paper describes OGDH as catalysing the fourth step and succinyl-CoA synthetase as producing GTP or ATP in the following step. It then attributes that fifth, substrate-level phosphorylation step to OGDH.

  • Citation 75 does not identify the stated Weiss study

    Minor

    The statement attributes an itaconate-ROS-Nrf2 finding to Weiss and colleagues and cites reference 75. Reference 75 instead lists Shi and colleagues' glioma microRNA study; the listed Weiss study is reference 74.

  • PHD inhibition is described as attenuating HIF

    Minor

    The paper says PHD activity marks HIF-1α for degradation. Inhibiting PHDs would therefore oppose, rather than provide, that mechanism for attenuating HIF.

3 of 3

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Related

Authors
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L.
Affiliations
  • Trinity College Dublin (IE)
  • University of Cambridge (GB)
  • Harvard University (US)
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2018-12-30
Volume
1
Issue
1
Pages
16-33
ISSN
2522-5812 (ISSN-L)
DOI
10.1038/s42255-018-0014-7
PMC
PMC6485344
OpenAlex
W2907926991
Semantic Scholar
b15b8b89360b980cc180d451684d173275b9488c
Cited by
398
References
205
Citations by year
2026: 35 · 2025: 39 · 2024: 70 · 2023: 41 · 2022: 66 · 2021: 66 · 2020: 61 · 2019: 20
FWCI
3.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (110158/Z/15/Z, 205455, 110159/Z/ 15/Z, 109443/Z/15/Z)
  • Medical Research Council (MC_UU_00015/3, MC_UU_12022/6)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
Krebs cycle metabolites, metabolic reprogramming, succinic acid, fumarate, itaconate, 2-hydroxyglutarate, acetyl-CoA, immune cell function, cancer, carcinogenesis, tumor immunology, therapeutic target
MeSH terms
Citric Acid Cycle, Humans, Immunity, Innate, Macrophages, Neoplasms, Succinate Dehydrogenase, Succinates, Signal Transduction, Succinic Acid

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 2026-10-10.

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

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