Hypoxia Induces Production of L-2-Hydroxyglutarate

Intlekofer, Andrew M.; DeMatteo, Raymond G.; Venneti, Sriram; Finley, Lydia W.S.; Lü, Chao; Judkins, Alexander R.; Rustenburg, Ariën S.; Grinaway, Patrick; Chodera, John D.; Cross, Justin R.; Thompson, Craig B.

doi:10.1016/j.cmet.2015.06.023

Cited by 402 publications

(467 citation statements)

References 28 publications

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“…As previously reported, addition of cell-permeable αKG resulted in a modest increase in 2HG production in cells cultured in standard medium in normoxia (Fig. 6c) 17 . However, we observed a synergistic enhancement of 2HG production when cells were cultured in acidified medium supplemented with cell-permeable αKG (Fig.…”

Section: Resultssupporting

confidence: 84%

“…Accumulation of L-2HG slows glycolysis and mitochondrial respiration by reducing the regeneration of NAD +18 . Moreover, hypoxia-induced L-2HG promotes the same repressive chromatin marks that characterize the differentiation blockade of IDH-mutant malignancies 8,17,19 , consistent with the well established association between hypoxic niches and stem cell populations 20 .…”

supporting

confidence: 78%

“…Prior reports implicated lactate dehydrogenase A (LDH) and malate dehydrogenase 1 and 2 (MDH) as contributing to hypoxia-induced L-2HG in cells (Fig. 1a) 17,18 . To determine if these enzymes could directly produce L-2HG, we tested the ability of purified LDH and MDH to catalyze NADH-dependent reduction of their canonical substrates as well as αKG.…”

Section: Resultsmentioning

confidence: 94%

“…It was recently reported that hypoxia induces production of L-2HG by both normal and malignant cells as a physiologic response to oxygen limitation 17,18 . Hypoxia-induced production of L-2HG occurs independently of HIF but acts to reinforce the hypoxic response, at least in part, through stabilization of HIF protein 13,17,18 .…”

mentioning

confidence: 99%

“…Hypoxia-induced production of L-2HG occurs independently of HIF but acts to reinforce the hypoxic response, at least in part, through stabilization of HIF protein 13,17,18 . Accumulation of L-2HG slows glycolysis and mitochondrial respiration by reducing the regeneration of NAD +18 .…”

mentioning

confidence: 99%

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L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via ‘promiscuous’ reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.

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Section: Resultssupporting

confidence: 84%

supporting

confidence: 78%

Section: Resultsmentioning

confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

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L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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Abundance of d‐2‐hydroxyglutarate in G2/M is determined by FOXM1 in mutant IDH1‐expressing cells

et al. 2019

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Isocitrate dehydrogenases (IDHs) are metabolic enzymes that are mutated in several cancers, resulting in overproduction of d‐2‐hydroxyglutarate (D‐2HG). However, the signalling pathways and factors that regulate mutant IDHs or their metabolites remain elusive. Here, we report that in synchronized cells and cells treated with anti‐mitotic agents, wild‐type and mutant IDH proteins are induced maximally in G2/M. Moreover, mutant IDH1‐expressing cells arrested in G2/M harbour high D2HG levels. Genetic or pharmacological perturbation of Forkhead box protein M1 (FOXM1) abrogates the levels of IDH1 mRNA, protein and D2HG in G2/M. Conversely, overexpression of FOXM1 or hyperactive FOXM1 activates the IDH1 promoter and increases the abundance of its protein levels. In summary, our results show that in G2/M, higher D2HG levels are dependent on FOXM1‐mediated transcription of IDH1.

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Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells

et al. 2022

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Mutations in genes encoding cytochrome c oxidase (mitochondrial complex IV) subunits and assembly factors [e.g., synthesis of cytochrome c oxidase 2 (SCO2)] are linked to severe metabolic syndromes. Notwithstanding that SCO2 is under transcriptional control of tumor suppressor p53, the role of mitochondrial complex IV dysfunction in cancer metabolism remains obscure. Herein, we demonstrate that the loss of SCO2 in HCT116 colorectal cancer cells leads to significant metabolic and signaling perturbations. Specifically, abrogation of SCO2 increased NAD+ regenerating reactions and decreased glucose oxidation through citric acid cycle while enhancing pyruvate carboxylation. This was accompanied by a reduction in amino acid levels and the accumulation of lipid droplets. In addition, SCO2 loss resulted in hyperactivation of the insulin‐like growth factor 1 receptor (IGF1R)/AKT axis with paradoxical downregulation of mTOR signaling, which was accompanied by increased AMP‐activated kinase activity. Accordingly, abrogation of SCO2 expression appears to increase the sensitivity of cells to IGF1R and AKT, but not mTOR inhibitors. Finally, the loss of SCO2 was associated with reduced proliferation and enhanced migration of HCT116 cells. Collectively, herein we describe potential adaptive signaling and metabolic perturbations triggered by mitochondrial complex IV dysfunction.

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Hypoxia Induces Production of L-2-Hydroxyglutarate

Cited by 402 publications

References 28 publications

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

Abundance of d‐2‐hydroxyglutarate in G2/M is determined by FOXM1 in mutant IDH1‐expressing cells

Mitochondrial complex IV defects induce metabolic and signaling perturbations that expose potential vulnerabilities in HCT116 cells

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