Hypoxia Induces Production of L-2-Hydroxyglutarate
Open accessAbstract
Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the "oncometabolite" D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of α-ketoglutarate (α-KG)-dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D-enantiomer or the L-enantiomer. Although cancer-associated IDH1/2 mutants produce D-2HG, biochemical studies have demonstrated that L-2HG also functions as a potent inhibitor of α-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of α-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage primarily by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3).
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Under hypoxic conditions, L-2-hydroxyglutarate (L-2-HG) is generated by lactate dehydrogenase A (LDHA) and malate dehydrogenase (MDH).
“Under hypoxic conditions, L-2-hydroxyglutarate (L-2-HG) was proven to be generated by lactate dehydrogenase A (LDHA) and malate dehydrogenase (MDH)88,89.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [88]
L-2-HG is implicated as metabolic mediator of cellular stress response to hypoxia.
“Furthermore, L-2-HG levels were found to increase in response to hypoxia as a result of promiscuous substrate use by LDH-A and malate dehydrogenase (MDH) (Intlekofer et al., 2015), and two recent studies implicate L-2-HG as a metabolic mediator of the cellular stress response to hypoxia (Intlekofer et al., 2015; Oldham et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Intlekofer et al., 2015
L-2-HG levels increase in response to hypoxia due to promiscuous substrate use by LDH-A and MDH.
“Furthermore, L-2-HG levels were found to increase in response to hypoxia as a result of promiscuous substrate use by LDH-A and malate dehydrogenase (MDH) (Intlekofer et al., 2015), and two recent studies implicate L-2-HG as a metabolic mediator of the cellular stress response to hypoxia (Intlekofer et al., 2015; Oldham et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Intlekofer et al., 2015
Succinate accumulates during ischaemia and is oxidised upon reperfusion to drive mitochondrial superoxide formation that contributes to ischaemia-reperfusion injury.
“succinate accumulated during ischaemia and is then oxidised upon reperfusion to drive the mitochondrial superoxide formation that contributes to ischaemia-reperfusion (IR) injury150,151.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [151]
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Self-citation
- Authors
- Intlekofer, A. M., Dematteo, R. G., Venneti, S., Finley, L. W. S., Lu, C., Judkins, A. R., Rustenburg, A. S., Grinaway, P. B., Chodera, J. D., Cross, J. R., & Thompson, C. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Michigan (US)
- University of Southern California (US)
- Corresponding author
- Thompson, Craig B.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 22
- Issue
- 2
- Pages
- 304-311
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4527873
- OpenAlex
- W1916910865
- Cited by
- 513
- References
- 27
- Citations by year
- 2026: 36 · 2025: 40 · 2024: 48 · 2023: 45 · 2022: 45 · 2021: 64 · 2020: 58 · 2019: 53 · 2018: 41 · 2017: 42 · 2016: 34 · 2015: 6
- FWCI
- 13.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (K08CA181475, R01CA177828, R01CA168802, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- L-2-hydroxyglutarate, hypoxia, LDHA, isocitrate dehydrogenase, D-2-hydroxyglutarate, oncometabolites, alpha-ketoglutarate, H3K9 methylation, histone methylation, oxygen limitation, cancer metabolism
- MeSH terms
- Lactate Dehydrogenase 5, Animals, Cell Line, Transformed, Glutarates, Histones, Humans, Isocitrate Dehydrogenase, Isoenzymes, Ketoglutaric Acids, L-Lactate Dehydrogenase, Methylation, Cell Hypoxia, Cell Line, Tumor, Mice, HEK293 Cells
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