ArticleThe Journal of biological chemistry2016
Acidic pH Is a Metabolic Switch for 2-Hydroxyglutarate Generation and Signaling.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 96 papers.
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Who cites it
96 citing papers in PubMed, 151 citations in OpenAlex.
- Resolving challenges in detection and quantification of D-2-hydroxyglutarate and L-2-hydroxyglutarate via LC/MS.Methods (San Diego, Calif.) · 2026Article
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- Acidosis and the role of nanotechnology in mitigating cancer progression.Oncology reviews · 2026Review
- 2-Hydroxyglutarate in onco-pathway: a metabolic driver of proto-oncogene activation.Frontiers in oncology · 2026Review
- Comprehensive analysis of human keratinocyte interactions withVirulence · 2025Article
- Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.Nature chemical biology · 2025Article
- Treatment of Isocitrate Dehydrogenase-Mutant Gliomas.Advances in oncology · 2025Article
- Lipoylation inhibition enhances radiation control of lung cancer by suppressing homologous recombination DNA damage repair.Science advances · 2025Article
- Hypoxia-inducible factor 1α is required to establish the larval glycolytic program in Drosophila melanogaster.Molecular metabolism · 2025Article
- Role of the tumor board when prescribing mutant isocitrate dehydrogenase inhibitors to patients with isocitrate dehydrogenase-mutant glioma.Neuro-oncology practice · 2025Review
- Metabolism-driven chromatin dynamics: Molecular principles and technological advances.Molecular cell · 2025Review
- Hypoxia-inducible factor 1α is required to establish the larval glycolytic program inbioRxiv : the preprint server for biology · 2025Article
- The role and regulatory mechanisms of the TCA cycle in early embryonic development.Frontiers in cell and developmental biology · 2025Review
- Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells.Nature metabolism · 2024Article
- Catalytic mechanism and kinetics of malate dehydrogenase.Essays in biochemistry · 2024Review
- ASIC3-activated key enzymes of de novo lipid synthesis supports lactate-driven EMT and the metastasis of colorectal cancer cells.Cell communication and signaling : CCS · 2024Article
- Branched chain α-ketoacids aerobically activate HIF1α signaling in vascular cells.bioRxiv : the preprint server for biology · 2024Article
- Review
36 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
2-Hydroxyglutarate (2-HG) is an important epigenetic regulator, with potential roles in cancer and stem cell biology. The d-(R)-enantiomer (d-2-HG) is an oncometabolite generated from α-ketoglutarate (α-KG) by mutant isocitrate dehydrogenase, whereas l-(S)-2-HG is generated by lactate dehydrogenase and malate dehydrogenase in response to hypoxia. Because acidic pH is a common feature of hypoxia, as well as tumor and stem cell microenvironments, we hypothesized that pH may regulate cellular 2-HG levels. Herein we report that cytosolic acidification under normoxia moderately elevated 2-HG in cells, and boosting endogenous substrate α-KG levels further stimulated this elevation. Studies with isolated lactate dehydrogenase-1 and malate dehydrogenase-2 revealed that generation of 2-HG by both enzymes was stimulated severalfold at acidic pH, relative to normal physiologic pH. In addition, acidic pH was found to inhibit the activity of the mitochondrial l-2-HG removal enzyme l-2-HG dehydrogenase and to stimulate the reverse reaction of isocitrate dehydrogenase (carboxylation of α-KG to isocitrate). Furthermore, because acidic pH is known to stabilize hypoxia-inducible factor (HIF) and 2-HG is a known inhibitor of HIF prolyl hydroxylases, we hypothesized that 2-HG may be required for acid-induced HIF stabilization. Accordingly, cells stably overexpressing l-2-HG dehydrogenase exhibited a blunted HIF response to acid. Together, these results suggest that acidosis is an important and previously overlooked regulator of 2-HG accumulation and other oncometabolic events, with implications for HIF signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.