Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Oldham, WM, Clish, CB, Yang, Y, Loscalzo, J |
Journal | Cell Metab |
Volume | 22 |
Issue | 2 |
Pages | 291-303 |
Date Published | 2015 Aug 04 |
ISSN | 1932-7420 |
Keywords | Adaptation, Physiological, Cell Hypoxia, Citric Acid Cycle, Glutarates, Glycolysis, HEK293 Cells, Hep G2 Cells, Humans, Malate Dehydrogenase, Oxidation-Reduction, Stress, Physiological |
Abstract | Metabolic adaptation to hypoxia is critical for survival in metazoan species for which reason they have developed cellular mechanisms for mitigating its adverse consequences. Here, we have identified L-2-hydroxyglutarate (L2HG) as a universal adaptive determinant of the hypoxia response. L2HG is a metabolite of unknown function produced by the reduction of mitochondrial 2-oxoglutarate by malate dehydrogenase. L2HG accumulates in response to increases in 2-oxoglutarate, which occur as a result of tricarboxylic acid cycle dysfunction and increased mitochondrial reducing potential. These changes are closely coupled to cellular redox homeostasis, as increased cellular L2HG inhibits electron transport and glycolysis to offset the adverse consequences of mitochondrial reductive stress induced by hypoxia. Thus, L2HG couples mitochondrial and cytoplasmic energy metabolism in a model of cellular redox regulation. |
URL | http://linkinghub.elsevier.com/retrieve/pii/S1550-4131(15)00288-0 |
DOI | 10.1016/j.cmet.2015.06.021 |
Pubmed | |
Alternate Journal | Cell Metab. |
PubMed ID | 26212716 |
PubMed Central ID | PMC4526408 |
Grant List | U01 HL108630 / HL / NHLBI NIH HHS / United States HL007633 / HL / NHLBI NIH HHS / United States T32 HL007633 / HL / NHLBI NIH HHS / United States P01 HL048743 / HL / NHLBI NIH HHS / United States HL048743 / HL / NHLBI NIH HHS / United States R01 HL061795 / HL / NHLBI NIH HHS / United States P50 GM107618 / GM / NIGMS NIH HHS / United States HL108630 / HL / NHLBI NIH HHS / United States HL061795 / HL / NHLBI NIH HHS / United States R37 HL061795 / HL / NHLBI NIH HHS / United States GM107618 / GM / NIGMS NIH HHS / United States |
Cell Metab DOI:10.1016/j.cmet.2015.06.021
Hypoxia-Mediated Increases in L-2-hydroxyglutarate Coordinate the Metabolic Response to Reductive Stress.
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