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Cell Metab DOI:10.1016/j.cmet.2015.06.021

Hypoxia-Mediated Increases in L-2-hydroxyglutarate Coordinate the Metabolic Response to Reductive Stress.

Publication TypeJournal Article
Year of Publication2015
AuthorsOldham, WM, Clish, CB, Yang, Y, Loscalzo, J
JournalCell Metab
Volume22
Issue2
Pages291-303
Date Published2015 Aug 04
ISSN1932-7420
KeywordsAdaptation, 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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1550-4131(15)00288-0
DOI10.1016/j.cmet.2015.06.021
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26212716?dopt=Abstract

Alternate JournalCell Metab.
PubMed ID26212716
PubMed Central IDPMC4526408
Grant ListU01 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