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

Cell Metab
Authors
Keywords
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.

Year of Publication
2015
Journal
Cell Metab
Volume
22
Issue
2
Pages
291-303
Date Published
2015 Aug 04
ISSN
1932-7420
URL
DOI
10.1016/j.cmet.2015.06.021
PubMed ID
26212716
PubMed Central ID
PMC4526408
Links
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