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

Cell Metab. 2015 Aug 4;22(2):291-303. doi: 10.1016/j.cmet.2015.06.021. Epub 2015 Jul 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / physiology*
  • Cell Hypoxia / physiology
  • Citric Acid Cycle / physiology*
  • Glutarates / metabolism*
  • Glycolysis / physiology*
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Malate Dehydrogenase / metabolism*
  • Oxidation-Reduction
  • Stress, Physiological*


  • Glutarates
  • alpha-hydroxyglutarate
  • Malate Dehydrogenase