Cell Metabolism
Volume 22, Issue 2, 4 August 2015, Pages 291-303
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Article
Hypoxia-Mediated Increases in l-2-hydroxyglutarate Coordinate the Metabolic Response to Reductive Stress

https://doi.org/10.1016/j.cmet.2015.06.021Get rights and content
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Highlights

  • Hypoxia increases cellular l-2-hydroxyglutarate (L2HG)

  • L2HG accumulates in response to mitochondrial dysfunction

  • This accumulation is independent of hypoxia-inducible factor activation

  • L2HG inhibits electron transport and glycolysis to mitigate reductive stress

Summary

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.

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