Hypoxia Induces Production of L-2-Hydroxyglutarate

Cell Metab. 2015 Aug 4;22(2):304-11. doi: 10.1016/j.cmet.2015.06.023. Epub 2015 Jul 23.

Abstract

Somatic mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) contribute to the pathogenesis of cancer via production of the "oncometabolite" D-2-hydroxyglutarate (D-2HG). Elevated D-2HG can block differentiation of malignant cells by functioning as a competitive inhibitor of α-ketoglutarate (α-KG)-dependent enzymes, including Jumonji family histone lysine demethylases. 2HG is a chiral molecule that can exist in either the D-enantiomer or the L-enantiomer. Although cancer-associated IDH1/2 mutants produce D-2HG, biochemical studies have demonstrated that L-2HG also functions as a potent inhibitor of α-KG-dependent enzymes. Here we report that under conditions of oxygen limitation, mammalian cells selectively produce L-2HG via enzymatic reduction of α-KG. Hypoxia-induced L-2HG is not mediated by IDH1 or IDH2, but instead results from promiscuous substrate usage primarily by lactate dehydrogenase A (LDHA). During hypoxia, the resulting increase in L-2HG is necessary and sufficient for the induction of increased methylation of histone repressive marks, including histone 3 lysine 9 (H3K9me3).

Publication types

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

MeSH terms

  • Animals
  • Cell Hypoxia / physiology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Glutarates / metabolism*
  • HEK293 Cells
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Ketoglutaric Acids / metabolism
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism
  • Lactate Dehydrogenase 5
  • Methylation
  • Mice

Substances

  • Glutarates
  • Histones
  • Isoenzymes
  • Ketoglutaric Acids
  • alpha-hydroxyglutarate
  • L-Lactate Dehydrogenase
  • Lactate Dehydrogenase 5
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • isocitrate dehydrogenase 2, mouse
  • IDH1 protein, human