D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2

Nat Commun. 2015 Jul 16;6:7768. doi: 10.1038/ncomms8768.

Abstract

Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2-HG into α-KG, mediated by D2-hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.

Publication types

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

MeSH terms

  • Alcohol Oxidoreductases / genetics*
  • Blotting, Western
  • Cell Line, Tumor
  • DNA Methylation / genetics
  • Dioxygenases / metabolism*
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • Hydroxylation / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Ketoglutaric Acids / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Methylation
  • Real-Time Polymerase Chain Reaction

Substances

  • HIF1A protein, human
  • Histones
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ketoglutaric Acids
  • Alcohol Oxidoreductases
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • D2HGDH protein, human
  • Dioxygenases