D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function

Genes Dev. 2012 Sep 15;26(18):2038-49. doi: 10.1101/gad.198200.112. Epub 2012 Aug 27.

Abstract

Isocitrate dehydrogenase-1 (IDH1) R132 mutations occur in glioma, but their physiological significance is unknown. Here we describe the generation and characterization of brain-specific Idh1 R132H conditional knock-in (KI) mice. Idh1 mutation results in hemorrhage and perinatal lethality. Surprisingly, intracellular reactive oxygen species (ROS) are attenuated in Idh1-KI brain cells despite an apparent increase in the NADP(+)/NADPH ratio. Idh1-KI cells also show high levels of D-2-hydroxyglutarate (D2HG) that are associated with inhibited prolyl-hydroxylation of hypoxia-inducible transcription factor-1α (Hif1α) and up-regulated Hif1α target gene transcription. Intriguingly, D2HG also blocks prolyl-hydroxylation of collagen, causing a defect in collagen protein maturation. An endoplasmic reticulum (ER) stress response induced by the accumulation of immature collagens may account for the embryonic lethality of these mutants. Importantly, D2HG-mediated impairment of collagen maturation also led to basement membrane (BM) aberrations that could play a part in glioma progression. Our study presents strong in vivo evidence that the D2HG produced by the mutant Idh1 enzyme is responsible for the above effects.

Publication types

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

MeSH terms

  • Animals
  • Basement Membrane / metabolism
  • Basement Membrane / pathology*
  • Brain / cytology
  • Brain / pathology
  • Collagen / metabolism*
  • Gene Knock-In Techniques
  • Genotype
  • Glioma / pathology
  • Glutarates / metabolism*
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism*
  • Mice
  • Mutation
  • Protein Stability
  • Reactive Oxygen Species / metabolism
  • Stress, Physiological

Substances

  • Glutarates
  • Reactive Oxygen Species
  • alpha-hydroxyglutarate
  • Collagen
  • Isocitrate Dehydrogenase

Grant support