D-2-hydroxyglutarate produced by mutant Idh1 perturbs collagen maturation and basement membrane function

Masato Sasaki, Christiane B. Knobbe, Momoe Itsumi, Andrew J. Elia, Isaac S. Harris, Iok In Christine Chio, Rob A. Cairns, Susan Mccracken, Andrew Wakeham, Jillian Haight, Annick You Ten, Bryan Snow, Takeshi Ueda, Satoshi Inoue, Kazuo Yamamoto, Myunggon Ko, Anjana Rao, Katharine E. Yen, Shinsan M. Su, Tak Wah Mak

Research output: Contribution to journalArticlepeer-review

245 Citations (Scopus)

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 knockin (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.

Original languageEnglish
Pages (from-to)2038-2049
Number of pages12
JournalGenes and Development
Volume26
Issue number18
DOIs
Publication statusPublished - 2012 Sept 15
Externally publishedYes

Keywords

  • Angiogenesis
  • Basement membrane
  • Brain hemorrhage
  • Collagen biosynthesis
  • Metabolism
  • Oxidative stress

ASJC Scopus subject areas

  • General Medicine

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