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

研究成果: Article査読

242 被引用数 (Scopus)


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.

ジャーナルGenes and Development
出版ステータスPublished - 2012 9月 15

ASJC Scopus subject areas

  • 医学(全般)


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