D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function
- Masato Sasaki1,
- Christiane B. Knobbe1,2,
- Momoe Itsumi1,
- Andrew J. Elia1,
- Isaac S. Harris1,3,
- Iok In Christine Chio1,3,
- Rob A. Cairns1,
- Susan McCracken1,
- Andrew Wakeham1,
- Jillian Haight1,
- Annick You Ten1,
- Bryan Snow1,
- Takeshi Ueda1,
- Satoshi Inoue1,
- Kazuo Yamamoto1,
- Myunggon Ko4,
- Anjana Rao4,
- Katharine E. Yen5,
- Shinsan M. Su5 and
- Tak Wah Mak1,3,6
- 1The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada;
- 2Department of Neuropathology, Heinrich Heine University, 40225 Düsseldorf, Germany;
- 3Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada;
- 4La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA;
- 5Agios Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA
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.
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Footnotes
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↵6 Corresponding author
E-mail tmak{at}uhnres.utoronto.ca
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.198200.112.
- Received June 8, 2012.
- Accepted July 31, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press