title: D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function.
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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Masato
authors.initials: M
authors.lastname: Sasaki
authors.forename: Christiane B
authors.initials: CB
authors.lastname: Knobbe
authors.forename: Momoe
authors.initials: M
authors.lastname: Itsumi
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Elia
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Harris
authors.forename: Iok In Christine
authors.initials: II
authors.lastname: Chio
authors.forename: Rob A
authors.initials: RA
authors.lastname: Cairns
authors.forename: Susan
authors.initials: S
authors.lastname: McCracken
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Jillian
authors.initials: J
authors.lastname: Haight
authors.forename: Annick You
authors.initials: AY
authors.lastname: Ten
authors.forename: Bryan
authors.initials: B
authors.lastname: Snow
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Myunggon
authors.initials: M
authors.lastname: Ko
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Yen
authors.forename: Shinsan M
authors.initials: SM
authors.lastname: Su
authors.forename: Tak Wah
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000166:cytology / Q000473:pathology; D003094:Collagen / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D005838:Genotype; D005910:Glioma / Q000473:pathology; D005977:Glutarates / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D055550:Protein Stability; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D005977:Glutarates; D017382:Reactive Oxygen Species; C019417:alpha-hydroxyglutarate; D003094:Collagen; D007521:Isocitrate Dehydrogenase