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D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function
Open accessAbstract
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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“High levels of succinate or 2-HG inhibit α-KGDDs. These include the PHDs, the TET DNA demethylases, and the JMJDs154-156”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [154]
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Metadata
- Authors
- Sasaki, M., Knobbe, C. B., Itsumi, M., Elia, A. J., Harris, I. S., Chio, I. I. C., Cairns, R. A., McCracken, S., Wakeham, A., Haight, J., Ten, A. Y., Snow, B., Ueda, T., Inoue, S., Yamamoto, K., Ko, M., Rao, A., Yen, K. E., Su, S. M., & Mak, T. W.
- Affiliations
- University Health Network (CA)
- La Jolla Institute for Immunology (US)
- Agios Pharmaceuticals (United States) (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-08-27
- Volume
- 26
- Issue
- 18
- Pages
- 2038-2049
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3444730
- OpenAlex
- W2132555177
- Cited by
- 296
- References
- 60
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 12 · 2023: 18 · 2022: 19 · 2021: 16 · 2020: 19 · 2019: 22 · 2018: 28 · 2017: 29 · 2016: 29 · 2015: 25 · 2014: 29 · 2013: 22 · 2012: 9
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- National Cancer Institute (R01CA151535)
- National Institute of Allergy and Infectious Diseases (R01AI044432)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD065812)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- D-2-hydroxyglutarate, IDH1 R132H mutation, glioma, collagen maturation, prolyl hydroxylation, HIF-1α, reactive oxygen species, NADPH/NADP+ ratio, endoplasmic reticulum stress, basement membrane, conditional knock-in mice, embryonic lethality, hypoxia
- MeSH terms
- Animals, Basement Membrane, Brain, Collagen, Genotype, Glioma, Glutarates, Isocitrate Dehydrogenase, Mutation, Stress, Physiological, Reactive Oxygen Species, Mice, Protein Stability, Gene Knock-In Techniques
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