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Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome
Open accessAbstract
Point mutations of the NADP + -dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite ( R )-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N -acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.
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“a portion of the succinate that accumulates during ischemia and inflammation is released from the cell into the extracellular environment through poorly defined processes. This occurs following IR injury158,159, inflammation10, or cold exposure160.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [159]
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“The primer-targeted regions in (G) are ell 150, 1135–1146, September 14, 2012 ª2012 Elsevier Inc. 1141 1.0 1.5 2.0 Nevus Melanoma *** ** ***** * e ex pr es si on sA α-Ketoglutarate Isocitrate CO2 Succinate IDH1, 2 B HP RT GA PD H ID H1 ID H2 TE T1 TE T2 TE T3 PT EN CT SB 0.0 0.5 R el at iv e 5-mC 5-hmC TET1, 2, 3 CO2…”
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Metadata
- Authors
- Reitman, Z. J., Jin, G., Karoly, E. D., Spasojevic, I., Yang, J., Kinzler, K. W., He, Y., Bigner, D. D., Vogelstein, B., & Yan, H.
- Affiliations
- Duke University (US)
- Metabolon (United States) (US)
- Duke Comprehensive Cancer Center,
- The Ludwig Center and
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-02-02
- Volume
- 108
- Issue
- 8
- Pages
- 3270-3275
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3044380
- OpenAlex
- W2171026968
- Cited by
- 449
- References
- 31
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 12 · 2023: 24 · 2022: 20 · 2021: 21 · 2020: 23 · 2019: 25 · 2018: 38 · 2017: 34 · 2016: 29 · 2015: 38 · 2014: 45 · 2013: 42 · 2012: 48
- FWCI
- 24.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- American Association for Cancer Research
- Pediatric Brain Tumor Foundation
- Virginia and D.K. Ludwig Fund for Cancer Research
- National Institutes of Health
- National Cancer Institute (CA43460, 5P30-CA-014236-36, R37CA043460, R01CA140316, P30CA014236)
- Topics
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- isocitrate dehydrogenase, IDH1 mutation, IDH2 mutation, 2-hydroxyglutarate, glioma, oligodendroglioma, N-acetylaspartylglutamate, glutathione metabolism, choline derivatives, TCA cycle intermediates, amino acids, cancer metabolism
- MeSH terms
- Dipeptides, Glioma, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, Oligodendroglioma, Cell Line, Tumor, Metabolome
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