Cited by 451Glioma Diagnosis and TreatmentCancer, Hypoxia, and MetabolismMetabolomics and Mass Spectrometry Studies

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome

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Reitman, Zachary J., Jin, Genglin, Karoly, Edward D., Spasojevic, Ivan, Yang, Jian, Kinzler, Kenneth W., He, Yiping, Bigner, Darell D. +2 more·2011·Proceedings of the National Academy of Sciences

Abstract

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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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)
Venue
Proceedings of the National Academy of Sciences
Published
2011-02-02
Volume
108
Issue
8
Pages
3270-3275
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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 › Genetics › 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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