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

Zachary J. Reitman, Genglin Jin, Edward D. Karoly, Ivan Spasojevic, Jian Yang, Kenneth W Kinzler, Yiping He, Darell D. Bigner, Bert Vogelstein, Hai Yan

Research output: Contribution to journalArticle

Abstract

Pointmutations 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.

Original languageEnglish (US)
Pages (from-to)3270-3275
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number8
DOIs
StatePublished - Feb 22 2011

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Keywords

  • Cancer
  • GC-MS
  • Liquid chromatography-MS/MS
  • N-acetylated amino acids

ASJC Scopus subject areas

  • General

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