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

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.ifferences in cellular metabolism between cancer and normal cells have long been noted by cancer researchers (1). Genetic alterations that occur in cancer, such as mutations and copy number changes that alter K-Ras and c-Myc, are thought to be responsible for at least some of these metabolic differences (2, 3). The genetic alterations that drive cancer pathogenesis may do so in part by deregulating cellular metabolism. Such deregulation could aberrantly signal cells to proliferate and provide molecular building blocks for cellular replication (4). This possibility has generated enthusiasm for the idea that that drug targets for the specific killing of cancer cells can be identified by studying the metabolic differences between normal and cancer cells.Gliomas are tumors of the central nervous system that respond poorly to therapy and are associated with a heterogeneous collection of genetic alterations (5, 6), including mutations in IDH1 and IDH2 (7,8). IDH1 and IDH2 are the cytoplasmic and mitochondrial NADP + -dependent isocitrate dehydrogenases, respectively, and are homologs. Isocitrate dehydrogenase 3 (IDH3), which is unrelated to IDH1 and IDH2, is a NAD + -dependent isocitrate dehydrogenase and has not been found to be mutated in cancer (Fig. S1A). These enzymes convert isocitrate to α-ketoglutarate (Fig. S1B). IDH1 catalyzes this reaction in the cytosol and peroxisome to mediate a variety of cellular housekeeping functions, whereas IDH2 and IDH3 catalyze a step in the tricarboxylic acid (TCA) cycle (reviewed in ref. 9). IDH1-R132 mutations occur frequently (50-93%) in astrocytomas and oligodendrogliomas, as well as in secondary glioblastomas, and may be the initiating lesion in these glioma subtypes (7,8). Mutations in the analogous IDH2-R172 codon also occur at a lower rate (3-5%) in these cancers (8). Interestingly, mutations in IDH1 and IDH2 were observed subsequently in 22% of ac...

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

“…This can occur through inactivation of components of the tricarboxylic acid (TCA) cycle and electron transport chain (ETC) (1)(2)(3)(4)(5). In particular, high-grade gliomas (HGGs) display mutations in the TCA enzymes isocitrate dehydrogenase IDH1 and IDH2 (5).…”

Genomics and metabolomics of muscular mass in a community-based sample of UK females

“…Non-targeted metabolomic profiling was performed on fasting plasma samples of TwinsUK participants by Metabolon Inc. using ultrahigh performance liquid chromatography and mass spectrometry (for detailed information on processing/QC, see Supplementary Material). 19,20 Raw data were median-normalized by dividing each MTB concentration by the day MTB median, then inverse normalized as MTB concentrations were not normally distributed. To avoid spurious false-positive associations due to small sample size, metabolic traits having 420% missing values were excluded.…”

Cancer-associated Isocitrate Dehydrogenase 1 (IDH1) R132H Mutation and d-2-Hydroxyglutarate Stimulate Glutamine Metabolism under Hypoxia

“…IDH1 mutations have been associated with several effects on cellular metabolism. IDH1 mutation is associated with lower levels of glutamine and other metabolites in primary glioma tissues (10,11). Cancer cells expressing mutant IDH1 are dependent on glutamine and are sensitive to inhibition of glutaminase, presumably because D-2HG production drains glutamine to sensitize cells to deficiencies in the production of these metabolites (11)(12)(13).…”