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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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“D-2HG has been termed an “oncometabolite” and can accumulate at very high levels (even into the mM range) in tumor cells harboring these IDH mutations [3,4].”
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malignancy, A. I. A. H. H., mutations, C. B. T. A. O. V. S. G. A. A. O. I. M. C. A. A. V. S. O. M. S. C. O. I. T. L. 2. D. H. L. T. T. I. O. T. B. T. O. G., (HPCs), W. C. T. S. D. O. T. L. P. T. C. I. M. C. A. S. A. T. H. S. C. (. A. P. C., in, S. A. T. M., of, T. L., in, O. T. M., HPCs, R. T. K. T. C. I. M. P. S.-R. A. B. T. D. O., involving, S. A. T. T. F., & involving, O. T. T. F. (2016) · Journal of Exploratory Research in Pharmacology · doi:10.14218/jerp.2016.00019 · Cited by 8
Tateishi, K., & Yamamoto, T. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.84543 · Cited by 7
“Altered amino acids, glutathione, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were observed in IDH-mutant cells [82, 83].”
BackgroundViswanath, P., & Ronen, S. M. (2015) · Molecular & Cellular Oncology · doi:10.1080/23723556.2015.1077922 · Cited by 7
“We and others have shown that, in addition to an altered epigenetic profile and elevated 2-HG levels, IDH1 mutant cells also undergo broader metabolic reprogramming compared to their wild-type IDH1 counterparts.(3,4) Most notably, we observed a significant reduction in (1)H magnetic resonance spectroscopy”
BackgroundValvi, S., Fouladi, M., Fisher, M. J., & Gottardo, N. G. (2025) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2025.1662414 · Cited by 12
New and Emerging Therapies for Patients with Low-Grade Glioma
Peters, K. B. (2025) · CNS Drugs · doi:10.1007/s40263-025-01238-9 · Cited by 6
“In the normal functioning of the Krebs cycle, isocitrate is converted to a-ketoglutarate, but when either IDH1 or IDH2 genes are mutated, a-ketoglutarate is enzymatically acted upon by the mutant enzyme to develop 2-hydroglu-tarate (2-HG) [20, 21] (Fig.”
Prognostic significance of carboxypeptidase Q and its methylation in glioblastoma
Liu, Q., Wang, R., Li, Z., Peng, Y., Qin, W., Peng, X.-M., & Liu, Z. (2023) · Translational Cancer Research · doi:10.21037/tcr-22-2562 · Cited by 6
“Metabolomics analysis of gliomas showed that NAA and NAAG were significantly reduced in IDH1/2 mutant gliomas (31) .”
Vitamin B6 Pathway Maintains Glioblastoma Cell Survival in 3D Spheroid Cultures
Moosa, N. Y., Azeem, S. A., Lodge, J. K., Cheung, W., & Ahmed, S. U. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910428 · Cited by 7
“2-HG 2-HG is thought to increase the expression of hypoxia-induced factor-1 α (HIF-1 α ) leading to upregulation of glucose transporter 1 (Glut 1) and hexokinase 2 (HK 2), as well as broader regulation of pathways associated with glutamine, fatty acids, and citrate biosynthesis [12–16].”
BackgroundMetabolomic Modularity Analysis (MMA) to Quantify Human Liver Perfusion Dynamics
Sridharan, G. V., Bruinsma, B. G., Bale, S. S., Swaminathan, A., Saeidi, N., Yarmush, M. L., & Uygun, K. (2017) · Metabolites · doi:10.3390/metabo7040058 · Cited by 6
“These data provide a wealth of information to characterize physiological states and are increasingly used for drug discovery and basic science research [5] as well as for disease diagnostics [6].”
BackgroundDiagnostic performance of edited 2HG MR spectroscopy of central glioma in the clinical environment
Juskanič, D., Mištinová, J. P., Hollý, S., Sekerešová, M., Koleják, K., & Pátrovič, L. (2022) · Magnetic Resonance Materials in Physics Biology and Medicine · doi:10.1007/s10334-021-00989-y · Cited by 6
“D-2-Hydroxyglutarate (2HG) is an oncometabolite that accumulates in cancer cells as a result of isocitrate dehydrogenase (IDH) mutation [1].”
BackgroundSingle-Voxel MR Spectroscopy of Gliomas with s-LASER at 7T
Prener, M., Opheim, G., Shams, Z., Søndergaard, C. B., Lindberg, U., Larsson, H. B. W., Ziebell, M., Larsen, V. A., Vestergaard, M. B., & Paulson, O. B. (2023) · Diagnostics · doi:10.3390/diagnostics13101805 · Cited by 6
“On the other hand, the downstream effects of increased levels of 2-HG in IDH-mutated gliomas may alter global cellular metabolism, leading to the malignant transformation of tumour cells [18].”
Clément, A., Doyen, M., Fauvelle, F., Hossu, G., Chen, B., Barberi‐Heyob, M., Hirtz, A., Stupar, V., Lamiral, Z., Pouget, C., et al. (2021) · NMR in Biomedicine · doi:10.1002/nbm.4490 · Cited by 8
“Although not all metabolites are detected with in vivo MRS due to the low magnetic field applied, our results are nevertheless in keeping with these previous studies by validating the concentration changes of other well known IDH1+-specific metabolites.(9,10,37,38) In particular, IDH1+ gliomas exhibited higher levels…”
BackgroundResultFinding a four-leaf clover—identifying long-term survivors in IDH-wildtype glioblastoma
Wong, D., & Yip, S. S. F. (2019) · Neuro-Oncology · doi:10.1093/neuonc/noz174 · Cited by 6
Metabolism and therapeutic response in acute myeloid leukemia with IDH1/2 mutations
Gabellier, L., Bosetta, E., Heiblig, M., & Sarry, J. (2025) · Trends in cancer · doi:10.1016/j.trecan.2025.01.011 · Cited by 6
Kikuchi, M., Takami, H., Kobayashi, Y., Nagaoka, K., Kitagawa, Y., Nomura, M., Takayanagi, S., Tanaka, S., Saito, N., & Kakimi, K. (2025) · Cells · doi:10.3390/cells14131035 · Cited by 5
“IDH mutations alter cellular metabolism by producing 2-hydroxyglutarate, leading to widespread epigenetic changes and contributing to gliomagenesis [10,11].”
Neural deception: Breast cancer co-opts neuronal mechanisms to evade the immune system
Layer, N., Bunse, L., & Venkataramani, V. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.05.007 · Cited by 5
Nuclear magnetic resonance metabolic fingerprint of bevacizumab in mutant IDH1 glioma cells
Mesti, T., Bouchemal, N., Banissi, C., Triba, M. N., Marbeuf‐Gueye, C., Čemažar, M., Moyec, L. L., Carpentier, A. F., Savarin, P., & Ocvirk, J. (2018) · Radiology and Oncology · doi:10.2478/raon-2018-0046 · Cited by 5
Comprehensive metabolomics study on the pathogenesis of anaplastic astrocytoma via UPLC-Q/TOF-MS
Du, C., Huang, Z., Wei, B., & Li, M. (2022) · Medicine · doi:10.1097/md.0000000000029594 · Cited by 5
“Until now, more molecular pathogenetic evidence has clarified the promoting role of IDH mutation in the pathogenesis of glioma, while brain glioma containing mutated IDH could also give rise to specific metabolic signatures.[29] In details, IDH mutation could cause competitive inhibition of α-ketoglutarate-dependent d…”
BackgroundQuantitative Analysis of Oncometabolite 2-Hydroxyglutarate
Yuan, B. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-51652-9_11 · Cited by 5
Maravat, M., Bertrand, M., Landon, C., Fayon, F., Morisset‐Lopez, S., Sarou‐Kanian, V., & Decoville, M. (2021) · Journal of Proteome Research · doi:10.1021/acs.jproteome.1c00304 · Cited by 5
Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib
Pang, Y. K., Qi, L., Sergi, Z., Yu, G., 桑雪雨, Kim, O., Wang, H., Ranjan, A., Merchant, M., Oudit, B., et al. (2025) · iScience · doi:10.1016/j.isci.2025.112283 · Cited by 6
“21,22 Previously, we demonstrated that ZTR induces mitochondria dysfunction in glioblastoma cells at 50nM. 23 To investigate ZTR-induced mitochondrial changes in IDH-mutant glioma, we first examined the cellular organelle morphological changes induced by LD ZTR using a transmission electron…”
Current and future directions for Phase II trials in high-grade glioma
Alexander, B. M., Lee, E. Q., Reardon, D. A., & Wen, P. Y. (2013) · Expert Review of Neurotherapeutics · doi:10.1586/ern.12.158 · Cited by 4
Auld, D., Simeonov, A. M., Lea, W., & Thomas, C. J. (2010) · Assay and Drug Development Technologies · doi:10.1089/adt.2010.0805.lr · Cited by 4
Isocitrate Dehydrogenase Mutations in Cancer: From Bench to Bedside Applications
Fang, Y., Wang, X., Luo, K., Dakal, T. C., Bai, H., Xu, C., & Zhang, G. (2026) · MedComm · doi:10.1002/mco2.70732 · Cited by 5
Inhibition of Glycolysis as a Therapeutic Strategy in Acute Myeloid Leukemias
Laister, R. C., Minden, M. D., & Mak, T. W. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1393-0_38 · Cited by 3
Diversity of metabolic features and relevance to clinical subtypes of gliomas
Dasgupta, P., & Puduvalli, V. K. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.03.008 · Cited by 3
Cologni, R., Holschbach, M. H., Schneider, D., Bier, D. D., Schulze, A., Stegmayr, C., Endepols, H., Ermert, J., Neumaier, F., & Neumaier, B. (2024) · Molecules · doi:10.3390/molecules29163939 · Cited by 3
“Indeed, considering that expression of mIDH is well known to have profound effects on numerous aspects of tumor biology and growth [54–58], it seemed conceivable that differences in the composition and/or structure of the tumors (percentage and distribution of hypoxic, necrotic, etc., cells) could…”
BackgroundMolecular Diagnostics for Neurological Disorders
Jain, K. (2013) · Humana Press eBooks · doi:10.1007/978-1-62703-272-8_5 · Cited by 1
The Role of Isocitrate Dehydrogenase Mutations in Glioma Brain Tumors
Chang, C.-M., Xu, K., & Hui-Kuo, G. (2011) · InTech eBooks · doi:10.5772/23238 · Cited by 3
“In addition, the cellular metabolite profiles of cells engineered either to express the R132H mutant or to suppress expression of wild type IDH1 have been assessed and showed very little similarity again consistent with the putative dominant negative function of mutant IDH1 having little if any role in vivo (Reitman e…”
BackgroundResultInfluentialRelation between tumor micro-environment and epigenetic alterations in hematological malignancies
Torres, X., & Cómbita, A. L. (2021) · Advances in Cancer Biology - Metastasis · doi:10.1016/j.adcanc.2021.100024 · Cited by 3
Lopci, E. (2017) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-017-3708-2 · Cited by 3
“Indeed, the first part of the statement is to be considered reliable, because we know that amino acids, including glycine, serine, threonine, asparagine, phenylalanine, tyrosine, tryptophan, and methionine, are increased in IDH1 mutants [6].”
BackgroundThe loss of peroxiredoxin 2 in mice disrupts the biochemical aging phenotype in erythrocytes
Jamshidi, N., von Löhneysen, K., Soldau, K., & Friedman, J. S. (2026) · iScience · doi:10.1016/j.isci.2025.114608 · Cited by 2
Prost, D. M., Nichelli, L., Rozenblum, L., Laurenge, A., Dehais, C., Mathon, B., Jacob, J., Drouiche, L., Escamilla-Ramírez, Á., Houillier, C., et al. (2026) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-25-0279 · Cited by 2
Mining cancer genomes for change-of-metabolic-function mutations
Tu, K. J., Diplas, B. H., Regal, J. A., Waitkus, M. S., Pirozzi, C. J., & Reitman, Z. J. (2023) · Communications Biology · doi:10.1038/s42003-023-05475-w · Cited by 2
“The accumulation of R-2-hydroxyglutarate causes widespread epigenetic reprogramming that likely drives oncogenesis 5 – 7 .”
BackgroundSelf-citationNovel metabolic subtypes in IDH-mutant gliomas: implications for prognosis and therapy
Wang, P., Wang, J., Fang, Z., Chen, Q., Zhang, Y., Qiu, X., & Bao, Z. (2025) · BMC Cancer · doi:10.1186/s12885-025-14176-y · Cited by 4
“[14–16].”
The 3PAs syndrome and succinate dehydrogenase deficiency in pituitary tumors
Xekouki, P., Daraki, V. N., Betsi, G., Chrysoulaki, M., Sfakiotaki, M., Mytilinaiou, M. G., & Stratakis, C. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-814537-1.00001-4 · Cited by 1
Rocha, G., Francés‐Gómez, C., Megías, J., Hidalgo, L. M., Casanova, P., Haro-Estevez, J. F., Teruel‐Martí, V., Monleón, D., & San‐Miguel, T. (2025) · Biomedicines · doi:10.3390/biomedicines13071584 · Cited by 1
“Other research links IDH1 mutations to mTOR pathway activation [33], promoting survival signaling, while 2HG modulates epigenetic regulators and provides early growth advantages [34,35].”
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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