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Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism
Open accessAbstract
Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2-4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.
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“There is a renewed interest in the area of cancer metabolism with metabolic reprogramming coined as a hallmark of cancer based on the discovery of mutations and alterations in IDH1 and IDH2 along with succinate dehydrogenase (SDH), fumarate hydratase (FH), and pyruvate kinase M2 (PKM2) [41, 42].”
From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [42]
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“Specifically, IDH1 and IDH2 mutations result in a neo-enzyme activity that converts α-ketoglutarate to 2-hydroxyglutarate rather than the normal reaction of IDH resulting in the conversion of isocitrate to α-ketoglutarate [72].”
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“IDH3 plays a central role in energy production in the TCA cycle by generating α -KG and NADH using NAD + as a cofactor (Reitman and Yan 2010).”
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“NR4A1 also regulates IDH1 expression which also generates cellular reductants and complements the function of TXNDC5 in terms of stress suppression [20, 28].”
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“Furthermore, induction of the TCA cycle intermediate, isocitrate, which is commonly found at high levels in cancer cells with a defective TCA cycle (20), positively correlated with cell death, suggesting the induction of mitochondrial dysfunction during reovirus-mediated oncolysis (Fig.”
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“IDH2, a key generator of NADPH in mitochondria, is critical for the maintenance of mitochondrial redox balance (Reitman and Yan, 2010) and is involved in glutathione reduction.”
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“In humans, IDH1 and IDH2 perform similar functions and share considerable sequence similarity.[16] A mutation in either IDH1 or IDH2 has been shown to be a very early event in the development of low-grade gliomas.”
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“Besides, it was evident that the clinical outcome for tumors with identical histology was different for IDH1-wildtype and IDH1-mutant diffuse gliomas [2,8,9,15,17,18].”
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“IDH1 and IDH2 are very similar NADP+ dependent isoforms involved in other metabolic processes, including lipid metabolism and glucose sensing (IDH1) and oxidative respiration (IDH2), and are cytoplasmic and mitochondrially localized, respectively [48].”
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“In addition, we provided evidence that the increase in a-KG levels in asthmatic ASM cells could be due to the increased expression of IDH2, which is a mitochondrion-specific IDH and functions in the conversion of isocitrate in the citric acid cycle (27).”
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“A similar conclusion can be drawn for isocitrate dehydrogenase (IDH) proteins which, under normal conditions, supply NADPH necessary for lipid biogenesis and protection from oxidative and radiation-induced damage [122].”
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“IDH1/2 are metabolic enzymes involved in the conversion of isocitrate to a -ketoglutarate ( a -KG) in the tricarboxylic acid cycle (47).”
BackgroundGenomic, epigenomic and transcriptomic landscape of glioblastoma
Dakal, T. C., Kakde, G. S., & Maurya, P. K. (2024) · Metabolic Brain Disease · doi:10.1007/s11011-024-01414-8 · Cited by 22
“In addition, both variants IDH1 and IDH2 are known for the regulation of lipid and glucose metabolism and oxidative respiration, respectively (Reitman and Yan 2010).”
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“IDCH can oxidize isocitrate to α-ketoglutarate, with the reduction of NAD(P)+ to NAD(P)H, and plays a central role in the TCA cycle [47,48].”
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“This could be due to the higher D-2-hydroxyglutarate concentration), which is structurally similar to glutamate, hence, capable of activating the NMDA receptors and lowering the seizure threshold [11,16,28].”
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“The concept of an “oncogenic metabolite” is a novel mechanism, and interest in “metabolic adaptation” as an important aspect of oncogenesis is increasing, with recent opinion articles focusing on 2-hydroxyglutarate as an “oncometabolite” [12-16].”
BackgroundBiliary tract cancer prognostic and predictive genomics
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“Cancer-associated mutations in IDH1/2 result in high levels of (R)-2-hydroxyglutarate, an onco-metabolite that seems to be associated with alterations in several cell processes including redox state and DNA repair mechanisms, also modulating the activity of epigenetic tumor suppressor enzymes (37-39).”
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“IDH1 mutations have also been studied in other neoplasms [18–22]: an investigation of a large number of acute myeloid leukemias showed IDH1 mutations in 16 out of 188 cases (8.”
Ma, T., Zou, F., Pusch, S., Yang, L., Zhu, Q., Xu, Y., Gu, Y., von Deimling, A., & Zha, X. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.10.009 · Cited by 19
Salhotra, A., Afkhami, M., Yang, D., Mokhtari, S., Telatar, M., Gu, D., Pillai, R. K., Weisenburger, D. D., Murata‐Collins, J. L., Weigel, D., et al. (2019) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2019.04.007 · Cited by 19
Biphasic Papillary and Lobular Breast Carcinoma With PIK3CA and IDH1 Mutations
Ang, D. C., VanSandt, A. M., Beadling, C., Warrick, A., West, R. B., Corless, C. L., & Troxell, M. L. (2012) · Diagnostic Molecular Pathology · doi:10.1097/pdm.0b013e31826ddbd1 · Cited by 19
The hypoxic microenvironment: A determinant of cancer stem cell evolution
Carnero, A., & LLeonart, M. E. (2015) · Inside the Cell · doi:10.1002/icl3.1039 · Cited by 23
IDH1 mutation-associated long non-coding RNA expression profile changes in glioma
Zhang, X., Kiang, K. M. Y., Wang, Y., Pu, J. K.-S., Ho, A. S.-W., Cheng, S. Y., Lee, D., Zhang, P., Chen, J., Lui, W., et al. (2015) · Journal of Neuro-Oncology · doi:10.1007/s11060-015-1916-9 · Cited by 19
Grelli, K. N., Palubinsky, A. M., Kale, A. C., Lizama, B. N., Stankowski, J. N., Milne, G. L., Singer, R. J., & McLaughlin, B. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/18715273113129990062 · Cited by 18
“While there are no known allosteric regulators of IDH1 or IDH2, there are many regulators of IDH3 [48], including Ca, citrate, ADP, and Mn [49-51], many of which are impacted by PC [16, 41].”
BackgroundChen, Y., Maniakas, A., Tan, L., Cui, M., Le, X., Niedzielski, J. S., Michel, K. A., Harlan, C. J., Lu, W., Henderson, Y. C., et al. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01297-x · Cited by 18
Feng, S., & Liu, Y. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-51652-9_18 · Cited by 18
Tomar, M. S., Kumar, A., & Shrivastava, A. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.149382 · Cited by 20
Multi-study Integration of Brain Cancer Transcriptomes Reveals Organ-Level Molecular Signatures
Sung, J., Kim, P., Ma, S., Funk, C. C., Magis, A. T., Wang, Y., Hood, L., Geman, D., & Price, N. D. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003148 · Cited by 16
“This reaction produces NADPH, which not only is an essential cofactor for many metabolic reactions, but also helps to protect the cell against oxidative damage [53].”
BackgroundAdvances in the Immunotherapeutic Potential of Isocitrate Dehydrogenase Mutations in Glioma
Tang, F. R., Pan, Z., Wang, Y., Lan, T., Wang, M., Li, F., Quan, W., Liu, Z., Wang, Z., & Li, Z. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00866-1 · Cited by 18
“IDH1 is localized to the cytoplasm and peroxisomes, while IDH2 and IDH3 are localized to the mitochondria [16].”
BackgroundKonieczna, A., Szczepańska, A., Sawiuk, K., Łyżeń, R., & Węgrzyn, G. (2014) · Medical Hypotheses · doi:10.1016/j.mehy.2014.11.016 · Cited by 17
The promise of mitochondria in the treatment of glioblastoma: a brief review
Liang, Z., Zhao, S., Liu, Y., & Cheng, C. (2025) · Discover Oncology · doi:10.1007/s12672-025-01891-y · Cited by 17
“The role of IDH includes the regulation of mitochondrial oxidative phosphorylation, glutamine metabolism, adipogenesis, and cellular redox state [2, 3].”
Chung, J., Saad, J., Kafri, A., Rossignol, J., Verbrugge, M., & Bakke, J. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1712576 · Cited by 19
“Three isoforms of the IDH enzyme are present in humans: IDH1, IDH2, and IDH3, each having unique cellular localization and metabolic functions (19 – 22) (Figure 1).”
Protein Phosphatases—A Touchy Enemy in the Battle Against Glioblastomas: A Review
Tomiyama, A., Kobayashi, T., Mori, K., & Ichimura, K. (2019) · Cancers · doi:10.3390/cancers11020241 · Cited by 16
“Importantly, in GBMs, DUSP4 promoter methylation is reported to be associated with alteration of the IDH1 gene encoding isocitrate dehydrogenase 1 (IDH1) [140], which catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate [142].”
BackgroundMutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas
Neumaier, F., Zlatopolskiy, B. D., & Neumaier, B. (2023) · Molecules · doi:10.3390/molecules28072890 · Cited by 17
Molecular basis of mast cell disease
Soucie, E. L., Brenet, F. A., & Dubreuil, P. C. (2014) · Molecular Immunology · doi:10.1016/j.molimm.2014.03.013 · Cited by 17
Isocitrate dehydrogenase 2 inhibits gastric cancer cell invasion via matrix metalloproteinase 7
Wu, D. (2015) · Tumor Biology · doi:10.1007/s13277-015-4358-2 · Cited by 17
Decreased expression of IDH1-R132H correlates with poor survival in gastrointestinal cancer
Li, J., Huang, J., Huang, F., Jin, Q., Zhu, H., Wang, X., & Chen, M. (2016) · Oncotarget · doi:10.18632/oncotarget.12039 · Cited by 17
Hu, C., Zuo, Y., Liu, J., Xu, H., Liao, W., Dang, Y., Luo, C., Tang, L., & Zhang, H. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126825 · Cited by 17
Prospects of biological and synthetic pharmacotherapies for glioblastoma
Altshuler, D. B., Kadiyala, P., Núñez, F. J., Núñez, F. M., Carney, S. V., Alghamri, M. S., Garcia-Fabiani, M. B., Asad, A. S., Candia, A. J. N., Candolfi, M., et al. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2020.1713085 · Cited by 16
“IDH1 is an enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) [86].”
BackgroundZou, F., Pusch, S., Hua, J., Ma, T., Yang, L., Zhu, Q., Xu, Y., Gu, Y., von Deimling, A., & Zha, X. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.12.030 · Cited by 17
Discovery of DC_H31 as potential mutant IDH1 inhibitor through NADPH-based high throughput screening
Duan, Z., Liu, J., Niu, L., Wang, J., Feng, M., Chen, H., & Luo, C. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.05.040 · Cited by 17
Li, Z., Zhao, W., He, B., Koh, T. S., Li, Y., Zeng, Y., Zhang, Z., Zhang, J., & Hou, Z. (2020) · Contrast Media & Molecular Imaging · doi:10.1155/2020/8843084 · Cited by 16
Yao, K., Liu, H., Yin, J., Yuan, J., & Tao, H. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02054-x · Cited by 16
“3K27M mutation showed a distinct metabolic pattern, such as enhanced glycolysis, glutaminolysis, and TCA metabolism with high α-KG production [90].”
BackgroundInfluentialOncogenic IDH1 mut drives robust loss of histone acetylation and increases chromatin heterogeneity
Furth, N., Cohen, N., Spitzer, A., Salame, T., Dassa, B., Mehlman, T., Brandis, A. S., Moussaieff, A., Friedmann‐Morvinski, D., Castro, M. G., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2403862122 · Cited by 17
“WT IDH enzymes convert the TCA metabolite isocitrate into alpha - ketoglutarate ( α KG) while generating NADPH ( 14 ).”
Pyridine Moiety: Recent Advances in Cancer Treatment
Sahu, R., Mishra, R., Kumar, R., Majee, C., Salahuddin, S., MAZUMDER, A., & Kumar, A. (2021) · Indian Journal of Pharmaceutical Sciences · doi:10.36468/pharmaceutical-sciences.763 · Cited by 16
“Recently IDH mutations have been recognized in somatic tumor associated numerous hematologic and solid tumors, such as glioma, acute myeloid leukemia (AML), cholangiocarcinoma cancer, malignant chondrosarcomas 4 and others[73-75].”
BackgroundSporikova, Z., Slavkovský, R., Tučková, L., Kalita, O., Houdova, M. M., Ehrmann, J., Hajdúch, M., Hrabálek, L., & Vaverka, M. (2021) · Applied immunohistochemistry & molecular morphology · doi:10.1097/pai.0000000000000997 · Cited by 16
Marine Compounds, Mitochondria, and Malignancy: A Therapeutic Nexus
Fakhri, S., Abdian, S., Moradi, S. Z., Delgadillo, B. E., Fimognari, C., & Bishayee, A. (2022) · Marine Drugs · doi:10.3390/md20100625 · Cited by 17
IDH1 mutation promotes lung cancer cell proliferation through methylation of Fibulin-5
Yan, B., Hu, Y., Ma, T., & Wang, Y. (2018) · Open Biology · doi:10.1098/rsob.180086 · Cited by 17
Savoia, M., Cencioni, C., Mori, M., Atlante, S., Zaccagnini, G., Devanna, P., Marcotullio, L. D., Botta, B., Martelli, F., Zeiher, A. M., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201800788r · Cited by 16
Amador‐Martínez, I., Aparicio‐Trejo, O. E., Aranda‐Rivera, A. K., Bernabe-Yepes, B., Medina‐Campos, O. N., Tapia, E., Cortés-González, C. C., Silva‐Palacios, A., Roldán, F., León‐Contreras, J. C., et al. (2025) · Antioxidants · doi:10.3390/antiox14030367 · Cited by 15
“Still, some of them, such as isocitrate dehydrogenase 3, are regulated allosterically by negative effectors such as ATP, NADH, and NADPH [82].”
B7 homologue 3 as a prognostic biomarker and potential therapeutic target in gastrointestinal tumors
Rašić, P., Jovanović-Tucović, M., Jeremić, M., Djuricic, S. M., Vasiljevic, Z. V., Miličković, M., & Savic, D. (2021) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v13.i8.799 · Cited by 15
Genomic and Epigenomic Features of Glioblastoma Multiforme and its Biomarkers
Jadoon, S. S., Ilyas, U., Zafar, H., Paiva‐Santos, A. C., Khan, S., Khan, S. A., Ahmed, T., Rasool, Y., Altaf, R., Raza, F., et al. (2022) · Journal of Oncology · doi:10.1155/2022/4022960 · Cited by 15
“As a result of this catalysis, NADPH is produced in the kreb or citric acid cycle [41, 42].”
BackgroundLi, S., Sun, C., Gu, Y., Gao, X., Zhao, Y., Yuan, Y., Zhang, F., Hu, P., Liang, W., Cao, K., et al. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.9903 · Cited by 14
“IDH mutations have been reported in glioma, AML, enchondroma and chondrosarcoma (7-10).”
Rapid and sensitive detection of NADPH via mBFP-mediated enhancement of its fluorescence
You, S.-H., Lim, H.-D., Cheong, D., Kim, E., & Kim, G. (2019) · PLoS ONE · doi:10.1371/journal.pone.0212061 · Cited by 15
Metadata
- Authors
- Reitman, Z. J., & Yan, H.
- Affiliations
- Duke University (US)
- Venue
- JNCI Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-05-31
- Volume
- 102
- Issue
- 13
- Pages
- 932-941
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC2897878
- OpenAlex
- W2124951199
- Cited by
- 562
- References
- 88
- Citations by year
- 2026: 22 · 2025: 41 · 2024: 20 · 2023: 33 · 2022: 31 · 2021: 44 · 2020: 40 · 2019: 43 · 2018: 40 · 2017: 36 · 2016: 31 · 2015: 34 · 2014: 28 · 2013: 34 · 2012: 38
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Cancer Institute (R01CA118822, R01CA140316)
- National Institute of General Medical Sciences (T32GM007171)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- IDH1, IDH2, IDH1 mutation, IDH2 mutation, cancer metabolism, glioma, acute myeloid leukemia, D-2-hydroxyglutarate, oxidative stress, lipogenesis, oxygen sensing, anticancer agents
- MeSH terms
- Animals, Hypoxia, Arginine, Brain Neoplasms, Codon, Glioblastoma, Glucose, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, NADP, Neoplasms, Oligodendroglioma, Oncogenes, Signal Transduction, Up-Regulation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor
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