The DOI matches its Crossref record; 29 of the 31 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197
The 2007 WHO Classification of Tumours of the Central Nervous System
Louis, D. N., Ohgaki, H., Wiestler, O. D., Cavenee, W. K., Burger, P. C., Jouvet, A., Scheithauer, B. W., & Kleihues, P. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0243-4 · Cited by 15,675
Chiang, L. H., Russell, E. L., & Braatz, R. D. (2001) · Advanced textbooks in control and signal processing · doi:10.1007/978-1-4471-0347-9_4 · Cited by 6,684
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
Self-citationIDH1 and IDH2 Mutations in Gliomas
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808710 · Cited by 5,847
Self-citationCancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766
DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622
Gao, P., Tchernyshyov, I., Chang, T.-C., Lee, Y.-S., Kita, K., Ochi, T., Zeller, K. I., De Marzo, A. M., Van Eyk, J. E., Mendell, J. T., et al. (2009) · Nature · doi:10.1038/nature07823 · Cited by 2,124
Cited by
Sorted by citations
Patsoukis, N., Bardhan, K., Chatterjee, P., Sari, D., Liu, B., Bell, L. N., Karoly, E. D., Freeman, G. J., Petkova, V., Seth, P., et al. (2015) · Nature Communications · doi:10.1038/ncomms7692 · Cited by 1,249
Self-citationTheriot, C. M., Koenigsknecht, M. J., Carlson, P. E., Hatton, G. E., Nelson, A. M., Li, B., Huffnagle, G. B., Z. Li, J., & Young, V. B. (2014) · Nature Communications · doi:10.1038/ncomms4114 · Cited by 974
Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma
Lian, C. G., Xu, Y., Ceol, C., Wu, F., Larson, A., Dresser, K., Xu, W., Tan, L., Hu, Y., Zhan, Q., et al. (2012) · Cell · doi:10.1016/j.cell.2012.07.033 · Cited by 789
“The primer-targeted regions in (G) are ell 150, 1135–1146, September 14, 2012 ª2012 Elsevier Inc. 1141 1.0 1.5 2.0 Nevus Melanoma *** ** ***** * e ex pr es si on sA α-Ketoglutarate Isocitrate CO2 Succinate IDH1, 2 B HP RT GA PD H ID H1 ID H2 TE T1 TE T2 TE T3 PT EN CT SB 0.0 0.5 R el at iv e 5-mC 5-hmC TET1, 2, 3 CO2…”
BackgroundInfluentialTransformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation
Koivunen, P., Lee, S., Duncan, C. G., Lopez, G., Lu, G., Ramkissoon, S., Losman, J. A., Joensuu, P., Bergmann, U., Gross, S., et al. (2012) · Nature · doi:10.1038/nature10898 · Cited by 727
Self-citation( R )-2-Hydroxyglutarate Is Sufficient to Promote Leukemogenesis and Its Effects Are Reversible
Losman, J.-A., Looper, R. E., Koivunen, P., Lee, S., Schneider, R. K., McMahon, C., Cowley, G. S., Root, D. E., Ebert, B. L., & Kaelin, W. G. (2013) · Science · doi:10.1126/science.1231677 · Cited by 703
IDH mutation in glioma: molecular mechanisms and potential therapeutic targets
Han, S., Liu, Y., Cai, S. J., Qian, M., Ding, J., Larion, M., Gilbert, M. R., & Yang, C. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0814-x · Cited by 701
Weller, M., Wen, P. Y., Chang, S. M., Dirven, L., Lim, M. K., Monje, M., & Reifenberger, G. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00516-y · Cited by 693
Emerging insights into the molecular and cellular basis of glioblastomaPreprint
Dunn, G. P., Rinne, M. L., Wykosky, J., Genovese, G., Quayle, S. N., Dunn, I. F., Agarwalla, P. K., Chheda, M. G., Campos, B., Wang, A., et al. (2012) · Genes & Development · doi:10.1101/gad.187922.112 · Cited by 573
Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
Bunse, L., Pusch, S., Bunse, T., Sahm, F., Sanghvi, K., Friedrich, M., Alansary, D., Sonner, J. K., Green, E., Deumelandt, K., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0095-6 · Cited by 566
BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1
Tönjes, M., Barbus, S., Park, Y. J., Wang, W., Schlotter, M., Lindroth, A. M., Pleier, S. V., Bai, A. H. C., Karra, D., Piro, R. M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3217 · Cited by 486
Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities
Cairns, R. A., & Mak, T. W. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0083 · Cited by 452
Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion
Tateishi, K., Wakimoto, H., Iafrate, A. J., Tanaka, S., Loebel, F., Lelic, N., Wiederschain, D., Bedel, O., Deng, G., Zhang, B., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.11.006 · Cited by 433
“Cells harboring mutant IDH1 have altered levels of metabolites in addition to 2-HG (Grassian et al., 2014; Metallo et al., 2012; Reitman et al., 2014; Reitman et al., 2011; Seltzer et al., 2010; Zhao et al., 2009).”
InfluentialAndronesi, O. C., Kim, G. S., Gerstner, E., Batchelor, T., Tzika, A. A., Fantin, V. R., Vander Heiden, M. G., & Sorensen, A. G. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3002693 · Cited by 438
“Moreover, existing data indicate that 2HG and Glu might be inversely proportional: a slight decrease of Glu together with a large increase of 2HG in IDH1R132H (9) compared with a slight increase of Glu (20) with virtually undetectable 2HG (7) in wild-type IDH1 gliomas.”
BackgroundInfluentialOncometabolites: linking altered metabolism with cancer
Yang, M. H., Soga, T., & Pollard, P. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67228 · Cited by 441
“Both events could suppress glutathione synthesis and regeneration in IDH mutant cells (85), potentially conferring an oxidative intracellular status and affecting biosynthesis.”
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398
McBrayer, S. K., Mayers, J. R., DiNatale, G. J., Shi, D. D., Khanal, J., Chakraborty, A. A., Sarosiek, K. A., Briggs, K. J., Robbins, A. K., Sewastianik, T., et al. (2018) · Cell · doi:10.1016/j.cell.2018.08.038 · Cited by 368
“Our findings help explain why IDH1mutant gliomas convert 2OG to glutamate more slowly than IDH1 wild-type tumors and have low glutamate and glutathione content (Bisdas et al., 2016; Chaumeil et al., 2014; Choi et al., 2012; Izquierdo-Garcia et al., 2015; Jalbert et al., 2017; Pope et al., 2012; Reitman et al., 2011).”
Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis
Daye, D., & Wellen, K. E. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.02.002 · Cited by 387
Coordination of the transcriptome and metabolome by the circadian clock
Eckel‐Mahan, K. L., Patel, V. R., Mohney, R. P., Vignola, K. S., Baldi, P., & Sassone‐Corsi, P. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1118726109 · Cited by 380
“The metabolic profiling platform used for this kind of analysis by Metabolon combines three independent platforms: ultrahigh performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) optimized for basic species, UHPLC/MS/MS optimized for acidic species, and gas chromatography/mass spectrometry (GC/MS) (…”
MethodAltered cellular metabolism in gliomas — an emerging landscape of actionable co-dependency targets
Bi, J., Chowdhry, S., Wu, S., Zhang, W., Masui, K., & Mischel, P. S. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0226-5 · Cited by 359
Metabolism of [U‐ 13 C]glucose in human brain tumors in vivo
Maher, E. A., Marin‐Valencia, I., Bachoo, R. M., Mashimo, T., Raisanen, J., Hatanpaa, K. J., Jindal, A., Jeffrey, F. M., Choi, C., Madden, C., et al. (2012) · NMR in Biomedicine · doi:10.1002/nbm.2794 · Cited by 341
Pope, W. B., Prins, R. M., Albert Thomas, M., Nagarajan, R., Yen, K. E., Bittinger, M. A., Salamon, N., Chou, A. P., Yong, W. H., Soto, H., et al. (2012) · Journal of Neuro-Oncology · doi:10.1007/s11060-011-0737-8 · Cited by 318
“High-throughput sequencing previously revealed that the metabolic enzymes, IDH1 and IDH2, are frequently mutated in a majority of several types of malignant gliomas [4, 5].”
InfluentialRole of mitochondrial dysfunction in cancer progression
Hsu, C., Tseng, L., & Lee, H. (2016) · Experimental Biology and Medicine · doi:10.1177/1535370216641787 · Cited by 320
“2-Hydroxyglutarate inhibits the enzymatic activity of Complex IV (cytochrome c oxidase) and Complex V (ATP synthase)(114,115) and alters the gene expression of TCA cycle enzymes in cancer cells.(116) These findings suggest that the accumulation of 2-hydroxyglutarate contributes to the alterations in energy metabolism…”
BackgroundFu, Q., Liu, Y., Fan, Y., Hua, S., Hong-ying, Q., Dong, S.-W., Li, R.-L., Zhao, M., Zhen, Y., Yu, X., et al. (2015) · Journal of Hematology & Oncology · doi:10.1186/s13045-015-0117-5 · Cited by 290
“Further sample preparation, metabolic profiling, peak identification, and curation were performed by Metabolon (Durham, NC, USA) using their described methods [48].”
MethodIsocitrate dehydrogenase mutations in gliomas
Waitkus, M. S., Diplas, B. H., & Yan, H. (2015) · Neuro-Oncology · doi:10.1093/neuonc/nov136 · Cited by 292
Self-citationMetabolomic markers reveal novel pathways of ageing and early development in human populations
Menni, C., Kastenmüller, G., Petersen, A. K., Bell, J. T., Psatha, M., Tsai, P.-C., Gieger, C., Schulz, H., Erte, I., John, S., et al. (2013) · International Journal of Epidemiology · doi:10.1093/ije/dyt094 · Cited by 282
Caveolin-1 and Cancer Metabolism in the Tumor Microenvironment: Markers, Models, and Mechanisms
Sotgia, F., Martinez‐Outschoorn, U., Howell, A., Pestell, R. G., Pavlides, S., & Lisanti, M. P. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011811-120856 · Cited by 290
Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition
Boudreau, A., Purkey, H. E., Hitz, A., Robarge, K., Peterson, D., Labadie, S., Kwong, M., Hong, R., Gao, M., Del Nagro, C., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2143 · Cited by 280
Grassian, A. R., Parker, S. J., Davidson, S. M., Divakaruni, A. S., Green, C. R., Zhang, X., Slocum, K. L., Pu, M., Lin, F., Vickers, C., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0772-t · Cited by 280
“Interestingly, previous studies have also found that overexpression of mutant IDH leads to a decrease in N-acetyl amino acids, and these changes were also observed when comparing WT human glioma tissue with that of tumors with mutant IDH1 (24).”
Tan, Z., Xiao, L., Tang, M., Bai, F., Li, J., Li, L., Shi, F., Li, N., Li, Y., Du, Q., et al. (2018) · Theranostics · doi:10.7150/thno.21451 · Cited by 279
“Further sample preparation, metabolic profiling, peak identification and curation were performed by Metabolon (Durham, NC, STATE, USA) [43].”
MethodRevisiting the TCA cycle: signaling to tumor formation
Raimundo, N., Baysal, B. E., & Shadel, G. S. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.06.001 · Cited by 281
“The decrease in α-ketoglutarate depletes the rest of the cycle (succinate, fumarate, malate), regardless of whether the mutation is in the cytoplasmic or the mitochondrial enzyme [12].”
BackgroundResultInfluentialOxidative Stress and Metabolic Perturbations in Wooden Breast Disorder in Chickens
Abasht, B., Mutryn, M. F., Michalek, R. D., & Lee, W. R. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153750 · Cited by 266
“The platform and methodology used by Metabolon Inc. for metabolomics profiling has been previously described by Evans et al., (2009)[10] and Reitman et al. (2011)[11].”
MethodCancer metabolism and mitochondria: Finding novel mechanisms to fight tumours
Missiroli, S., Perrone, M., Genovese, I., Pinton, P., & Giorgi, C. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102943 · Cited by 263
“In addition, D-2-HG inhibits the enzymatic activity of complex V and alters gene expression in tumour cells [42].”
BackgroundMiller, J. J., Castro, L. N. G., McBrayer, S. K., Weller, M., Cloughesy, T. F., Portnow, J., Andronesi, O. C., Barnholtz‐Sloan, J. S., Baumert, B. G., Berger, M. S., et al. (2022) · Neuro-Oncology · doi:10.1093/neuonc/noac207 · Cited by 265
Self-citationIsocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma
Kipp, B. R., Voss, J. S., Kerr, S. E., Fritcher, E. G. B., Graham, R. P., Zhang, L., Highsmith, W. E., Zhang, J., Roberts, L. R., Gores, G. J., et al. (2012) · Human Pathology · doi:10.1016/j.humpath.2011.12.007 · Cited by 243
“Increased levels of 2-HG are thought to promote carcinogenesis by competitively inhibiting enzymes that use α-KG as a cofactor [17-20].”
BackgroundMetabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates
Ye, D., Guan, K.-L., & Xiong, Y. (2018) · Trends in Cancer · doi:10.1016/j.trecan.2017.12.005 · Cited by 242
Spectrum of somatic mitochondrial mutations in five cancers
Larman, T., DePalma, S. R., Hadjipanayis, A. G., Protopopov, A. I., Zhang, J., Gabriel, S., Chin, L., Seidman, C. E., Kucherlapati, R., & Seidman, J. G. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1211502109 · Cited by 240
2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling
Fu, X., Chin, R., Vergnes, L., Hwang, H., Deng, G., Xing, Y., Pai, M. Y., Li, S., Ta, L. H., Fazlollahi, F., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.06.009 · Cited by 230
“The elevated (R)-2HG levels are comparable with those found in cells treated with octyl (R)2HG (Figure 3H), and levels reported for IDH1mutant tumor samples (Dang et al., 2009; Gross et al., 2010; Reitman et al., 2011).”
BackgroundJames, E. L., Michalek, R. D., Pitiyage, G. N., de Castro, A. M., Vignola, K. S., Jones, J., Mohney, R. P., Karoly, E. D., Prime, S. S., & Parkinson, E. K. (2015) · Journal of Proteome Research · doi:10.1021/pr501221g · Cited by 231
Self-citationTryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas
Friedrich, M., Sankowski, R., Bunse, L., Kilian, M., Green, E., Guevara, C. R., Pusch, S., Poschet, G., Sanghvi, K., Hahn, M., et al. (2021) · Nature Cancer · doi:10.1038/s43018-021-00201-z · Cited by 241
Turkalp, Z. T., Karamchandani, J., & Das, S. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.1205 · Cited by 222
Stable isotope-resolved metabolomics and applications for drug development
Fan, T. W. ‐., Lorkiewicz, P., Sellers, K., Moseley, H., Higashi, R. M., & Lane, A. N. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.12.007 · Cited by 215
“However more recently, widespread changes in central metabolism were reported by profiling steadystate levels of a wide range of metabolites, although the authors indicated that stable isotope labeling studies are essential to define fully the metabolic consequences of the mutations (Reitman et al., 2011).”
BackgroundMolecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer
Clark, O., Yen, K. E., & Mellinghoff, I. K. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1333 · Cited by 210
“These metabolic changes can have a profound effect on the ability of cells to proliferate, differentiate, and escape cell death, and may introduce therapeutic vulnerabilities (56-64).”
BackgroundHinard, V., Mikhail, C., Pradervand, S., Curie, T., Houtkooper, R. H., Auwerx, J. H., Franken, P., & Tafti, M. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.2306-12.2012 · Cited by 209
“Metabolomic profiling analysis was performed by Metabolon as previously described (Reitman et al., 2011).”
MethodDang, L., & Su, S.-S. M. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044732 · Cited by 204
“In particular, expression of IDH1-R132H or IDH2-R172K mutants resulted in reduction of the TCA metabolites citrate, cis-aconitate, α-KG, malate, and fumarate, accompanied by an accumulation of biosynthetic precursors, which suggests that IDH mutation can result in TCA cycle downregulation (46).”
Oginuma, M., Moncuquet, P., Xiong, F., Karoly, E. D., Chal, J., Guevorkian, K., & Pourquié, O. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.02.001 · Cited by 202
“(Durham, NC, USA) for metabolomics analysis and Metabolomic profiling analysis was performed by Metabolon as described below and in (Evans et al., 2009; Reitman et al., 2011).”
MethodSelf-citationXiao, L., Hu, Z., Dong, X., Tan, Z. W., Li, W., Tang, M., Chen, L., Yang, L., Tao, Y., Jiang, Y., et al. (2014) · Oncogene · doi:10.1038/onc.2014.32 · Cited by 197
An in vivo patient-derived model of endogenous IDH1-mutant glioma
Luchman, H. A., Stechishin, O. D. M., Dang, N. H., Blough, M. D., Chesnelong, C., Kelly, J. J., Nguyen, S. A., Chan, J. A.-W., Weljie, A. M., Cairncross, J. G., et al. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor207 · Cited by 194
A joint analysis of metabolomics and genetics of breast cancer
Tang, X., Lin, C., Spasojević, I., Iversen, E. S., Chi, J., & Marks, J. R. (2014) · Breast Cancer Research · doi:10.1186/s13058-014-0415-9 · Cited by 202
“ation events [2-6].”
Drake, J. C., Wilson, R. J., Laker, R. C., Guan, Y., Spaulding, H. R., Nichenko, A. S., Shen, W., Shang, H., Dorn, M. V., Huang, K. A., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2025932118 · Cited by 198
“S1 A ), a gold standard method of mitochondrial isolation for striated muscles (28), and performed immunoblotting using anti-AMPK pan-α antibodies.”
Metabolic symbiosis in cancer: Refocusing the Warburg lens
Nakajima, E. C., & Houten, B. V. (2012) · Molecular Carcinogenesis · doi:10.1002/mc.21863 · Cited by 194
A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylationPreprint
Duncan, C. G., Barwick, B. G., Jin, G., Rago, C., Kapoor-Vazirani, P., Powell, D. R., Chi, J., Bigner, D. D., Vertino, P. M., & Yan, H. (2012) · Genome Research · doi:10.1101/gr.132738.111 · Cited by 183
“Human oligodendroglioma (HOG) cell lines expressing mutant IDH1 or empty vector were generated as described previously (Reitman et al. 2011).”
BackgroundMethodSelf-citationElevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation
Vohwinkel, C. U., Lecuona, E., Sun, H., Sommer, N., Vadász, I., Chandel, N. S., & Sznajder, J. I. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.290056 · Cited by 173
Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate
Andronesi, O. C., Rapalino, O., Gerstner, E. R., Chi, A. S., Batchelor, T. T., Cahill, D. P., Sorensen, A. G., & Rosen, B. R. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67229 · Cited by 178
“Evidence is mounting that high levels of D-2HG alter the biology of tumor cells toward malignancy by influencing the activity of enzymes critical for regulating the metabolic (14) and epigenetic state of cells (6, 7, 16–18).”
Predicting IDH mutation status in grade II gliomas using amide proton transfer‐weighted (APTw) MRI
Jiang, S., Zou, T., Eberhart, C. G., Villalobos, M. A. V., Heo, H., Zhang, Y., Wang, Y., Wang, X., Yu, H., Du, Y., et al. (2017) · Magnetic Resonance in Medicine · doi:10.1002/mrm.26820 · Cited by 172
“Because IDH geneencoded enzymes are closely involved in the energyproducing Krebs cycle as catalytic isozymes, mutations in IDH genes may cause widespread disturbances of cellular metabolism, including alteration of amino acid concentrations and enzymatic activity (7,8), and raise global DNA hypermethylation and globa…”
BackgroundCancer Metabolism and Drug Resistance
Rahman, M., & Hasan, M. R. (2015) · Metabolites · doi:10.3390/metabo5040571 · Cited by 175
“IDH1 derived 2-HG has also been shown to increase CpG island methylation [28,83].”
BackgroundThe Metabolomic Signature of Malignant Glioma Reflects Accelerated Anabolic Metabolism
Chinnaiyan, P., Kensicki, E., Bloom, G. C., Prabhu, A. H., Sarcar, B., Kahali, S., Eschrich, S. A., Qu, X., Forsyth, P. A., & Gillies, R. J. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1572-t · Cited by 172
“org Cancer Res; 72(22) November 15, 2012 OF7”
InfluentialPTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype
Duan, S., Yuan, G., Liu, X., Ren, R., Li, J., Zhang, W., Wu, J., Xu, X., Fu, L., Li, Y., et al. (2015) · Nature Communications · doi:10.1038/ncomms10068 · Cited by 172
Self-citationWhat do we know about IDH1/2 mutations so far, and how do we use it?
Horbinski, C. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1106-9 · Cited by 169
“Some have used a 2-HG octyl ester to increase cell permeability [30, 108, 184], but others have shown effects by exogenous 2-HG even without esterification [140].”
InfluentialChumpitazi, B. P., Hollister, E. B., Oezguen, N., Tsai, C. M., McMeans, A. R., Luna, R. A., Savidge, T. C., Versalovic, J., & Shulman, R. J. (2014) · Gut Microbes · doi:10.4161/gmic.27923 · Cited by 156
“Samples were processed as described previously.(46,47) For quality assurance (QA)/QC, additional samples were included with each day’s analysis.”
MethodDysregulation of fatty acid synthesis and glycolysis in non-Hodgkin lymphoma
Bhatt, A. P., Jacobs, S. R., Freemerman, A. J., Makowski, L., Rathmell, J. C., Dittmer, D. P., & Damania, B. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1205995109 · Cited by 163
“Metabolic profiling, peak identification, and curationwas performed by Metabolon using described methods (35).”
MethodLeonardi, R., Subramanian, C., Jackowski, S., & Rock, C. O. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.c112.353946 · Cited by 171
“In addition, the KG carbon destined for citrate is instead converted to 2HG, which reduces KG levels (29).”
BackgroundTCA Cycle Defects and Cancer: When Metabolism Tunes Redox State
Cardaci, S., & Ciriolo, M. R. (2012) · International Journal of Cell Biology · doi:10.1155/2012/161837 · Cited by 169
“As IDH1/2 mutant cells are characterized by lower levels of glutamate with respect to their wt matching parts [62], it is possible that oncogenic defects in IDH result in impaired GSH synthesis due to a lower glutamate availability, thus phenocopying the prooxidant conditions observed in glutaminase deficient cells [6…”
BackgroundOncogene-induced senescence results in marked metabolic and bioenergetic alterations
Quijano, C., Cao, L., Fergusson, M. M., Romero, H., Liu, J., Gutkind, S., Rovira, I. I., Mohney, R. P., Karoly, E. D., & Finkel, T. (2012) · Cell Cycle · doi:10.4161/cc.19800 · Cited by 155
Self-citationLandscape of the mitochondrial Hsp90 metabolome in tumours
Chae, Y. C., Angelin, A., Lisanti, S., Kossenkov, A. V., Speicher, K. D., Wang, H., Powers, J. F., Tischler, A. S., Pacák, K., Fliedner, S. M. J., et al. (2013) · Nature Communications · doi:10.1038/ncomms3139 · Cited by 162
Self-citationMetabolic consequences of oncogenic IDH mutations
Parker, S. J., & Metallo, C. M. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.05.003 · Cited by 162
“An in vivo knock-in model of IDH1-R132H exhibited increased NADP+/NADPH ratio, decreased GSH, and decreased ascorbate in whole brains, consistent with a decrease in NADPH production and redox control capacity (Sasaki et al., 2012a).”
BackgroundInfluentialGamble, L. D., Purgato, S., Murray, J. E., Xiao, L., Yu, D. M. T., Hanssen, K. M., Giorgi, F. M., Carter, D. R., Gifford, A. J., Valli, E., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau1099 · Cited by 155
The Roles of 2-Hydroxyglutarate
Du, X., & Hu, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.651317 · Cited by 160
Andronesi, O. C., Loebel, F., Bogner, W., Marjańska, M., Heiden, M. G. V., Iafrate, A. J., Dietrich, J., Batchelor, T. T., Gerstner, E. R., Kaelin, W. G., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0656 · Cited by 153
“Lower glutamate and glutamine levels have been measured in mutant versus wild-type IDH cell cultures (45), while results from animal models have yielded a more complex fate of glutamate and glutamine (46, 47).”
Teicher, B. A., Linehan, W. M., & Helman, L. J. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-2587 · Cited by 152
Stockhammer, F., Misch, M., Helms, H., Lengler, U., Prall, F., von Deimling, A., & Hartmann, C. J. (2012) · Seizure · doi:10.1016/j.seizure.2011.12.007 · Cited by 147
“scarcity of TCA metabolites, by withdrawal due to 2HG accumulation.(8,26) There are numerous reports on seizures in patients or animal models when the TCA is impaired by inherited disease or toxic interference.”
BackgroundFack, F., Tardito, S., Hochart, G., Oudin, A., Zheng, L., Fritah, S., Golebiewska, A., Nazarov, P. V., Bernard, A., Hau, A., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201707729 · Cited by 148
“In line with earlier data (Reitman et al , 2011), NAAG levels were heterogeneous in IDHm gliomas, suggesting differential activation of metabolic pathways.”
Oncometabolites: tailoring our genes
Nowicki, S., & Gottlieb, E. (2015) · FEBS Journal · doi:10.1111/febs.13295 · Cited by 148
Inhaled ozone (O3)-induces changes in serum metabolomic and liver transcriptomic profiles in rats
Miller, D. B., Karoly, E. D., Jones, J. C., Ward, W. O., Vallanat, B., Andrews, D. L., Schladweiler, M. C. J., Snow, S. J., Bass, V. L., Richards, J. H., et al. (2015) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2015.03.025 · Cited by 144
Self-citationOncogenic Activities of IDH1/2 Mutations: From Epigenetics to Cellular Signaling
Gagné, L. M., Boulay, K., Topisirović, I., Huot, M., & Mallette, F. A. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.06.002 · Cited by 143
Fessel, J. P., Hamid, R., Wittmann, B. M., Robinson, L. J., Blackwell, T., Tada, Y., Tanabe, N., Tatsumi, K., Hemnes, A. R., & West, J. D. (2012) · Pulmonary Circulation · doi:10.4103/2045-8932.97606 · Cited by 141
Schuler, K., Rambally, B. S., DiFurio, M. J., Sampey, B. P., Gehrig, P. A., Makowski, L., & Bae-Jump, V. L. (2014) · Cancer Medicine · doi:10.1002/cam4.353 · Cited by 137
Sun, Y., Daemen, A., Hatzivassiliou, G., Arnott, D. P., WILSON, C. A., Zhuang, G., Gao, M., Liu, P. J., Boudreau, A., Johnson, L., et al. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-20 · Cited by 134
“The cell pellets were snap-frozen and submitted to Metabolon Inc for global metabolomic analysis [12].”
MethodYoussef, G., & Miller, J. J. (2020) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-020-01040-8 · Cited by 144
Biological insights through nontargeted metabolomics
Sévin, D. C., Kuehne, A., Zamboni, N., & Sauer, U. (2014) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2014.10.001 · Cited by 141
IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma
Zhang, C., Moore, L. M., Li, X., Yung, W. K. A., & Zhang, W. (2013) · Neuro-Oncology · doi:10.1093/neuonc/not087 · Cited by 136
“On the other hand, the genetic alterations observed in tumors may lead to deregulation of cellular metabolism.(57) Aberrant cellular metabolism and aberrant gene expression affect each other and together drive cancer pathogenesis.”
BackgroundGlobal Profiling Strategies for Mapping Dysregulated Metabolic Pathways in Cancer
Benjamin, D. I., Cravatt, B. F., & Nomura, D. K. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.09.013 · Cited by 131
“Carbon atoms arising from CO 2 are labeled as black dots. amino acids NAA and NAAG (most commonly found as dipeptides in the brain) were significantly lowered in cells containing a mutated IDH1 (Reitman et al., 2011).”
Odagiri, H., Kadomatsu, T., Endo, M., Masuda, T., Morioka, M. S., Fukuhara, S., Miyamoto, T. K., Kobayashi, E., Miyata, K., Aoi, J., et al. (2014) · Science Signaling · doi:10.1126/scisignal.2004612 · Cited by 130
“Ten-eleven translocation (TET) family proteins contribute to DNA demethylation by converting 5-methylcytosine (5mC) to the demethylation intermediate 5-hydroxymethylcytosine (5hmC) in an a-ketoglutarate– dependent manner (10–12). a-Ketoglutarate is produced primarily by isocitrate dehydrogenase (IDH) (11, 13).”
BackgroundInfluentialDisruption of Wild-Type IDH1 Suppresses D-2-Hydroxyglutarate Production in IDH1-Mutated Gliomas
Jin, G., Reitman, Z. J., Duncan, C. G., Spasojević, I., Gooden, D. M., Rasheed, B. A., Yang, R. R., Lopez, G. Y., He, Y., McLendon, R. E., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2852 · Cited by 130
“IDH1 or IDH1 was ectopically expressed using lentivirus constructs described previously (16) after 1-month selectionwith 0.”
Self-citationShiroto, T., Romero, N., Sugiyama, T., Sartoretto, J. L., Kalwa, H., Yan, Z., Shimokawa, H., & Michel, T. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0087871 · Cited by 125
“All cell treatments, metabolite analysis, sample preparation, quality assurance procedures, spectroscopy, and statistical analysis was performed as previously described[21].”
MethodIDH1 Mutation Induces Reprogramming of Pyruvate Metabolism
Izquierdo-Garcia, J. L., Viswanath, P., Eriksson, P., Cai, L., Radoul, M., Chaumeil, M. M., Blough, M., Luchman, H. A., Weiss, S., Cairncross, J. G., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0840 · Cited by 123
“To confirm that increased HIF1a and PDK3 levels and reduced PDH activity were associated with mutant IDH1-induced 2-HG production, we measured PDH activity in NHAIDHwt and U87IDHwt cells treated with exogenous 2-HG, previously shown to model the effect of the IDH1 mutation (10, 34, 35).”
BackgroundMethodQuantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation
Ohka, F., Ito, M., Ranjit, M., Senga, T., Motomura, A., Motomura, K., Saito, K., Kato, K., Kato, Y., Wakabayashi, T., et al. (2014) · Tumor Biology · doi:10.1007/s13277-014-1784-5 · Cited by 124
“suggested that Nacetyltransferase may be downregulated or that destruction/ consumption of N-acetylated amino acids may be associated with IDH mutation [24].”
BackgroundDesideri, E., Vegliante, R., & Ciriolo, M. R. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.02.023 · Cited by 116
“for the biosynthesis of glutathione, the most abundant cellular antioxidant [57] that is involved in the regulation of many cellular”
BackgroundProfiling metabolic networks to study cancer metabolism
Hiller, K., & Metallo, C. M. (2012) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2012.11.001 · Cited by 113
Kaminska, B., Czapski, B., Guzik, R., Król, S. K., & Gielniewski, B. (2019) · Molecules · doi:10.3390/molecules24050968 · Cited by 114
“A similar reduction of NAAG was detected in IDH‐mut glioma tissues [21].”
BackgroundInfluentialSalamanca-Cardona, L., Shah, H., Poot, A. J., Correa, F. M., Di Gialleonardo, V., Lui, H., Miloushev, V. Z., Granlund, K. L., Tee, S. S., Cross, J. R., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.10.001 · Cited by 106
“These findings suggest a fundamental difference in the metabolic rewiring of each type of mutant cell, which has also been suggested in previous reports using isogenic mutants (Reitman et al., 2011; Wen et al., 2015).”
ResultGlobal Profiling of Metabolic Adaptation to Hypoxic Stress in Human Glioblastoma Cells
Kucharzewska, P., Christianson, H. C., & Belting, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116740 · Cited by 107
“Comprehensive metabolomics approaches that simultaneously detect changes in a variety of metabolites in cells from different oxygenation conditions should be critical for the identification of potential metabolic ‘Achilles’ heels’ of cancer cells [10].”
BackgroundMolecular pathology in adult high‐grade gliomas: from molecular diagnostics to target therapies
Masui, K., Cloughesy, T. F., & Mischel, P. S. (2011) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2011.01238.x · Cited by 113
“However, heterozygous IDH1/2 mutations may be consistent with a gain of function, and the mutant enzyme was reported to increase the formation of 2-hydroxyglutarate, which might be tumorigenic [46,47].”
BackgroundThe Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells
Smolková, K., & Ježek, P. (2012) · International Journal of Cell Biology · doi:10.1155/2012/273947 · Cited by 114
“Interestingly, IDH2 mutations also lead to increases in amino acid levels [35] as would be expected for ongoing glutaminolysis.”
BackgroundMolecular Distinction of Chondrosarcoma From Chondroblastic Osteosarcoma Through IDH1/2 Mutations
Kerr, D. A., Lopez, H. U., Deshpande, V., Hornicek, F. J., Duan, Z., Zhang, Y., Rosenberg, A. E., Borger, D. R., & Nielsen, G. P. (2013) · The American Journal of Surgical Pathology · doi:10.1097/pas.0b013e31827ab703 · Cited by 105
GC/MS-based metabolomic analysis of cerebrospinal fluid (CSF) from glioma patients
Nakamizo, S., Sasayama, T., Shinohara, M., Irino, Y., Nishiumi, S., Nishihara, M., Tanaka, H., Tanaka, K., Mizukawa, K., Itoh, T., et al. (2013) · Journal of Neuro-Oncology · doi:10.1007/s11060-013-1090-x · Cited by 101
“[44] reported that amino acid, choline lipid, and TCA cycle metabolite levels were altered in cells expressing IDH mutants.”
BackgroundPerrone, C. E., Mattocks, D. A. L., Plummer, J. D., Chittur, S. V., Mohney, R. P., Vignola, K. S., Orentreich, D. S., & Orentreich∥, N. (2012) · Lifestyle Genomics · doi:10.1159/000339347 · Cited by 100
Applications of metabolomics in cancer research
Styczynski, M. P., & Vermeersch, K. A. (2013) · Journal of Carcinogenesis · doi:10.4103/1477-3163.113622 · Cited by 107
“[44] The effects of IDH1/2 mutations on the metabolome were very similar to the changes caused by treating normal cells with 2HG, showing that it is the production of the oncometabolite 2HG and not the loss of IDH1/2’s normal operation that causes these changes.[44]”
BackgroundTateishi, K., Higuchi, F., Miller, J. J., Koerner, M. V. A., Lelic, N., Shankar, G. M., Tanaka, S., Fisher, D. E., Batchelor, T. T., Iafrate, A. J., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2263 · Cited by 100
“dehydrogenase(21), as well as altered citric acid cycle flux(22), and depleted steady-state pools of several canonical metabolites including glutathione(23) and nicotinamide adenine dinucleotide (NAD+)(24).”
Biochemical alterations associated with ALS
Lawton, K. A., Cudkowicz, M., Brown, M. V., Alexander, D. C., Caffrey, R., Wulff, J. E., Bowser, R. P., Lawson, R. J., Jaffa, M., Milburn, M. V., et al. (2011) · Amyotrophic Lateral Sclerosis · doi:10.3109/17482968.2011.619197 · Cited by 92
Carrillo, J. A., He, Y., Li, Y., Liu, J., Erdman, R. A., Sonstegard, T. S., & Song, J. (2016) · Scientific Reports · doi:10.1038/srep25948 · Cited by 99
Self-citation
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
