Hypoxia-Mediated Increases in l -2-hydroxyglutarate Coordinate the Metabolic Response to Reductive Stress
Open accessAbstract
Metabolic adaptation to hypoxia is critical for survival in metazoan species for which reason they have developed cellular mechanisms for mitigating its adverse consequences. Here, we have identified L-2-hydroxyglutarate (L2HG) as a universal adaptive determinant of the hypoxia response. L2HG is a metabolite of unknown function produced by the reduction of mitochondrial 2-oxoglutarate by malate dehydrogenase. L2HG accumulates in response to increases in 2-oxoglutarate, which occur as a result of tricarboxylic acid cycle dysfunction and increased mitochondrial reducing potential. These changes are closely coupled to cellular redox homeostasis, as increased cellular L2HG inhibits electron transport and glycolysis to offset the adverse consequences of mitochondrial reductive stress induced by hypoxia. Thus, L2HG couples mitochondrial and cytoplasmic energy metabolism in a model of cellular redox regulation.
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
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?
Different enantiomeric forms of 2-HG may induce different responses to hypoxia, including a HIF-independent one and an altogether different tumour phenotype.
“The different enantiomeric forms of 2-HG may thus induce different responses to hypoxia, including a HIF-independent one and an altogether different tumour phenotype.”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [157]
The Results section ('HIF1α Is Sufficient But Not Necessary for 2HG Accumulation'; page unavailable) reports a HIF-independent mechanism for hypoxic L2HG accumulation. The Discussion says L2HG and D2HG have distinct effects on metabolic regulation, but does not establish that they induce different tumour phenotypes or that an enantiomer induces a HIF-independent response to hypoxia. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIncreased L-2-HG production in response to mitochondrial dysfunction in hypoxia is independent of HIF activation and may constitute a common hypoxia response mechanism.
“Accumulation of 2-HG has been confirmed in various normal and immortalised cell types, and increased amounts of L-2-HG were shown to be produced in response to mitochondrial dysfunction in hypoxia. This process was shown to be independent of HIF activation and may constitute a common hypoxia response mechanism [157].”
From HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells (2021) · cites this paper as [157]
Under hypoxic conditions, L-2-hydroxyglutarate (L-2-HG) is generated by lactate dehydrogenase A (LDHA) and malate dehydrogenase (MDH).
“Under hypoxic conditions, L-2-hydroxyglutarate (L-2-HG) was proven to be generated by lactate dehydrogenase A (LDHA) and malate dehydrogenase (MDH)88,89.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [89]
L-2-HG is implicated as metabolic mediator of cellular stress response to hypoxia.
“Furthermore, L-2-HG levels were found to increase in response to hypoxia as a result of promiscuous substrate use by LDH-A and malate dehydrogenase (MDH) (Intlekofer et al., 2015), and two recent studies implicate L-2-HG as a metabolic mediator of the cellular stress response to hypoxia (Intlekofer et al., 2015; Oldham et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Oldham et al., 2015
L-2-HG levels increase in response to hypoxia due to promiscuous substrate use by LDH-A and MDH.
“Furthermore, L-2-HG levels were found to increase in response to hypoxia as a result of promiscuous substrate use by LDH-A and malate dehydrogenase (MDH) (Intlekofer et al., 2015), and two recent studies implicate L-2-HG as a metabolic mediator of the cellular stress response to hypoxia (Intlekofer et al., 2015; Oldham et al., 2015).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Oldham et al., 2015
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to Hypoxia
Zhang, H., Bosch-Marce, M., Shimoda, L. A., Tan, Y. S., Baek, J. H., Wesley, J. B., Gonzalez, F. J., & Semenza, G. L. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800102200 · Cited by 1,601 · cited 1× · see citing works
“These changes limit carbon entry into the tricarboxylic acid cycle (TCA) and mitigate damage from reactive oxygen species (ROS) generated by dysfunctional (uncoupled) electron transport in the mitochondria (Zhang et al., 2008).”
RetractedCancer-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 · see citing works
Hypoxia-inducible factors in physiology and medicine
Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645 · cited 2× · see citing works
“This programmed response is mediated primarily through stabilization of hypoxia-inducible factor 1a (HIF1a), a transcription factor that coordinates a shift in energy metabolism away from oxidative phosphorylation and toward glycolysis and lactate fermentation through the increased expression of glucose transporters (…”
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251 · see citing works
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 · cited 5× · see citing works
“While studies have shown that both D2HG and L2HG can inhibit PHD (Figueroa et al., 2010; Lu et al., 2012; Xu et al., 2011), the observations that HIF is stabilized in siD2HGDHtreated cells despite no change in intracellular D2HG levels and that blocking L2HG accumulation in hypoxia through L2HGDH overexpression has no…”
InfluentialSelf-citationFigueroa, 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 · cited 9× · see citing works
“These data support an alternative mechanism for HIF stabilization beyond direct PHD inhibition by 2HG.”
InfluentialAssessing mitochondrial dysfunction in cells
Brand, M. D., & Nicholls, D. G. (2011) · Biochemical Journal · doi:10.1042/bj20110162 · Cited by 2,436 · cited 11× · see citing works
“These studies suggest that L2HGDH contributes to the generation of DJm, as shown by reduced FCCP-stimulated OCR in normoxia and decreased TMRM fluorescence in hypoxia.”
InfluentialMetaboAnalyst: a web server for metabolomic data analysis and interpretation
Xia, J., Psychogios, N., Young, N., & Wishart, D. S. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp356 · Cited by 2,238 · cited 2× · see citing works
“…biosynthesis, energy production (glycolysis, TCA cycle, and electron transport chain), and redox homeostasis (malate-aspartate shuttle, glycerol phosphate shuttle, nicotinamide metabolism, and glutathione metabolism), as identified by metabolite set enrichment analysis (Xia et al., 2009, 2012).”
Ward, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.020 · Cited by 2,020 · cited 1× · see citing works
“By contrast, D2HG has been identified as the product of cancer-associated mutant IDH enzymes (Cairns and Mak, 2013; Dang et al., 2009; Ward et al., 2010).”
IDH mutation impairs histone demethylation and results in a block to cell differentiation
Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., et al. (2012) · Nature · doi:10.1038/nature10860 · Cited by 1,985 · cited 9× · see citing works
“These data support an alternative mechanism for HIF stabilization beyond direct PHD inhibition by 2HG.”
InfluentialMetaboAnalyst 2.0--a comprehensive server for metabolomic data analysis
Xia, J., Mandal, R., Sinelnikov, I., Broadhurst, D., & Wishart, D. S. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks374 · Cited by 1,146 · cited 2× · see citing works
“…biosynthesis, energy production (glycolysis, TCA cycle, and electron transport chain), and redox homeostasis (malate-aspartate shuttle, glycerol phosphate shuttle, nicotinamide metabolism, and glutathione metabolism), as identified by metabolite set enrichment analysis (Xia et al., 2009, 2012).”
Glucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells
Le, A., Lane, A. N., Hamaker, M., Bose, S., Gouw, A., Barbi, J., Tsukamoto, T., Rojas, C. J., Slusher, B. S., Zhang, H., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2011.12.009 · Cited by 1,095 · cited 7× · see citing works
“Given that PASMC proliferate in response to hypoxia, one interesting hypothesis is that the D2HG represents incomplete reductive carboxylation by IDH in these cells as has been observed in a variety of cancer cell lines (Gameiro et al., 2013; Scott et al., 2011; Wise et al., 2011).”
InfluentialKamentsky, L. D., Jones, T. R., Fraser, A. N., Bray, M., Logan, D. J., Madden, K. L., Ljosa, V., Rueden, C., Eliceiri, K. W., & Carpenter, A. E. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr095 · Cited by 1,002 · cited 1× · see citing works
“Mean cell fluorescence intensity for each image was determined using CellProfiler (Kamentsky et al., 2011).”
Wise, D. R., Ward, P. S., Shay, J. E. S., Cross, J. R., Gruber, J. J., Sachdeva, U. M., Platt, J. M., DeMatteo, R. G., Simon, M. C., & Thompson, C. B. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117773108 · Cited by 975 · cited 5× · see citing works
“Given that PASMC proliferate in response to hypoxia, one interesting hypothesis is that the D2HG represents incomplete reductive carboxylation by IDH in these cells as has been observed in a variety of cancer cell lines (Gameiro et al., 2013; Scott et al., 2011; Wise et al., 2011).”
InfluentialWu, M., Neilson, A., Swift, A. L., Moran, R., Tamagnine, J., Parslow, D., Armistead, S., Lemire, K., Orrell, J., Teich, J., et al. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00247.2006 · Cited by 922 · cited 1× · see citing works
“As glycolysis is a major determinant of cytoplasmic reducing potential under hypoxic conditions, we next measured the effect of 2HGDH knockdown on glycolytic flux by measuring the extracellular acidification rate (ECAR) in response to glucose and oligomycin (Wu et al., 2007).”
Transformation 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 · cited 9× · see citing works
“These data support an alternative mechanism for HIF stabilization beyond direct PHD inhibition by 2HG.”
InfluentialLosman, 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 · cited 3× · see citing works
“2HGDH Knockdown Activates HIF1a Independent of 2HG Levels Both L2HG and D2HG have been shown to inhibit the function of 2OG-dependent dioxygenases, like PHD (Xu et al., 2011), although D2HG has also been shown to activate PHD (Koivunen et al., 2012; Losman et al., 2013).”
What a difference a hydroxyl makes: mutant IDH, (<i>R</i>)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570 · cited 5× · see citing works
“, 2011), although D2HG has also been shown to activate PHD (Koivunen et al., 2012; Losman et al., 2013).”
InfluentialMovafagh, S., Crook, S., & Vo, K. (2015) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25074 · Cited by 469 · cited 2× · see citing works
“…of HIF is complex, and a variety ofmechanisms have been implicated in its stabilization, includingmicroRNA, other post-translationalmodifications, and intracellular signaling cascades (e.g., ERK and AKT), in addition to ROS and PHD inhibition (Movafagh et al., 2015; Yee Koh et al., 2008).”
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 · cited 3× · see citing works
“While D2HG is a so-called ‘‘oncometabolite’’ produced bymutations in IDH associated with an increasing number of human malignancies (Cairns and Mak, 2013), these data reinforce the notion that D2HG and L2HG are separate and distinct metabolites with unique effects on metabolic regulation (Struys,…”
Zhao, Y., Hu, Q., Cheng, F., Su, N., Wang, A., Zou, Y., Hu, H., Chen, X., Hai‐Meng, Z. H. O. U., Huang, X., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.04.009 · Cited by 434 · cited 3× · see citing works
“…also increase cellular NADH/NAD+, LF Cell Metabolism 22, 291–30 expressing a genetically encoded fluorescence sensor of NADH/NAD+ in situ, SoNar (Zhao et al., 2015), were treated with permeable trifluoromethylbenzyl ester (TFMB) derivatives of 2OG, D2HG, and L2HG (Losman et al., 2013;…”
Self-citationIncreasing NADH oxidation reduces overflow metabolism in Saccharomyces cerevisiae
Vemuri, G. N., Eiteman, M. A., McEwen, J. E., Lisbeth Olsson, A., & Nielsen, J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607469104 · Cited by 373 · cited 1× · see citing works
“This oxygen tension is below the P50 for mitochondrial respiration (Vemuri et al., 2007), which would enhance any differences between glycolytic and oxidative metabolism.”
MacKenzie, E. D., Selak, M. A., Tennant, D. A., Payne, L. J., Crosby, S., Frederiksen, C. M., Watson, D. G., & Gottlieb, E. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01927-06 · Cited by 359 · see citing works
HIF-1 regulation: not so easy come, easy go
Koh, M. Y., Spivak-Kroizman, T. R., & Powis, G. (2008) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.08.002 · Cited by 339 · cited 2× · see citing works
“…of HIF is complex, and a variety ofmechanisms have been implicated in its stabilization, includingmicroRNA, other post-translationalmodifications, and intracellular signaling cascades (e.g., ERK and AKT), in addition to ROS and PHD inhibition (Movafagh et al., 2015; Yee Koh et al., 2008).”
Mullen, A. R., Hu, Z., Shi, X., Jiang, L., Boroughs, L. K., Kovacs, Z., Boriack, R., Rakheja, D., Sullivan, L. B., Linehan, W. M., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.037 · Cited by 337 · cited 2× · see citing works
“In addition to hypoxia, mutations in CYTB in osteosarcoma cells (Complex III deficiency), and fumarate hydratase deficiency in renal carcinoma cells, and Complex I inhibition with rotenone increase L2HG (Mullen et al., 2014; Worth et al., 2015).”
Comparative Metabolic Flux Profiling of Melanoma Cell Lines
Scott, D. A., Richardson, A. D., Filipp, F. V., Knutzen, C. A., Chiang, G. G., Ronai, Z. A., Osterman, A. L., & Smith, J. W. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.282046 · Cited by 328 · cited 4× · see citing works
“Given that PASMC proliferate in response to hypoxia, one interesting hypothesis is that the D2HG represents incomplete reductive carboxylation by IDH in these cells as has been observed in a variety of cancer cell lines (Gameiro et al., 2013; Scott et al., 2011; Wise et al., 2011).”
InfluentialGameiro, P. A., Yang, J., Metelo, A. M., Pérez-Carro, R., Baker, R., Wang, Z., Arreola, A., Rathmell, W. K., Olumi, A., López-Larrubia, P., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.02.002 · Cited by 325 · cited 4× · see citing works
“Given that PASMC proliferate in response to hypoxia, one interesting hypothesis is that the D2HG represents incomplete reductive carboxylation by IDH in these cells as has been observed in a variety of cancer cell lines (Gameiro et al., 2013; Scott et al., 2011; Wise et al., 2011).”
InfluentialProgress in understanding 2‐hydroxyglutaric acidurias
Kranendijk, M., Struys, E. A., Salomons, G. S., Van der Knaap, M. S., & Jakobs, C. (2012) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-012-9462-5 · Cited by 292 · cited 1× · see citing works
“Two enantiomers of 2HG, L and D, have been associated with separate, rare inborn errors of metabolism resulting in increased urinary excretion of 2HG linked to neurological deficits in children (Chalmers et al., 1980; Duran et al., 1980; Kranendijk et al., 2012).”
<scp>l</scp> -2-Hydroxyglutarate: An Epigenetic Modifier and Putative Oncometabolite in Renal Cancer
Shim, E.-H., Livi, C. B., Rakheja, D., Tan, J., Benson, D., Parekh, V., Kho, E.-Y., Ghosh, A. P., Kirkman, R., Velu, S., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0696 · Cited by 280 · cited 2× · see citing works
“…of regional hypoxia in tumor biology, this work also highlights the importance of enantiomeric characterization of 2HG elevations, particularly as L2HG has recently been identified in association with renal cell carcinoma tissues, many of which contained VHL mutations (Shim et al., 2014).”
L‐2‐Hydroxyglutaric aciduria: an inborn error of metabolism?
Duran, M., Kamerling, J. P., Bakker, H. D., van Gennip, A. H., & Wadman, S. K. (1980) · Journal of Inherited Metabolic Disease · doi:10.1007/bf02312543 · Cited by 226 · cited 1× · see citing works
“Two enantiomers of 2HG, L and D, have been associated with separate, rare inborn errors of metabolism resulting in increased urinary excretion of 2HG linked to neurological deficits in children (Chalmers et al., 1980; Duran et al., 1980; Kranendijk et al., 2012).”
Rzem, R., Veiga-da-Cunha, M., Noël, G., Goffette, S., Nassogne, M.-C., Tabarki, B., Schöller, C., Marquardt, T., Vikkula, M., & Van Schaftingen, E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404840101 · Cited by 195 · cited 4× · see citing works
“L2HGDH is a mito- chondrial protein that catalyzes the oxidation of L2HG to 2OG coupled to the reduction of FAD (Rzem et al., 2004, 2006; Topçu et al., 2004) (Figure 3A).”
InfluentialMutations in the d-2-Hydroxyglutarate Dehydrogenase Gene Cause d-2-Hydroxyglutaric Aciduria
Struys, E. A., Salomons, G. S., Achouri, Y., Van Schaftingen, E., Grosso, S., Craigen, W. J., Verhoeven, N. M., & Jakobs, C. (2005) · The American Journal of Human Genetics · doi:10.1086/427890 · Cited by 172 · cited 2× · see citing works
“Similarly, D2HG has a specific mitochondrial dehydrogenase, D2HGDH, that catalyzes its oxidation to 2OG and transfers electrons to FADH2 (Achouri et al., 2004; Struys et al., 2005).”
l ‐2‐Hydroxyglutaric aciduria, a defect of metabolite repair
Rzem, R., Vincent, M., SCHAFTINGEN, E. V., & Veiga‐da‐Cunha, M. (2007) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-007-0487-0 · Cited by 149 · cited 4× · see citing works
“Indeed, L2HG aciduria, caused by mutations in L2HGDH, has been described as a ‘‘disorder of metabolite repair’’ (Rzem et al., 2007).”
InfluentialStruys, E. A., Jansen, E. E. W., Verhoeven‐Duif, N. M., & Jakobs, C. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2004.033399 · Cited by 147 · cited 8× · see citing works
“Quantification of 2HG Enantiomers Metabolite extracts were derivatized with diacetyl-L-tartaric anhydride (DATAN) using an adaptation of a previously described method (Struys et al., 2004a).”
InfluentialD‐2‐hydroxyglutaric aciduria: Case report and biochemical studies
Chalmers, R. A., Lawson, A. M., Watts, R. W. E., Tavill, A. S., Kamerling, J. P., Hey, E., & Ogilvie, D. (1980) · Journal of Inherited Metabolic Disease · doi:10.1007/bf02312516 · Cited by 135 · cited 1× · see citing works
“Two enantiomers of 2HG, L and D, have been associated with separate, rare inborn errors of metabolism resulting in increased urinary excretion of 2HG linked to neurological deficits in children (Chalmers et al., 1980; Duran et al., 1980; Kranendijk et al., 2012).”
Topçu, M., Jobard, F., Halliez, S., Coskun, T., Yalçinkayal, C., Gerceker, F. O., Wanders, R. J. A., Prud'homme, J.-F., Lathrop, M., Özguc, M., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh300 · Cited by 133 · cited 5× · see citing works
“The metabolites 2OG and L2HG form a redox couple linked to NADH/NAD+ and FADH2/FAD.”
InfluentialIdentification of a dehydrogenase acting on D -2-hydroxyglutarate
Achouri, Y., NOËL, G., Vertommen, D., Rider, M. H., Veiga‐da‐Cunha, M., & SCHAFTINGEN, E. V. (2004) · Biochemical Journal · doi:10.1042/bj20031933 · Cited by 129 · cited 2× · see citing works
“Similarly, D2HG has a specific mitochondrial dehydrogenase, D2HGDH, that catalyzes its oxidation to 2OG and transfers electrons to FADH2 (Achouri et al., 2004; Struys et al., 2005).”
Metabolic dysfunction in pulmonary hypertension: the expanding relevance of the W arburg effect
Cottrill, K. A., & Chan, S. Y. (2013) · European Journal of Clinical Investigation · doi:10.1111/eci.12104 · Cited by 94 · cited 4× · see citing works
“Global Metabolic Reprogramming of Pulmonary Vascular Cells in Response to Hypoxia Hypoxia is a potent stimulus for pulmonary vascular remodeling in patients with pulmonary hypertension, characterized by smooth muscle and endothelial cell proliferation and metabolic dysregulation (Cottrill and Chan, 2013).”
InfluentialMitochondrial energy metabolism is markedly impaired by d-2-hydroxyglutaric acid in rat tissues
Latini, A., da Silva, C. G., Ferreira, G. C., Schuck, P. F., Scussiato, K., Sarkis, J. J., Dutra Filho, C. S., Wyse, A. T. S., Wannmacher, C. M. D., & Wajner, M. (2005) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2005.05.002 · Cited by 88 · cited 4× · see citing works
“, 2005); however, L2HG was able to decrease the respiratory control ratio (RCR), suggesting uncoupling of electron transport from ATP production (Latini et al., 2005).”
Influentialda Silva, C. G., Ribeiro, C. A. J., Leipnitz, G., Dutra‐Filho, C. S., Wyse, Â. T. D. S., Wannmacher, C. M. D., Sarkis, J. J. F., Jakobs, C., & Wajner, M. (2002) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(01)00088-6 · Cited by 87 · cited 1× · see citing works
“…work has shown no direct effect of L2HG on electron flux through the respiratory chain in rat cortical homogenates and striated muscle cells (da Silva et al., 2002; Latini et al., 2005); however, L2HG was able to decrease the respiratory control ratio (RCR), suggesting uncoupling of electron…”
Metabolomics of urinary organic acids in respiratory chain deficiencies in children
Reinecke, C. J., Koekemoer, G., van der Westhuizen, F. H., Louw, R., Lindeque, J. Z., Mienie, L. J., & Smuts, I. (2011) · Metabolomics · doi:10.1007/s11306-011-0309-0 · Cited by 78 · see citing works
Superoxide and derived reactive oxygen species in the regulation of hypoxia-inducible factors
Görlach, A., & Kietzmann, T. (2007) · Methods in Enzymology · doi:10.1016/s0076-6879(07)35022-2 · Cited by 73 · cited 2× · see citing works
“Superoxide through its metabolism to H2O2 is a known activator of HIF (Görlach and Kietzmann, 2007).”
The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase
Rzem, R., SCHAFTINGEN, E. V., & Veiga‐da‐Cunha, M. (2005) · Biochimie · doi:10.1016/j.biochi.2005.06.005 · Cited by 67 · cited 4× · see citing works
“L2HGDH is a mito- chondrial protein that catalyzes the oxidation of L2HG to 2OG coupled to the reduction of FAD (Rzem et al., 2004, 2006; Topçu et al., 2004) (Figure 3A).”
InfluentialFan, J., Kamphorst, J. J., Rabinowitz, J. D., & Shlomi, T. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.502740 · Cited by 67 · cited 1× · see citing works
“However, the overall contribution of reductive carboxylation to net reductive carbon flux has been questioned (Fan et al., 2013).”
An update on the role of mitochondrial α-ketoglutarate dehydrogenase in oxidative stress
Starkov, A. A. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.07.005 · Cited by 60 · cited 1× · see citing works
“OGDHC activity is decreased by chronic hypoxia or oxidative stress, suggesting a potential mechanism by which to account for the increases in 2OG and 2HG in hypoxia (Lai et al., 2003; Starkov, 2013; Tretter and Adam-Vizi, 1999).”
A Mouse Model of L-2-Hydroxyglutaric Aciduria, a Disorder of Metabolite Repair
Rim, R., Achouri, Y., Marbaix, É., Schakman, O., Wiame, E., Marie, S., Gailly, P. L., Vincent, M., Veiga‐da‐Cunha, M., & SCHAFTINGEN, E. V. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119540 · Cited by 58 · cited 2× · see citing works
“These findings were confirmed in HEK293 cells (Figure 3S) and were similar to results from mouse embryonic fibroblasts isolated from l2hgdh / mice (Rzem et al., 2015).”
Patel, M. S. (1974) · Biochemical Journal · doi:10.1042/bj1440091 · Cited by 54 · cited 4× · see citing works
“We, therefore, treated cells with an inhibitor of OGDHC, a-keto-b-methylvaleric acid (KMV) (Patel, 1974).”
InfluentialLai, J. C. K., White, B. K., Buerstatte, C. R., Haddad, G. G., Novotny, E. J., & Behar, K. L. (2003) · Neurochemical Research · doi:10.1023/a:1023235712524 · Cited by 45 · cited 1× · see citing works
“OGDHC activity is decreased by chronic hypoxia or oxidative stress, suggesting a potential mechanism by which to account for the increases in 2OG and 2HG in hypoxia (Lai et al., 2003; Starkov, 2013; Tretter and Adam-Vizi, 1999).”
2-Hydroxyglutarate is not a metabolite; d -2-hydroxyglutarate and l -2-hydroxyglutarate are!
Struys, E. A. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1318777110 · Cited by 41 · cited 2× · see citing works
“While the roles of L2HG and D2HG in normal human metabolism are unknown, L2HG has recently been shown to accumulate in renal cell carcinoma (Struys, 2013) and in children and cell lines with electron transport chain defects (Mullen et al., 2014; Reinecke et al., 2012; Worth et al., l Metabolism 22,…”
Mitochondrial 2-hydroxyglutarate metabolism
Engqvist, M. K. M., Eßer, C., Maier, A., Lercher, M. J., & Maurino, V. G. (2014) · Mitochondrion · doi:10.1016/j.mito.2014.02.009 · Cited by 41 · cited 1× · see citing works
“L2HGDH is found in bacteria, plants, and animals (Engqvist et al., 2014).”
Struys, E. A., Verhoeven‐Duif, N. M., Brunengraber, H., & Jakobs, C. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)01459-5 · Cited by 40 · cited 8× · see citing works
“Quantification of 2HG Enantiomers Metabolite extracts were derivatized with diacetyl-L-tartaric anhydride (DATAN) using an adaptation of a previously described method (Struys et al., 2004a).”
InfluentialUmemura, K., & Kimura, H. (2005) · Analytical Biochemistry · doi:10.1016/j.ab.2004.10.020 · Cited by 35 · cited 2× · see citing works
“published enzymatic fluorimetric cycling assay (Umemura and Kimura, 2005; Zhu and Rand, 2012).”
Identification ofEscherichia coliYgaF as an l -2-Hydroxyglutarate Oxidase
Kalliri, E., Mulrooney, S. B., & Hausinger, R. P. (2008) · Journal of Bacteriology · doi:10.1128/jb.01977-07 · Cited by 34 · cited 1× · see citing works
“Despite its evolutionary conservation, the only ascribed role for this enzyme is the recovery of 2OG mistakenly reduced by non-specific enzymatic activity (Kalliri et al., 2008; Rzem et al., 2007).”
Zhu, C.-T., & Rand, D. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0047584 · Cited by 34 · cited 2× · see citing works
“published enzymatic fluorimetric cycling assay (Umemura and Kimura, 2005; Zhu and Rand, 2012).”
Struys, E. A., Gibson, K. M., & Jakobs, C. (2007) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-007-0697-5 · Cited by 30 · cited 1× · see citing works
“Mass isotopomer studies of lymphoblasts derived from patients with D2HG or L2HG aciduria suggest that the mitochondrial pool of 2OG is reduced in 2HG synthesis (Struys et al., 2004b, 2007).”
Matsunaga, H., Futakuchi-Tsuchida, A., Takahashi, M., ISHIKAWA, T., Tsuji, M., & Ando, O. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.06.002 · Cited by 28 · cited 3× · see citing works
“Notably, siD2HGDH treatment did not result in significant changes in D2HG, contrary to a previous study of MCF7 breast cancer cells where siD2HGDH treatment induced a 4-fold increase in total 2HG (enantiomeric quantification was not performed) (Matsunaga et al., 2012).”
InfluentialInhibition of α‐Ketoglutarate Dehydrogenase due to H2O2‐Induced Oxidative Stress in Nerve Terminals
Tretter, L., & Ádám‐Vizi, V. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07867.x · Cited by 21 · cited 1× · see citing works
“OGDHC activity is decreased by chronic hypoxia or oxidative stress, suggesting a potential mechanism by which to account for the increases in 2OG and 2HG in hypoxia (Lai et al., 2003; Starkov, 2013; Tretter and Adam-Vizi, 1999).”
Rotenone Stereospecifically Increases (S)-2-Hydroxyglutarate in SH-SY5Y Neuronal Cells
Worth, A. J., Gillespie, K. P., Mesaros, C., Guo, L., Basu, S. S., Snyder, N. W., & Blair, I. A. (2015) · Chemical Research in Toxicology · doi:10.1021/tx500535c · Cited by 12 · cited 1× · see citing works
“In addition to hypoxia, mutations in CYTB in osteosarcoma cells (Complex III deficiency), and fumarate hydratase deficiency in renal carcinoma cells, and Complex I inhibition with rotenone increase L2HG (Mullen et al., 2014; Worth et al., 2015).”
Flagged first, then by citations
Cited by
Sorted by citations
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · see citing works
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013 · see citing works
Mitochondrial TCA cycle metabolites control physiology and disease
Martínez-Reyes, I., & Chandel, N. S. (2020) · Nature Communications · doi:10.1038/s41467-019-13668-3 · Cited by 2,813 · see citing works
NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism
Xiao, W., Wang, R., Handy, D. E., & Loscalzo, J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7216 · Cited by 1,074 · see citing works
“This paradoxical phenomenon could be explained by the findings that IDO can utilize superoxide anion (O2 ) as its substrate (88), and O2 - production is increased under hypoxia (98).”
BackgroundInfluentialSelf-citationGlutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
Glutaminolysis: A Hallmark of Cancer Metabolism
Yang, L., Venneti, S., & Nagrath, D. (2017) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071516-044546 · Cited by 859 · see citing works
“L-2HG is also a potent inhibitor of α-ketoglutarate-dependent dioxygenases, resulting in increased histone H3K9 trimethylation (122, 123).”
BackgroundMetabolic reprogramming and epigenetic modifications on the path to cancer
Sun, L., Zhang, H., & Gao, P. (2021) · Protein & Cell · doi:10.1007/s13238-021-00846-7 · Cited by 796 · see citing works
“L2HG accumulation is necessary and sufficient for the activation of H3K9me3 and repressive histone methylation (Intlekofer et al., 2015) and inhibits electron transport and glycolysis to alleviate reductive stress (Oldham et al., 2015).”
BackgroundSulkowski, P. L., Corso, C. D., Robinson, N. D., Scanlon, S. E., Purshouse, K. R., Bai, H., Liu, Y., Sundaram, R. K., Hegan, D. C., Fons, N. R., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal2463 · Cited by 556 · see citing works
“Knockdown of L2HGDH, which metabolizes (S)-2HG, was recently shown to increase (S)-2HG in log-phase, normoxic cells (12).”
BackgroundRegulation and function of the mammalian tricarboxylic acid cycle
Arnold, P. K., & Finley, L. W. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102838 · Cited by 535 · see citing works
“This promiscuous enzymatic activity is amplified during hypoxia (175, 176) and under acidic pH (177, 178), raising the possibility that 2HG accumulation may play a regulatory role under normal physiological conditions.”
BackgroundMitochondrial complex III is essential for suppressive function of regulatory T cells
Weinberg, S. E., Singer, B. D., Steinert, E. M., Martinez, C. A., Mehta, M., Martínez‐Reyes, I., Gao, P., Helmin, K. A., Abdala‐Valencia, H., Sena, L. A., et al. (2019) · Nature · doi:10.1038/s41586-018-0846-z · Cited by 496 · see citing works
Therapeutic targeting of the hypoxic tumour microenvironment
Singleton, D. C., Macann, A., & Wilson, W. R. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00539-4 · Cited by 493 · see citing works
Mitochondria as Signaling Organelles Control Mammalian Stem Cell Fate
Chakrabarty, R. P., & Chandel, N. S. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.02.011 · Cited by 490 · see citing works
Metabolic Responses to Reductive Stress
Xiao, W., & Loscalzo, J. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7803 · Cited by 467 · see citing works
“We and others showed that l-2-hydroxyglutarate (L2HG), a reduced metabolite of a-KG by MDH1/2 or LDHA, selectively accumulated as a fundamental response to hypoxia in various primary and cancer cells (39, 72).”
BackgroundInfluentialSelf-citationHistone demethylase KDM6A directly senses oxygen to control chromatin and cell fate
Chakraborty, A. A., Laukka, T., Myllykoski, M., Ringel, A. E., Booker, M. A., Tolstorukov, M. Y., Meng, Y. J., Meier, S. R., Jennings, R. B., Creech, A. L., et al. (2019) · Science · doi:10.1126/science.aaw1026 · Cited by 432 · see citing works
Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension
Bertero, T., Oldham, W. M., Cottrill, K. A., Pisano, S., Vanderpool, R. R., Yu, Q., Zhao, J., Tai, Y., Tang, Y., Zhang, Y.-Y., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86387 · Cited by 438 · see citing works
“analyzed by targeted LC-MS/MS as previously described (52).”
MethodSelf-citationOxygen availability and metabolic adaptations
Nakazawa, M. S., Keith, B., & Simon, M. C. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.84 · Cited by 431 · see citing works
S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate
Tyrakis, P. A., Palazon, A., Macias, D., Lee, K. L., Phan, A. T., Veliça, P., You, J., Chia, G. S., Sim, J., Doedens, A., et al. (2016) · Nature · doi:10.1038/nature20165 · Cited by 433 · see citing works
Altered metabolite levels in cancer: implications for tumour biology and cancer therapy
Sullivan, L. B., Gui, D. Y., & Heiden, M. G. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.85 · Cited by 406 · see citing works
Metabolic control of epigenetics in cancer
Kinnaird, A. S., Zhao, S., Wellen, K. E., & Michelakis, E. D. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.82 · Cited by 419 · see citing works
The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8
Zhang, J.-Y., Zhou, B., Sun, R.-Y., Ai, Y.-L., Cheng, K., Li, F.-N., Wang, B.-R., Liu, F.-J., Jiang, Z., Wang, W., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00506-9 · Cited by 392 · see citing works
Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy
Bertero, T., Oldham, W. M., Grasset, E. M., Bourget, I., Boulter, E., Pisano, S., Hofman, P., Bellvert, F., Meneguzzi, G., Bulavin, D. V., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.012 · Cited by 393 · see citing works
Self-citationThe Significance of Mitochondrial Dysfunction in Cancer
Luo, Y., Ma, J., & Lu, W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165598 · Cited by 367 · see citing works
“The accumulated L-2HG was found to regulate repressive histone methylation levels, such as H3K9me3, in response to hypoxia, which helps to mitigate reductive stress through inhibition of electron transport and glycolysis [49,50].”
BackgroundThe Link Between Angiogenesis and Endothelial Metabolism
Potente, M., & Carmeliet, P. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105134 · Cited by 353 · see citing works
Finley, L. W. S. (2023) · Cell · doi:10.1016/j.cell.2023.01.038 · Cited by 331 · see citing works
The mitochondrial respiratory chain is essential for haematopoietic stem cell function
Ansó, E., Weinberg, S. E., Diebold, L. P., Thompson, B. J., Malinge, S., Schumacker, P. T., Liu, X., Zhang, Y., Shao, Z., Steadman, M., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3529 · Cited by 310 · see citing works
“Normal cells produce L(S)-2-HG from promiscuous substrate usage of α - KG by lactate dehydrogenase or malate dehydrogenase under conditions with a decreased NAD+/NADH ratio (e.g. oxygen limitation 32, 33 ).”
Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism
Walsh, C. T., Tu, B. P., & Tang, Y. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00510 · Cited by 302 · see citing works
Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells
Colwell, N. A., Larion, M., Giles, A. J., Seldomridge, A. N., Sizdahkhani, S., Gilbert, M. R., & Park, D. M. (2016) · Neuro-Oncology · doi:10.1093/neuonc/now258 · Cited by 287 · see citing works
L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH
Intlekofer, A. M., Wang, B., Liu, H., Shah, H., Carmona-Fontaine, C., Rustenburg, A. S., Salah, S., Gunner, M. R., Chodera, J. D., Cross, J. R., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2307 · Cited by 268 · see citing works
“In order to separate alpha-hydroxyacid enantiomers, we adapted a liquid chromatography-mass spectrometry (LC-MS) protocol involving derivatization of metabolites with the chiral compound diacetyl-L-tartaric anhydride (Supplementary Results, Supplementary Fig.”
InfluentialMetabolic adaptation in hypoxia and cancer
Paredes, F., Williams, H. C., & Martín, A. S. (2021) · Cancer Letters · doi:10.1016/j.canlet.2020.12.020 · Cited by 269 · see citing works
“The D-2-HG enantiomer, L-2-HG, was recently identified as an abnormal α-KG metabolism product under hypoxia [63].”
BackgroundPérez-Torres, I., Guarner‐Lans, V., & Rubio-Ruiz, M. E. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102098 · Cited by 252 · see citing works
Metabolic Regulation of the Immune Humoral Response
Boothby, M. R., & Rickert, R. C. (2017) · Immunity · doi:10.1016/j.immuni.2017.04.009 · Cited by 245 · see citing works
“The actual (not just relative) concentrations of αKG - a cofactor enhancing activity of histone lysine demethylases and TET enzymes that can drive loss of CpG methylation – and the inhibitors succinate and stereo-isomers of 2-hydroxyglutarate (Oldham et al., 2015; Tannahill et al., 2013; Tyrakis et al., 2016) need to…”
BackgroundInfluentialMetabolism, 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 · see citing works
“Subsequent metabolomics studies discovered that hypoxia increased α-KG and L-2-HG in a broad range of transformed human cell lines [55,56].”
BackgroundChang, S., Yim, S., & Park, H. (2019) · Experimental & Molecular Medicine · doi:10.1038/s12276-019-0230-6 · Cited by 228 · see citing works
Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs
Phillips, R. M. (2016) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2920-7 · Cited by 240 · see citing works
“Biologically, hypoxia is implicated in promoting resistance to apoptosis [4], suppression of DNA repair pathways and promotion of genomic instability [5] increased invasion and metastasis [6], promotion of angiogenesis [7], modulation of tyrosine kinase mediated cell signalling pathways [8], evasion from immune survei…”
BackgroundMetabolic regulation of chromatin modifications and gene expression
Schvartzman, J. M., Thompson, C. B., & Finley, L. W. S. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201803061 · Cited by 233 · see citing works
“201803061 7 Low oxygen or acidic pH induce chromatin hypermethylation in part by stimulating the production of L-2HG (the enantiomer of D-2HG) by wild-type forms of malate dehydrogenase or lactate dehydrogenase (Intlekofer et al., 2015, 2017; Oldham et al., 2015).”
MethodInfluentialMitocellular communication: Shaping health and disease
Mottis, A., Herzig, S., & Auwerx, J. H. (2019) · Science · doi:10.1126/science.aax3768 · Cited by 238 · see citing works
2-Oxoglutarate-dependent dioxygenases in cancer
Losman, J.-A., Koivunen, P., & Kaelin, W. G. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-00303-3 · Cited by 225 · see citing works
Oncometabolites in renal cancer
Yong, C., Stewart, G. D., & Frezza, C. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0210-z · Cited by 212 · see citing works
Oxygen availability and metabolic reprogramming in cancer
Xie, H. J., & Simon, M. C. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.799973 · Cited by 203 · see citing works
“However, in murine CD8 T lymphocytes, Hif1 / abolished 2HG accumulation under hypoxia, and L-2HG constitutes more than 90% of the 2HG pool, suggesting L-2HG production is dependent on HIF1 in this case (64).”
BackgroundInfluentialGe, T., Gu, X., Jia, R., Ge, S., Chai, P., Zhuang, A., & Fan, X. (2022) · 癌症：英文版 · doi:10.1002/cac2.12374 · Cited by 206 · see citing works
Revisiting the role of metabolism during development
Miyazawa, H., & Aulehla, A. (2018) · Development · doi:10.1242/dev.131110 · Cited by 188 · see citing works
“Production of 2-HG can occur in cells with wild-type IDH upon exposure to hypoxia via malate dehydrogenase or via the promiscuous catalytic activity of lactate dehydrogenase (LDH) (Intlekofer et al., 2015; Oldham et al., 2015), thus affecting histone methylation (Intlekofer et al., 2015).”
BackgroundRedox Imbalance in Inflammation: The Interplay of Oxidative and Reductive Stress
Bellanti, F., Coda, A. R. D., Trecca, M. I., Buglio, A. L., Serviddio, G., & Vendemiale, G. (2025) · Antioxidants · doi:10.3390/antiox14060656 · Cited by 212 · see citing works
de Boer, R. A., Hulot, J., Tocchetti, C. G., Aboumsallem, J. P., Ameri, P., Anker, S. D., Bauersachs, J. K., Bertero, E., Coats, A. J. S., Čelutkienė, J., et al. (2020) · European Journal of Heart Failure · doi:10.1002/ejhf.2029 · Cited by 186 · see citing works
Metabolic Signaling to the Nucleus in Cancer
Campbell, S. L., & Wellen, K. E. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.015 · Cited by 182 · see citing works
Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains
Culley, M. K., & Chan, S. Y. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120847 · Cited by 178 · see citing works
Zhao, Y., Wang, A., Zou, Y., Su, N., Loscalzo, J., & Yang, Y. A. (2016) · Nature Protocols · doi:10.1038/nprot.2016.074 · Cited by 179 · see citing works
Self-citationGerminal center‐derived lymphomas: The darkest side of humoral immunity
Mlynarczyk, C., Fontán, L., & Melnick, A. (2019) · Immunological Reviews · doi:10.1111/imr.12755 · Cited by 179 · see citing works
Oncometabolites: Unconventional triggers of oncogenic signalling cascades
Sciacovelli, M., & Frezza, C. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.04.025 · Cited by 177 · see citing works
“2), either via reductive carboxylation [87] or via promiscuous substrate usage of LDHA [88] and Malic Dehydrogenase 1/2 [89].”
BackgroundAddiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells
Smith, B., Schafer, X., Ambeskovic, A., Spencer, C. M., Land, H., & Munger, J. C. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.045 · Cited by 168 · see citing works
“The coupling between glycolysis and TCA anaplerosis described here may shed further light on the unexpected finding that 2HG pools in cancer cells are increased during hypoxia and correlate with LDH activity (Intlekofer et al., 2015; Oldham et al., 2015).”
BackgroundHIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells
Lee, S.-H., Golinska, M., & Griffiths, J. R. (2021) · Cells · doi:10.3390/cells10092371 · Cited by 169 · see citing works
Burr, S. P., Costa, A. S. H., Grice, G. L., Timms, R. T., Lobb, I. T., Freisinger, P., Dodd, R. B., Dougan, G., Lehner, P. J., Frezza, C., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.015 · Cited by 155 · see citing works
“…Activity Is Impaired Because L-2-HG is formed from 2-OG by spurious activity of lactate dehydrogenase A (LDHA) and the malate dehyodrogenases (MDH1 and MDH2) (Intlekofer et al., 2015; Oldham et al., 2015), depletion of these enzymes should restore PHD function in the OGDH- or LIAS-deficient cells.”
BackgroundInfluentialMetabolic remodelling during early mouse embryo development
Zhao, J., Yao, K., Yu, H., Zhang, L., Xu, Y., Chen, L., Sun, Z., Zhu, Y., Zhang, C., Qian, Y., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00464-x · Cited by 164 · see citing works
Acidic pH Is a Metabolic Switch for 2-Hydroxyglutarate Generation and Signaling
Nadtochiy, S. M., Schafer, X., Fu, D., Nehrke, K., Munger, J., & Brookes, P. S. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.738799 · Cited by 143 · see citing works
The Roles of 2-Hydroxyglutarate
Du, X., & Hu, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.651317 · Cited by 152 · see citing works
Mitochondrial Metabolism Regulation of T Cell–Mediated Immunity
Steinert, E. M., Vasan, K., & Chandel, N. S. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101819-082015 · Cited by 153 · see citing works
Koenis, D. S., Medzikovic, L., van Loenen, P. B., van Weeghel, M., Huveneers, S., Vos, M., Gogh, I. J. E.-V., den Bossche, J. V., Speijer, D., Kim, Y., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.065 · Cited by 150 · see citing works
“Similar to succinate, it can stabilize the pro-inflammatory transcription factor HIF-1a (Oldham et al., 2015).”
BackgroundDysregulation of the TET family of epigenetic regulators in lymphoid and myeloid malignancies
Lio, C. J., Yuita, H., & Rao, A. (2019) · Blood · doi:10.1182/blood.2019791475 · Cited by 146 · see citing works
Responses to reductive stress in the cardiovascular system
Handy, D. E., & Loscalzo, J. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.006 · Cited by 147 · see citing works
“Additionally, accumulation of L2HG redirects cellular metabolism by inhibiting glycolysis and increasing the pentose phosphate pathway [79, 80].”
BackgroundSelf-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 141 · see citing works
Morandi, A., Taddei, M. L., Chiarugi, P., & Giannoni, E. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00040 · Cited by 139 · see citing works
“The enantiomer l-2HG (L2HG) can be generated by the non-canonical activity of malate dehydrogenase and LDH and not by the IDH1-/IDH2-mutated enzymes (198, 199).”
BackgroundAmelio, I., Mancini, M., Petrova, V., Cairns, R. A., Вихрева, П. Н., Nicolai, S., Marini, A., Antonov, A. A., Quesne, J. P. C. L., Acevedo, J. D. B., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1808314115 · Cited by 139 · see citing works
Control of endothelial quiescence by FOXO-regulated metabolites
Andrade, J., Shi, C., Costa, A. S. H., Choi, J., Kim, J., Doddaballapur, A., Sugino, T., Ong, Y. T., Castro, M., Zimmermann, B., et al. (2021) · Nature Cell Biology · doi:10.1038/s41556-021-00637-6 · Cited by 129 · see citing works
Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis
Torrino, S., Grasset, E. M., Audebert, S., Belhadj, I., Lacoux, C., Haynes, M., Pisano, S., Abélanet, S., Brau, F., Chan, S. Y., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.05.009 · Cited by 139 · see citing works
Self-citation2-Hydroxyglutarate in Cancer Cells
Ježek, P. (2020) · Antioxidants & Redox Signaling · doi:10.1089/ars.2019.7902 · Cited by 130 · see citing works
The α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity
Vatrinet, R., Leone, G., Luise, M. D., Girolimetti, G., Vidone, M., Gasparre, G., & Porcelli, A. M. (2017) · Cancer & Metabolism · doi:10.1186/s40170-017-0165-0 · Cited by 130 · see citing works
Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice
An, D., Zeng, Q., Zhang, P., Ma, Z., Zhang, H., Liu, Z., Li, J., Ren, H., & Xu, D. (2021) · Redox Biology · doi:10.1016/j.redox.2021.102088 · Cited by 126 · see citing works
Hallmarks of Pulmonary Hypertension: Mesenchymal and Inflammatory Cell Metabolic Reprogramming
D’Alessandro, A., Kasmi, K. C. E., Plecitá‐Hlavatá, L., Ježek, P., Li, M., Zhang, H., Gupte, S. A., & Stenmark, K. R. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7217 · Cited by 110 · see citing works
Immunometabolic Endothelial Phenotypes: Integrating Inflammation and Glucose Metabolism
Xiao, W., Oldham, W. M., Priolo, C., Pandey, A. K., & Loscalzo, J. (2021) · Circulation Research · doi:10.1161/circresaha.120.318805 · Cited by 106 · see citing works
Self-citationMetabolic recoding of epigenetics in cancer
Wang, Y., & Lei, Q. (2018) · 癌症：英文版 · doi:10.1186/s40880-018-0302-3 · Cited by 107 · see citing works
Yang, L., Lin, X., Tang, H., Fan, Y., Zeng, S., Jia, L., Li, Y., Shi, Y., He, S., Wang, H., et al. (2020) · Aging Cell · doi:10.1111/acel.13206 · Cited by 107 · see citing works
Self-citationHypoxia in Solid Tumors: How Low Oxygenation Impacts the “Six Rs” of Radiotherapy
Rakotomalala, A., Escande, A., Furlan, A., Meignan, S., & Lartigau, E. F. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.742215 · Cited by 108 · see citing works
“Nevertheless, these KDM enzymes are a-ketoglutarate-dependent enzymes and are inhibited by L-2-hydroxyglutarate (2HG), a metabolite notably produced under hypoxia by lactate dehydrogenase A (LDHA) (96, 97).”
BackgroundTCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma
Todisco, S., Convertini, P., Iacobazzi, V., & Infantino, V. (2019) · Cancers · doi:10.3390/cancers12010068 · Cited by 103 · see citing works
“Thus, αKG-dependent PHDs would be regulated by L-2-HG/αKG ratio as αKG supplementation or KGDHC inhibition leads to a low increase of L-2-HG levels in normoxia condition, and high increase in hypoxia condition [91].”
BackgroundMetabolic dysfunction in pulmonary hypertension: from basic science to clinical practice
Chan, S. Y., & Rubin, L. J. (2017) · European Respiratory Review · doi:10.1183/16000617.0094-2017 · Cited by 97 · see citing works
“In human pulmonary vascular cell types, hypoxia increases L2HG levels, thus controlling glycolysis and oxidative phosphorylation [29].”
BackgroundShenoy, N. K., Bhagat, T. D., Cheville, J. C., Lohse, C. M., Bhattacharyya, S., Tischer, A., Machha, V. R., Gordon-Mitchell, S., Choudhary, G. S., Wong, L.-F., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci98747 · Cited by 95 · see citing works
“Interestingly, von Hippel–Lindau (VHL) knockdown, HIF stabilization, and activation of a hypoxia gene-expression pattern (which is seen in a majority of ccRCC) has been shown to be associated with an increase in L2HG levels via enhanced reductive carboxylation and without a change in L2HGDH mRNA expression (20).”
BackgroundMetabolite Repair Enzymes Control Metabolic Damage in Glycolysis
Bommer, G. T., SCHAFTINGEN, E. V., & Veiga‐da‐Cunha, M. (2019) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2019.07.004 · Cited by 94 · see citing works
Granata, C., Caruana, N. J., Botella, J., Jamnick, N. A., Huynh, K., Kuang, J., Janssen, H. A., Reljic, B., Mellett, N. A., Laskowski, A., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27153-3 · Cited by 93 · see citing works
Gupta, V. K., Sharma, N., Durden, B. C., Garrido, V. T., Kesh, K., Edwards, D., Wang, D., Myer, C., Mateo-Victoriano, B., Kollala, S. S., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2562 · Cited by 94 · see citing works
“Accumulation of L-2HG inhibits regeneration of NADþ (19) and additionally promotes the chromatin condensation as observedby theD-2HGproducedby the IDH1/mutant cancers (17, 20) consistent with the well-established association between hypoxic niches and stem cell populations (21).”
BackgroundTET2 in Normal and Malignant HematopoiesisPreprint
Bowman, R. L., & Levine, R. L. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026518 · Cited by 92 · see citing works
“Recent work has identified that under hypoxic conditions the L enantiomer of 2-HG is produced as a promiscuous bioproduct of lactate dehydrogenase A (LDHA)-mediated and malate dehydrogenase 1 (MDH1)-mediated reduction ofa-KG (Intlekofer et al. 2015; Oldham et al. 2015).”
Shelar, S. B., Shim, E., Brinkley, G. J., Kundu, A., Carobbio, F., Poston, T. L., Tan, J. C., Parekh, V., Benson, D. G., Crossman, D. K., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1727 · Cited by 89 · see citing works
“Recent studies have also demonstrated increases of L-2-HG in the setting of hypoxia, mitochondrial dysfunction, and acidic conditions(23-29).”
BackgroundADHFE1 is a breast cancer oncogene and induces metabolic reprogramming
Mishra, P., Tang, W., Putluri, V., Dorsey, T. H., Jin, F., Wang, F., Zhu, D., Amable, L., Deng, T., Zhang, S., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci93815 · Cited by 89 · see citing works
“Other studies showed that L-2HG accumulates under hypoxia by different mechanisms (41, 42).”
BackgroundRecurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas
Remacha, L., Pirman, D. A., Mahoney, C. E., Coloma, J., Calsina, B., Currás-Freixes, M., Letón, R., Torres‐Pérez, R., Richter, S., Pita, G., et al. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.02.017 · Cited by 88 · see citing works
Molecular Pathways: Metabolic Control of Histone Methylation and Gene Expression in Cancer
Tran, T. Q., Lowman, X. H., & Kong, M. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2506 · Cited by 89 · see citing works
“Finally, lactate dehydrogenase A enzyme, under hypoxic conditions, can produce oncometabolite 2HG, independentof IDHenzymes (53, 54).”
BackgroundComparative transcriptomics of 3 high-altitude passerine birds and their low-altitude relatives
Hao, Y., Xiong, Y., Cheng, Y., Song, G., Jia, C., Qu, Y., & Lei, F. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819657116 · Cited by 85 · see citing works
“CYP2R1 is involved in cardiomyocyte proliferation and hypertrophy (41), L2HGDH contributes to electron transport and glycolysis (42), HN1L affects the systolic function of the left ventricle (43), and IFNAR2 is related to angiogenesis (44).”
BackgroundFriend or foe—IDH1 mutations in glioma 10 years on
Huang, L. E. (2019) · Carcinogenesis · doi:10.1093/carcin/bgz134 · Cited by 82 · see citing works
“Furthermore, IDH1R132H-induced hydrocephalic neuropathy (26,61,62,66), hypoxic induction of oncogenic L-2HG (107,108) and IDH1R132Hassociated genetic instability (99–101) might have complicated the interpretations of the studies.”
BackgroundChen, F., Bian, K., Tang, Q., Fedeles, B. I., Singh, V., Humulock, Z. T., Essigmann, J. M., & Li, D. (2017) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.7b00009 · Cited by 87 · see citing works
Molenaar, R. J., Coelen, R. J. S., Khurshed, M., Roos, E., Caan, M. W. A., Linde, M. E. V., Kouwenhoven, M. C. M., Bramer, J. A. M., Bovée, J. V. M. G., Mathôt, R. A. A., et al. (2017) · BMJ Open · doi:10.1136/bmjopen-2016-014961 · Cited by 82 · see citing works
“Most aforementioned measurements determined total 2HG levels and thus did not discriminate between the D-enantiomer of 2HG (which is specific for IDH1/2 mutations) and the L-enantiomer of 2HG (which is unspecific and is generated during hypoxia).(59) 60 Better separation of D-2HG and L-2HG may allow for IDH1/2 mutatio…”
BackgroundLi, H., Chawla, G., Hurlburt, A. J., Sterrett, M. C., Zaslaver, O., Cox, J. E., Karty, J. A., Rosebrock, A. P., Caudy, A. A., & Tennessen, J. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614102114 · Cited by 76 · see citing works
“There is a clear link, however, between disruption of mitochondrial metabolism and L-2HG production, as hypoxia, activation of HIFα signaling (21), disruption of the electron transport chain, and defects in citrate transport result in elevated L-2HG synthesis (17, 20–23).”
InfluentialHlouschek, J., Hansel, C., Jendrossek, V., & Matschke, J. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00170 · Cited by 78 · see citing works
“Both enantiomers of 2-HG have been shown to promote malignant progression by their inhibitory action on α-ketoglutarate (αKG)-dependent dioxygenases; they are either synthesized as so-called “oncometabolite” as a result of gain-of-function mutations in IDH1/IDH2 (62, 63) or as pathologic metabolites in Hx cancer cells…”
BackgroundYu, Q., Tai, Y., Tang, Y. M., Zhao, J., Negi, V., Culley, M. K., Pilli, J., Sun, W., Brugger, K., Mayr, J. A., et al. (2019) · Circulation · doi:10.1161/circulationaha.118.035889 · Cited by 78 · see citing works
Zhang, Z., Cheng, X., Zhao, Y., & Yang, Y. (2020) · Annual Review of Analytical Chemistry · doi:10.1146/annurev-anchem-091619-091306 · Cited by 81 · see citing works
Self-citationMetabolic determinants of tumour initiation
Brunner, J. S., & Finley, L. W. S. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00773-5 · Cited by 76 · see citing works
“Hypoxia also induces a metabolic state that favours the reduction of α-ketoglutarate to l-2-hydroxyglutarate by lactate dehydrogenase and malate dehydrogenases 1/2 (refs.(143,144)).”
BackgroundSexual dimorphism in glioma glycolysis underlies sex differences in survival
Ippolito, J. E., Yim, A. K., Luo, J. R., Chinnaiyan, P., & Rubin, J. B. (2017) · JCI Insight · doi:10.1172/jci.insight.92142 · Cited by 73 · see citing works
“The mechanism by which IDH mutations lead to improved prognoses is unclear but involvement of the metabolite 2-HG and its potential inhibition of glucose metabolism has been proposed (29, 30).”
BackgroundRole of tyrosine phosphorylation in modulating cancer cell metabolism
Taddei, M. L., Pardella, E., Pranzini, E., Raugei, G., & Paoli, P. D. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188442 · Cited by 70 · see citing works
“PDH, resulting in HIF-1α stabilization and in the promotion of Warburg metabolism [99].”
BackgroundHu, Q., Wu, D., Walker, M. A., Wang, P., Tian, R., & Wang, W. (2021) · Cell Reports Methods · doi:10.1016/j.crmeth.2021.100116 · Cited by 69 · see citing works
“Non-targeted SoNar has been characterized and used to monitor the cytosolic NAD + /NADH ratio in live cells and in a real-time manner (Chen et al., 2021; Gu et al., 2020; Hao et al., 2019; Oldham et al., 2015; Titov et al., 2016; Zhao et al., 2016).”
Jiang, H., Li, A. M., & Ye, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1004978 · Cited by 66 · see citing works
“HIF Hypoxia is a common tumor microenvironment stress that induces DNA methylation (105) and generation of the oncometabolite 2-hydroxyglutarate (2-HG) (27, 29) and is associated with poor prognosis and therapeutic resistance (106).”
BackgroundInfluentialZhang, M., Gao, C., Guo, X., Guo, S., Kang, Z., Xiao, D., Yan, J., Tao, F., Zhang, W., Dong, W., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04513-0 · Cited by 66 · see citing works
Pheochromocytoma: The First Metabolic Endocrine Cancer
Jochmanová, I., & Pacák, K. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-0606 · Cited by 65 · see citing works
Li, Y., Gruber, J. J., Litzenburger, U. M., Zhou, Y., Miao, Y. R., LaGory, E. L., Li, A. M., Hu, Z., Yip, M., Hart, L. S., et al. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2303-9 · Cited by 65 · see citing works
The PHGDH enigma: Do cancer cells only need serine or also a redox modulator?
Li, A. M., & Ye, J. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.01.036 · Cited by 65 · see citing works
Cellular Compartmentation and the Redox/Nonredox Functions of NAD +
Kulkarni, C. A., & Brookes, P. S. (2019) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7722 · Cited by 64 · see citing works
“In addition, under acidic or hypoxic conditions, either MDH or LDH can adopt a similar neomorphic activity to use NADH to reduce a-KG to the l-enantiomer of 2-HG (72, 108, 113).”
Background
- Authors
- Oldham, W. M., Clish, C. B., Yang, Y., & Loscalzo, J.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- East China University of Science and Technology (CN)
- Corresponding author
- Loscalzo, Joseph
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 22
- Issue
- 2
- Pages
- 291-303
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4526408
- OpenAlex
- W1900467627
- Cited by
- 364
- References
- 58
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 33 · 2023: 27 · 2022: 40 · 2021: 46 · 2020: 29 · 2019: 45 · 2018: 29 · 2017: 33 · 2016: 27 · 2015: 6
- FWCI
- 10.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL007633, HL048743, HL 108630, R01HL061795, U01HL108630, P01HL048743, HL-061795, R37HL061795, T32HL007633)
- National Institute of General Medical Sciences (P50GM107618, GM107618)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- L-2-hydroxyglutarate, hypoxia, reductive stress, alpha-ketoglutarate, malate dehydrogenase, TCA cycle, redox homeostasis, electron transport inhibition, glycolysis, energy metabolism, hypoxia adaptation
- MeSH terms
- Adaptation, Physiological, Citric Acid Cycle, Glutarates, Glycolysis, Humans, Malate Dehydrogenase, Oxidation-Reduction, Stress, Physiological, Cell Hypoxia, Hep G2 Cells, HEK293 Cells
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
