The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.
Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer
Abstract
The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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
“In animal models, fumarate hydratase inactivation induces a precancerous phenotype associated with chronic HIF pathway activation, highlighting the intersection of mitochondrial metabolism, redox homeostasis, and HIF regulation [229,230].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [230]
In the citing paper
“These metabolic perturbations, which are tightly linked to altered cellular redox balance, result in pseudohypoxic signaling and increased cancer susceptibility [229,230].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [230]
In the citing paper
“Mitochondrial dysfunction could impair oxidative phosphorylation, the TCA cycle, fatty acid oxidation, the urea cycle, gluconeogenesis, and apoptotic pathways (King et al., 2006; Modica-Napolitano and Singh, 2004).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as King et al., 2006
In the citing paper
“Loss-of-function mutations in SDH and FH cause a build-up of succinate and fumarate, respectively87. Accordingly, increased levels of succinate and fumarate caused by mutations in these genes can compete with αKG and inhibit activity of HIF hydroxylases and thus induce normoxic HIF1α activity in vitro88,89.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [87]
In the citing paper
“Interestingly, inherited mutations in fumarate hydratase, another Krebs cycle enzyme, have also been linked to a separate and equally rare inherited cancer syndrome 96 .”
From The common biology of cancer and ageing (2007) · cites this paper as [96]
Citations
Cites
Why Do Cancers Have High Aerobic Glycolysis?
Gatenby, R. A., & Gillies, R. J. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1478 · Cited by 4,784
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108 · cited 4×
“Although both molecules were shown to mediate HIF induction (Isaacs et al., 2005; Selak et al., 2005), it is possible that they inhibit different PHDs with different efficiency.”
BackgroundInfluentialSelf-citationOxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
Mutations in SDHD , a Mitochondrial Complex II Gene, in Hereditary Paraganglioma
Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., Mey, A. V. D., Taschner, P. E. M., Rubinstein, W. S., Myers, E. N., et al. (2000) · Science · doi:10.1126/science.287.5454.848 · Cited by 1,638
The Multiple Leiomyoma Consortium (2002) · Nature Genetics · doi:10.1038/ng849 · Cited by 1,635
The key role of anaplerosis and cataplerosis for citric acid cycle function
Owen, O. E., Kalhan, S. C., & Hanson, R. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.r200006200 · Cited by 1,172 · cited 1×
“Moreover, enhanced glucose breakdown provides building blocks for the synthesis of nucleotides (via the pentose phosphate pathway), and amino and fatty acids (from glycolytic and TCA cycle intermediates) (Figure 1) (Owen et al., 2002).”
BackgroundOncogenic alterations of metabolism
Dang, C. V., & Semenza, G. L. (1999) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(98)01344-9 · Cited by 1,106
Astuti, D., Latif, F., Dallol, A., Dahia, P. L. M., Douglas, F., George, E., Sköldberg, F., Husebye, E. S., Eng, C., & Maher, E. R. (2001) · The American Journal of Human Genetics · doi:10.1086/321282 · Cited by 1,087
Mitochondria, oxygen free radicals, disease and ageing
Raha, S., & Robinson, B. H. (2000) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)01674-1 · Cited by 1,066 · cited 1×
“These are reactive oxygen species (ROS), which can be generated by the ETC, especially in complex I and III (Raha and Robinson, 2000).”
BackgroundDysregulation of the TSC-mTOR pathway in human disease
Inoki, K., Corradetti, M. N., & Guan, K. (2004) · Nature Genetics · doi:10.1038/ng1494 · Cited by 980
Isaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.017 · Cited by 958
Role of VHL Gene Mutation in Human Cancer
Kim, W. Y., & Kaelin, W. G. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.05.061 · Cited by 953
Architecture of succinate dehydrogenase and reactive oxygen species generation
Yankovskaya, V., Horsefield, R., Törnroth, S., Luna-Chavez, C., Miyoshi, H., Léger, C., Byrne, B., Cecchini, G., & Iwata, S. (2003) · Science · doi:10.1126/science.1079605 · Cited by 927 · cited 1×
“Structural and functional analysis of SDH (complex II) from Escherichia coli did indicate the potential of ROS production on the SDHA site (Yankovskaya et al., 2003).”
BackgroundNeumann, H. P. H. (2004) · JAMA · doi:10.1001/jama.292.8.943 · Cited by 893
Mutations in SDHC cause autosomal dominant paraganglioma, type 3
Niemann, S., & Müller, U. (2000) · Nature Genetics · doi:10.1038/81551 · Cited by 875
Pollard, P. J., Brière, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi227 · Cited by 865
A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes.
Ishii, N., Fujii, M., Hartman, P. S., Tsuda, M., Yasuda, K., Senoo-Matsuda, N., Yanase, S., Ayusawa, D., & Suzuki, K. (1998) · Nature · doi:10.1038/29331 · Cited by 687 · cited 1×
“This was in fact shown to occur in a specific SDHC mutant (mev-1) of the Caenorhabditis elegans nematode (Ishii et al., 1998; Senoo-Matsuda et al., 2001).”
BackgroundMitochondrial tumour suppressors: a genetic and biochemical update
Gottlieb, E., & Tomlinson, I. P. M. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1737 · Cited by 626
Self-citationCancer metabolism: facts, fantasy, and fiction
Zu, X. L., & Guppy, M. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.11.136 · Cited by 618
JunD Reduces Tumor Angiogenesis by Protecting Cells from Oxidative Stress
Gerald, D., Berra, E., Frapart, Y. M., Chan, D. A., Giaccia, A. J., Mansuy, D., Pouysségur, J., Yaniv, M., & Mechta-Grigoriou, F. (2004) · Cell · doi:10.1016/j.cell.2004.08.025 · Cited by 588
Mitochondrial defects in cancer.
Carew, J. S., & Huang, P. (2002) · Molecular Cancer · doi:10.1186/1476-4598-1-9 · Cited by 586
Clinical Presentation and Penetrance of Pheochromocytoma/Paraganglioma Syndromes
Benn, D. E., Gimenez‐Roqueplo, A., Reilly, J. R., Bertherat, J. Y., Burgess, J. R., Byth, K., CROXSON, M. S., Dahia, P. L. M., Elston, M. S., Gimm, O., et al. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1862 · Cited by 565
Lee, S., Nakamura, E., Yang, H., Wei, W., Linggi, M. S., Sajan, M. P., Farese, R. V., Freeman, R. S., Carter, B. D., Kaelin, W. G., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.015 · Cited by 527
Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia
Ang, S. O., Chen, H., Hirota, K., Gordeuk, V. R., Jelinek, J., Guan, Y., Liu, E., Sergueeva, A. I., Miasnikova, G. Y., Mole, D., et al. (2002) · Nature Genetics · doi:10.1038/ng1019 · Cited by 510
Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway
Kung, A. L., Zabludoff, S. D., France, D. S., Freedman, S. J., Tanner, E. A., Vieira, A., Cornell-Kennon, S., Lee, J., Wang, B., Wang, J., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.009 · Cited by 480
A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas
Dahia, P. L. M., Ross, K. N., Wright, M. E., Hayashida, C. Y., Santagata, S., Barontini, M., Kung, A. L., Sanso, G., Powers, J. F., Tischler, A. S., et al. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010008 · Cited by 443
Akt-dependent transformation: there is more to growth than just surviving
Plas, D. R., & Thompson, C. B. (2005) · Oncogene · doi:10.1038/sj.onc.1209097 · Cited by 431
A role for mitochondrial enzymes in inherited neoplasia and beyond
Eng, C., Kiuru, M., Fernandez, M. J., & Aaltonen, L. A. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1013 · Cited by 392
Vanharanta, S., Buchta, M., McWhinney, S. R., Virta, S. K., Peçzkowska, M., Morrison, C. D., Lehtonen, R., Januszewicz, A., Järvinen, H., Juhola, M., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/381054 · Cited by 389
Hoffman, M. A. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.10.1019 · Cited by 382
Gimenez-Roqueplo, A.-P., Favier, J., Rustin, P., Mourad, J.-J., Plouin, P.-F., Corvol, P., Rötig, A., & Jeunemaitre, X. (2001) · The American Journal of Human Genetics · doi:10.1086/324413 · Cited by 364
Signalling hypoxia by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.08.111 · Cited by 343
Predictors and Prevalence of Paraganglioma Syndrome Associated With Mutations of the SDHC Gene
Schiavi, F. (2005) · JAMA · doi:10.1001/jama.294.16.2057 · Cited by 332
Percy, M. J., Zhao, Q., Flores, A., Harrison, C., Lappin, T. R. J., Maxwell, P. H., McMullin, M. F., & Lee, F. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508423103 · Cited by 330
Wei, M. H., Toure, O., Glenn, G. M., Pithukpakorn, M., Neckers, L., Stolle, C., Choyke, P., Grubb, R., Middelton, L., Turner, M. L., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2005.033506 · Cited by 315
Mitochondrial dysfunction in cancer
Modica-Napolitano, J. S., & Singh, K. K. (2004) · Mitochondrion · doi:10.1016/j.mito.2004.07.027 · Cited by 299
Elson, D. A., Thurston, G., Huang, E. L., Ginzinger, D. G., McDonald, D. M., Johnson, R. S., & Arbeit, J. M. (2001) · Genes & Development · doi:10.1101/gad.914801 · Cited by 297
Senoo-Matsuda, N., Yasuda, K., Tsuda, M., Ohkubo, T., Yoshimura, S., Nakazawa, H., Hartman, P. S., & Ishii, N. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104718200 · Cited by 271
Ishii, T., Yasuda, K., Akatsuka, A., Hino, O., Hartman, P. S., & Ishii, N. (2005) · Cancer Research · doi:10.1158/0008-5472.203.65.1 · Cited by 253
Pharmacological manipulation of cell death: clinical applications in sight?
Green, D. R. (2005) · Journal of Clinical Investigation · doi:10.1172/jci26321 · Cited by 243
Welsh, S., Williams, R., Kirkpatrick, L., Paine-Murrieta, G., & Powis, G. (2004) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.233.3.3 · Cited by 240
Functional Consequences of a SDHB Gene Mutation in an Apparently Sporadic Pheochromocytoma
Gimenez-Roqueplo, A.-P., Favier, J., Rustin, P., Rieubland, C., Kerlan, V., Plouin, P.-F., Rötig, A., & Jeunemaitre, X. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-020525 · Cited by 209
Lehtonen, R., Kiuru, M. H., Vanharanta, S., Sjöberg, J., Aaltonen, L., Aittomäki, K., Arola, J. T., Bützow, R. C., Eng, C., Husgafvel‐Pursiainen, K., et al. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63091-x · Cited by 184
Maxwell, P. H. (2005) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2005.03.001 · Cited by 171
Hypoxia‐inducible factor as a physiological regulator
Maxwell, P. H. (2005) · Experimental Physiology · doi:10.1113/expphysiol.2005.030924 · Cited by 170
Brière, J.-J., Favier, J., Bénit, P., Ghouzzi, V. E., Lorenzato, A., Rabier, D., Renzo, M. F. D., Gimenez‐Roqueplo, A., & Rustin, P. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi359 · Cited by 162
The HIF pathway as a therapeutic target
Hewitson, K. S., & Schofield, C. J. (2004) · Drug Discovery Today · doi:10.1016/s1359-6446(04)03202-7 · Cited by 148
Chau, N., Rogers, P., Aherne, W., Carroll, V. A., Collins, I., McDonald, E., Workman, P., & Ashcroft, M. A. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4453 · Cited by 148
Inborn errors of complex II – Unusual human mitochondrial diseases
Rustin, P., & Rötig, A. (2002) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(01)00228-6 · Cited by 135
Glycobiology and Cancer: Meeting Summary and Future Directions
Hart, G. W., Lowe, J. B., & Sathyamoorthy, N. (2004) · Cancer Biology & Therapy · doi:10.4161/cbt.3.2.775 · Cited by 122
Beginnings of a signal-transduction pathway for bioenergetic control of cell survival
Hammerman, P. S., Fox, C. J., & Thompson, C. B. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2004.09.008 · Cited by 117
Mitochondrial Hexokinases: Guardians of the Mitochondria
Robey, R. B., & Hay, N. (2005) · Cell Cycle · doi:10.4161/cc.4.5.1678 · Cited by 109
On the association of succinate dehydrogenase mutations with hereditary paraganglioma
Baysal, B. E. (2003) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2003.08.004 · Cited by 106
Pollard, P., Wortham, N., Barclay, E., Alam, A., Elia, G., Manek, S., Poulsom, R., & Tomlinson, I. (2005) · The Journal of Pathology · doi:10.1002/path.1686 · Cited by 100
Douwes Dekker, P., Hogendoorn, P., Kuipers‐Dijkshoorn, N., Prins, F., van Duinen, S., Taschner, P., van der Mey, A., & Cornelisse, C. (2003) · The Journal of Pathology · doi:10.1002/path.1461 · Cited by 94
Hereditary Paraganglioma/Pheochromocytoma and Inherited Succinate Dehydrogenase Deficiency
Favier, J., Brière, J.-J., Strompf, L., Amar, L., Filali, M., Jeunemaı̂tre, X., Rustin, P., & Gimenez‐Roqueplo, A. (2005) · Hormone Research in Paediatrics · doi:10.1159/000084685 · Cited by 92
An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma
Baysal, B. E., Willett-Brozick, J. E., Filho, P. A. A., Lawrence, E. C., Myers, E. N., & Ferrell, R. E. (2004) · Journal of Medical Genetics · doi:10.1136/jmg.2004.019224 · Cited by 78
Distinct expression profile in fumarate-hydratase-deficient uterine fibroids
Vanharanta, S., Pollard, P. J., Lehtonen, H. J., Laiho, P., Sjöberg, J., Leminen, A., Aittomäki, K., Arola, J. T., Kruhøffer, M., Orntoft, T. F., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi431 · Cited by 73
Evolving concepts in pheochromocytoma and paraganglioma
Dahia, P. L. M. (2005) · Current Opinion in Oncology · doi:10.1097/01.cco.0000198017.45982.06 · Cited by 69
Mutations of the SDHB and SDHD genes
Pawlu, C., Bausch, B., & Neumann, H. P. H. (2005) · Familial Cancer · doi:10.1007/s10689-004-4227-4 · Cited by 60
Dioxygenases as O2-dependent regulators of the hypoxic response pathway
Dann, C. E., & Bruick, R. K. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.08.140 · Cited by 56
Cited by
Sorted by citations
Regulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744
Otto Warburg's contributions to current concepts of cancer metabolism
Koppenol, W. H., Bounds, P. L., & Dang, C. V. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3038 · Cited by 3,427
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380
Role of Mitochondria in Ferroptosis
Gao, M., Yi, J., Zhu, J., Minikes, A. M., Monian, P., Thompson, C. B., & Jiang, X. (2019) · Molecular Cell · doi:10.1016/j.molcel.2018.10.042 · Cited by 2,120
Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond
Lee, P., Chandel, N. S., & Simon, M. C. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0227-y · Cited by 1,272
Metadata
- Authors
- King, A., Selak, M. A., & Gottlieb, E.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Corresponding author
- Gottlieb, E
- Venue
- Oncogene
- Published
- 2006-08-07
- Volume
- 25
- Issue
- 34
- Pages
- 4675-4682
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2005828644
- Semantic Scholar
- 960f2f114b8beb17db8bd6d91cd79f788b80738a
- Cited by
- 672
- References
- 61
- Citations by year
- 2026: 21 · 2025: 22 · 2024: 19 · 2023: 25 · 2022: 42 · 2021: 39 · 2020: 38 · 2019: 37 · 2018: 37 · 2017: 42 · 2016: 39 · 2015: 37 · 2014: 42 · 2013: 37 · 2012: 52
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Keywords
- succinate dehydrogenase, fumarate hydratase, mitochondrial dysfunction, tumour suppressor, succinic acid, fumarate, metabolic signalling, prolyl hydroxylase inhibition, pseudohypoxia, hypoxia-inducible factor, apoptosis resistance, carcinogenesis
- MeSH terms
- Fumarate Hydratase, Humans, Mitochondria, Neoplasms, Succinate Dehydrogenase, Genes, Tumor Suppressor
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
