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.
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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
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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
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