Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

King, A; Selak, M A; Gottlieb, E

doi:10.1038/sj.onc.1209594

Cited by 674Cancer, Hypoxia, and MetabolismMitochondrial Function and PathologyFerroptosis and cancer prognosis

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

King, A, Selak, M A, Gottlieb, E·2006·Oncogene

DOI 10.1038/sj.onc.1209594

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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 animal models, fumarate hydratase inactivation induces a precancerous phenotype associated with chronic HIF pathway activation.
“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]
These metabolic perturbations result in pseudohypoxic signaling and increased cancer susceptibility.
“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]
Mitochondrial dysfunction can impair oxidative phosphorylation, the TCA cycle, fatty acid oxidation, the urea cycle, gluconeogenesis, and apoptotic pathways.
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From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as King et al., 2006
SDH and FH loss-of-function mutations accumulate succinate and fumarate, which compete with αKG, inhibit HIF hydroxylases, and produce normoxic HIF1α activity in vitro.
“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]
Inherited mutations in fumarate hydratase are linked to a separate rare inherited cancer syndrome.
“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]

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Self-citation
Fumarate hydratase in cancer: A multifaceted tumour suppressor
Schmidt, C., Sciacovelli, M., & Frezza, C. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.002 · Cited by 163 · see citing works

Authors: King, A., Selak, M. A., & Gottlieb, E.
Affiliations: Cancer Research UK Scotland Institute (GB)
Corresponding author: Gottlieb, E
ORCID: Selak, M A
Gottlieb, E
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2006-08-07
Volume: 25
Issue: 34
Pages: 4675-4682
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/sj.onc.1209594
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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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Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

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