Key Points
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Mitochondrial tumour-suppressors are nuclear-encoded mitochondrial proteins that show loss-of-function mutations in inherited or sporadic tumours. To date, four such genes are known, and they encode three of the four subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) and fumarate hydratase (FH).
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Mutations in the genes encoding SDH are predominantly linked to phaeochromocytoma or paraganglioma, whereas mutations in FH lead to leiomyoma, leiomyosarcoma and in some cases to renal cell carcinoma.
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Both FH and SDH are enzymes of the tricarboxylic acid (TCA) cycle, whereas SDH is also a functional member of the mitochondrial respiratory chain (complex II). They are crucial elements of cellular energy metabolism, and therefore it is important to understand their role in tumour suppression.
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The leading biological explanation for the link between loss-of-function of SDH or FH to tumorigenesis is the induction of a pseudo-hypoxic pathway. This is manifest by the induction of hypoxia-inducible factor (HIF) and its target genes under normoxic conditions.
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Two important biochemical mechanisms that explain how mutations in mitochondrial tumour suppressor genes (particularly SDHD) contribute to tumour formation have been suggested. These mechanisms are: redox stress, resulting from increased reactive oxygen species (ROS) production in mitochondria, or metabolic signalling, involving TCA cycle metabolites as intracellular messengers.
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Some types of mutant SDH proteins generate ROS, and these inhibit HIF prolyl hydroxylase (PHD), an enzyme that targets the α-subunit of HIF for degradation under normoxic conditions. Therefore, it was suggested that ROS can mediate pseudo-hypoxia in tumours with mutant SDH.
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Metabolic signalling was proposed recently as an alternative, but not mutually exclusive mechanism to ROS in inducing pseudo-hypoxia — succinate levels are increased in SDH-deficient tumours and succinate can inhibit PHD, leading to HIF induction.
Abstract
Since the discovery 5 years ago that the D-subunit of succinate dehydrogenase (SDHD) can behave as a classic tumour suppressor, other nuclear-encoded mitochondrial proteins (SDHB, SDHC and fumarate hydratase) have been implicated in tumour susceptibility. Mutations in these proteins are principally involved in familial predisposition to benign tumours, but the spectrum of inherited lesions is increasingly recognized to include malignant tumours, such as malignant phaeochromocytomas and renal cell carcinomas. Here we review recent advances in the field of mitochondrial tumour suppressors, the biochemical pathway that links mitochondrial dysfunction with tumorigenesis, and potential therapeutic approaches to these malignancies.
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We thank Ayala King, Mary Selak and Patricia Dahia for critical discussions and excellent editorial work.
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DATABASES
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FURTHER INFORMATION
Glossary
- PHAEOCHROMOCYTOMA
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The most frequent subtype of paraganglioma that usually arises in the adrenal medulla and consists of catecholamine-secreting chromaffin cells.
- PARAGANGLIOMA
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Typically benign tumours of chromaffin cells arising from the paraganglial system. These are neuronal ectoderm-derived cells found in the sympathetic or parasympathetic nervous systems that run from the head and neck to the pelvis.
- LEIOMYOMA
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A benign tumour of smooth muscle in which parallel arrays of smooth muscle cells form bundles that are arranged in a whorled pattern. Leiomyoma of the uterus (fibroid) is the most common form.
- MYOCLONUS EPILEPSY AND RAGGED-RED FIBRES SYNDROME
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Maternally-inherited disorder caused by mutations in mitochondrial DNA. Several mitochondrial genes are involved, and the severity of the disease is dependent on the ratio between wild-type and mutant mitochondrial DNA molecules (heteroplasmy).
- HEREDITARY PARAGANGLIOMA SYNDROME
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Disease resulting from pathogenic germline mutations in the SDHB, SDHC or SDHD genes, characterized by paragangliomas (usually arising from the carotid body) and phaeochromocytomas (usually arising from the adrenal medulla).
- LEIGH SYNDROME
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An early-onset, progressive, neurodegenerative disorder with a characteristic neuropathology. The most common underlying cause is a defect in oxidative phosphorylation as a result of mutations in nuclear or mitochondrial genes.
- CAROTID BODY
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A small (3–5 mm), capillary-rich organ, attached to the carotid artery branches in the neck. The organ contains cells that sense oxygen and carbon dioxide levels in blood and are involved in the autonomic control of the respiratory and cardiovascular systems.
- IMPRINTING
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Monoallelic gene expression or inactivation of either the maternal or paternal allele of a particular locus.
- NON-DISJUNCTION
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Lack of the physiological separation of the two copies of each chromosome during cell division.
- VON HIPPEL–LINDAU SYNDROME
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A dominantly inherited familial cancer syndrome predisposing to various malignant and benign neoplasms, most often retinal, cerebellar and spinal hemangioblastoma, renal-cell carcinoma, phaeochromocytoma and pancreatic tumours.
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Gottlieb, E., Tomlinson, I. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5, 857–866 (2005). https://doi.org/10.1038/nrc1737
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DOI: https://doi.org/10.1038/nrc1737
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