Author: Eng, Charis; Kiuru, Maija; Fernandez, Magali J.; Aaltonen, Lauri A.
Description: Germline heterozygous mutations in the autosomally encoded mitochondrial enzyme subunits of succinate dehydrogenase (SDH), SDHB, SDHC and SDHD, are associated with hereditary predisposition to phaeochromocytoma and paraganglioma. By contrast, homozygous germline mutations in the catalytic active-site-bearing subunit SDHA causes Leigh syndrome, which is characterized by severe neurological dysfunction and seizures. Germline heterozygous mutations in another autosomally encoded mitochondrial enzyme ? fumarate hydratase (fumarase, FH) ? are associated with hereditary predisposition to papillary renal-cell carcinoma and leiomyomatosis, whereas homozygous FH mutations cause neurodegeneration. SDH and FH catalyse sequential steps in the Krebs tricarboxylic-acid cycle, which generates ATP ? the cell’s currency of energy. SDH is a component of complex II of the respiratory electron-transport chain. The hereditary neurological diseases might be explained by complete or near-complete lack of energy generation during development, leading to free-radical formation and mitochondrial-mediated apoptotic cell death. Little data exist to explain the mechanism of predisposition to cancer. Hypotheses invoke free-radical formation, leading to activation of the HIF/angiogenesis pathway and mitochondrial-mediated anti-apoptotic activity. The link between mitochondrial-associated inherited neurological disease and inherited cancer might be exploited for uncovering novel functions and mechanisms for mitochondrial enzymes beyond energy production, for novel gene discovery and for clinical utility.
Subject headings: Mitochondrial enzymes; Cancer; Neurological disease
Publication year: 2003
Journal or book title: Nature Reviews Cancer
Volume: 3
Issue: 3
Pages: 193-202
Find the full text: https://www.nature.com/articles/nrc1013
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Serial number: 3496