Key Points
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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.
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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.
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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.
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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.
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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.
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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.
Abstract
Mitochondrial defects have been associated with neurological disorders, as well as cancers. Two ubiquitously expressed mitochondrial enzymes ? succinate dehydrogenase (SDH) and fumarate hydratase (FH, fumarase) ? catalyse sequential steps in the Krebs tricarboxylic-acid cycle. Inherited heterozygous mutations in the genes encoding these enzymes cause predispositions to two types of inherited neoplasia syndromes that do not share any component tumours. Homozygous mutations in the same genes result in severe neurological impairment. Understanding this link between inherited cancer syndromes and neurological disease could provide further insights into the mechanisms by which mitochondrial deficiencies lead to tumour development.
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Acknowledgements
C. E. is a recipient of the Doris Duke Distinguished Clinical Scientist Award and is supported by grants from the National Institutes of Health, National Cancer Institute, American Cancer Society, US Department of Defense Breast and Prostate Cancer Research Programs, Susan G. Komen Breast Cancer Research Foundation and Jimmy V Golf Classic Translational Cancer Research Award from the V Foundation. M. K. is supported by the Finnish Cancer Society, Duodecim, Kidney Foundation, Paulo Foundation, Maud Kuistila Foundation, Ida Montin Foundation, Finnish Oncology Foundation, Research and Science Foundation of Pharmos, and AstraZeneca. L. A. A. is supported by the Finnish Cancer Society, Sigrid Juselius Foundation, Helsinki Central Hospital and the Academy of Finland's Center of Excellence Award.
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Glossary
- MATERNALLY IMPRINTED
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Genes come in pairs (alleles) ? one inherited from the father and one from the mother. Maternal imprinting occurs when the maternal allele is transcriptionally silenced, usually because of promoter hypermethylation. In this situation, only the paternal allele is expressed.
- FOUNDER EFFECT
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When a germline mutation occurs in a community that has been isolated from the outside, or where little emigration or immigration has occurred for many decades or centuries, this 'founding' germline mutation is established and perpetrated for generations.
- HYPERBARIC OXYGEN
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Oxygen that is delivered at high tension/pressure, which is well above atmospheric oxygen tension at sea level (defined as 1 atm).
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Eng, C., Kiuru, M., Fernandez, M. et al. A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 3, 193–202 (2003). https://doi.org/10.1038/nrc1013
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DOI: https://doi.org/10.1038/nrc1013
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