Phenotypic dichotomy in mitochondrial complex II genetic disorders

This review presents our current knowledge on the genetic and phenotypic as pects of mitochondrial complex II gene defects, The mutations of the comple x II subunits cause two strikingly different group of disorders, revealing a phenotypic dichotomy. Genetic disorders of the mitochondrial respiratory chain are often characterized by hypotonia, growth retardation, cardiomyopa thy, myopathy, neuropathy, organ failure, and metabolic derangement. These disorders are transmitted through maternal lineage if the defective gene is located in the mitochondrial genome or may follow a Mendelian pattern if i t is in the nucleus. Mitochondrial complex II (succinate:ubiquinone oxidore ductase) is the smallest complex in the respiratory chain and is composed o f four subunits encoded by nuclear genes SDHA, SDHB, SDHC, and SDHD. Comple x II oxidizes succinate to fumarate in the Krebs cycle and is involved in t he mitochondrial electron transport chain. SDHA and SDHB encode the flavopr otein and iron-sulfur proteins, respectively, and SDHC and SDHD encode the two hydrophobic membrane-spanning subunits. While mutations in SDHA display a phenotype resembling other mitochondrial and Krebs cycle gene defects, t hose in SDHB, SDHC and SDHD cause hereditary paraganglioma. Paraganlioma is characterized by slow-growing vascular tumors of the paraganglionic tissue (i.e., adrenal and extraadrenal paragangliomas, including those in the hea d and neck, mediastinum, abdomen, and pheochromocytomas). Paraganglioma cau sed by SDHD mutations occurs exclusively after paternal transmission, sugge sting that genomic imprinting influences gene expression. Association of a mitochondrial gene defect with tumorigenesis expands the phenotypic spectru m of mitochondrial diseases and adds genomic imprinting as a new transmissi on mode in mitochondrial genetics. The phenotypic features of complex II ge ne mutations suggest that whereas the catalytic subunit SDHA mutations may compromise the Krebs cycle, those in other structural subunits may affect o xygen sensing and signaling.