SDH5, a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma

• Published in: Science (American Association for the Advancement of Science) Vol. 325; no. 5944; pp. 1139 - 1142
• Main Authors: Hao, Huai-Xiang, Khalimonchuk, Oleh, Schraders, Margit, Dephoure, Noah, Bayley, Jean-Pierre, Kunst, Henricus, Devilee, Peter, Cremers, Cor W.R.J, Schiffman, Joshua D, Bentz, Brandon G, Gygi, Steven P, Winge, Dennis R, Kremer, Hannie, Rutter, Jared
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 28.08.2009
• Subjects: Adenine; Amino Acid Sequence; Antibodies; Biological and medical sciences; Cell Line; Cell Line, Tumor; chromosomes; Dehydrogenases; electron transport chain; Female; flavin-adenine dinucleotide; Flavin-Adenine Dinucleotide - metabolism; Flavoproteins - metabolism; Fluorescence; Genes; Genetic mutation; germ cells; Germ-Line Mutation; Haplotypes; human diseases; Humans; Inheritance Patterns; loss-of-function mutation; Male; Medical sciences; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Molecular Sequence Data; Nervous system diseases; Neurology; Oxygen Consumption; Paraganglioma - genetics; Pedigree; Plasmids; protein subunits; Protein Subunits - metabolism; proteins; Proteomics; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; succinate dehydrogenase (quinone); Succinate Dehydrogenase - metabolism; tricarboxylic acid cycle; Tumors; Tumors of the nervous system. Phacomatoses; Yeasts; Human; Nervous system diseases; Mitochondria; Succinate dehydrogenase; Cell organelle; Enzyme; Diseases of the autonomic nervous system; FAD; Paraganglioma; Tumor; Oxidoreductases; Cofactor
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1175689

Mammalian mitochondria contain about 1100 proteins, nearly 300 of which are uncharacterized. Given the well-established role of mitochondrial defects in human disease, functional characterization of these proteins may shed new light on disease mechanisms. Starting with yeast as a model system, we investigated an uncharacterized but highly conserved mitochondrial protein (named here Sdh5). Both yeast and human Sdh5 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both the electron transport chain and the tricarboxylic acid cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor). Germline loss-of-function mutations in the human SDH5 gene, located on chromosome 11q13.1, segregate with disease in a family with hereditary paraganglioma, a neuroendocrine tumor previously linked to mutations in genes encoding SDH subunits. Thus, a mitochondrial proteomics analysis in yeast has led to the discovery of a human tumor susceptibility gene.