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

Tapping the Mitochondrial Proteome Mitochondria produce the energy that cells need to survive, function, and divide. A growing list of human disorders has been traced to defects in mitochondrial function. About 300 mammalian mitochondrial proteins are functionally uncharacterized, and Hao et al. (p. 1139, published online 23 July) reasoned that the most highly conserved proteins within this group might provide insights into human disease. A combination of bioinformatics, yeast genetics, biochemistry, and human genetics was used to show that a previously uncharacterized mitochondrial protein (Sdh5) is required for the activity of respiratory complex II. Inactivating mutations in the human gene encoding SDH5 were found in individuals with hereditary paraganglioma, a rare neuroendocrine tumor. Thus, analysis of a mitochondrial protein in yeast has revealed a human tumor susceptibility gene. Analysis of a yeast mitochondrial protein reveals a human tumor susceptibility gene. 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.