SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma

Huai Xiang Hao, Oleh Khalimonchuk, Margit Schraders, Noah Dephoure, Jean Pierre Bayley, Henricus Kunst, Peter Devilee, Cor W.R.J. Cremers, Joshua D. Schiffman, Brandon G. Bentz, Steven P. Gygi, Dennis R. Winge, Hannie Kremer, Jared Rutter

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523 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1139-1142
Number of pages4
JournalScience
Volume325
Issue number5944
DOIs
StatePublished - 2009

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    Hao, H. X., Khalimonchuk, O., Schraders, M., Dephoure, N., Bayley, J. P., Kunst, H., Devilee, P., Cremers, C. W. R. J., Schiffman, J. D., Bentz, B. G., Gygi, S. P., Winge, D. R., Kremer, H., & Rutter, J. (2009). SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science, 325(5944), 1139-1142. https://doi.org/10.1126/science.1175689