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Originally published in Science Express on 23 July 2009
Science 28 August 2009:
Vol. 325. no. 5944, pp. 1139 - 1142
DOI: 10.1126/science.1175689
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Reports
SDH5, a Gene Required for Flavination of Succinate Dehydrogenase, Is Mutated in Paraganglioma
Huai-Xiang Hao,1
Oleh Khalimonchuk,1,2
Margit Schraders,5,6
Noah Dephoure,7
Jean-Pierre Bayley,8
Henricus Kunst,5
Peter Devilee,8,9
Cor W. R. J. Cremers,5
Joshua D. Schiffman,3
Brandon G. Bentz,4
Steven P. Gygi,7
Dennis R. Winge,1,2
Hannie Kremer,5,6
Jared Rutter1,*
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.
2 Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
3 Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
4 Department of Surgery, Division of Otolaryngology–Head and Neck Surgery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
5 Department of Otorhinolaryngology, Donders Centre for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, Netherlands.
6 Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, Netherlands.
7 Department of Cell Biology, Harvard University Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
8 Department of Human Genetics, Leiden University Medical Centre, Leiden 2333 ZA, Netherlands.
9 Department of Pathology, Leiden University Medical Centre, Leiden 2333 ZA, Netherlands.
* To whom correspondence should be addressed. E-mail: rutter{at}biochem.utah.edu
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