SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma.
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.
Hao
Huai-Xiang
HX
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Khalimonchuk
Oleh
O
Schraders
Margit
M
Dephoure
Noah
N
Bayley
Jean-Pierre
JP
Kunst
Henricus
H
Devilee
Peter
P
Cremers
Cor W R J
CW
Schiffman
Joshua D
JD
Bentz
Brandon G
BG
Gygi
Steven P
SP
Winge
Dennis R
DR
Kremer
Hannie
H
Rutter
Jared
J
D000595:Amino Acid Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D005420:Flavoproteins / Q000378:metabolism; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010101:Oxygen Consumption; D010235:Paraganglioma / Q000235:genetics*; D010375:Pedigree; D021122:Protein Subunits / Q000378:metabolism; D040901:Proteomics; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000378:metabolism*
D005420:Flavoproteins; D024101:Mitochondrial Proteins; D021122:Protein Subunits; C528541:SDH1 protein, S cerevisiae; C543342:SDH5 protein, S cerevisiae; C543341:SDHAF2 protein, human; D029701:Saccharomyces cerevisiae Proteins; D005182:Flavin-Adenine Dinucleotide; D013385:Succinate Dehydrogenase