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

Science. 2009 Aug 28;325(5944):1139-42. doi: 10.1126/science.1175689. Epub 2009 Jul 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Cell Line, Tumor
  • Female
  • Flavin-Adenine Dinucleotide / metabolism
  • Flavoproteins / metabolism
  • Germ-Line Mutation*
  • Haplotypes
  • Humans
  • Inheritance Patterns
  • Male
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Molecular Sequence Data
  • Oxygen Consumption
  • Paraganglioma / genetics*
  • Pedigree
  • Protein Subunits / metabolism
  • 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 / metabolism*

Substances

  • Flavoproteins
  • Mitochondrial Proteins
  • Protein Subunits
  • SDH1 protein, S cerevisiae
  • SDH5 protein, S cerevisiae
  • SDHAF2 protein, human
  • Saccharomyces cerevisiae Proteins
  • Flavin-Adenine Dinucleotide
  • Succinate Dehydrogenase