Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator

Hum Mol Genet. 2010 Mar 15;19(6):1098-107. doi: 10.1093/hmg/ddp581. Epub 2009 Dec 30.


A peculiar form of hepatocerebral mtDNA depletion syndrome is caused by mutations in the MPV17 gene, which encodes a small hydrophobic protein of unknown function located in the mitochondrial inner membrane. In order to define the molecular basis of MPV17 variants associated with the human disorder, we have previously taken advantage of S. cerevisiae as a model system thanks to the presence of an MPV17 ortholog gene, SYM1. We demonstrate here that the SYM1 gene product is essential to maintain OXPHOS, glycogen storage, mitochondrial morphology and mtDNA stability in stressing conditions such as high temperature and ethanol-dependent growth. To gain insight into the molecular basis of the Sym1-less phenotype, we identified and characterized multicopy suppressor genes and metabolic suppressor compounds. Our results suggest that (i) metabolic impairment and mtDNA instability occur independently from each other as a consequence of SYM1 ablation; (ii) ablation of Sym1 causes depletion of glycogen storage, possibly due to defective anaplerotic flux of tricarboxylic acid (TCA) cycle intermediates to the cytosol; (iii) flattening of mitochondrial cristae in Sym1-defective organelles suggests a role for Sym1 in the structural preservation of the inner mitochondrial membrane, which could in turn control mtDNA maintenance and stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Blotting, Northern
  • Blotting, Western
  • Citric Acid Cycle / genetics
  • Energy Metabolism*
  • Gene Dosage / genetics
  • Gene Expression Regulation, Fungal
  • Genes, Suppressor
  • Genetic Complementation Test
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Proteins / chemistry*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Morphogenesis*
  • Mutation / genetics
  • Oxidation-Reduction
  • Phenotype
  • Promoter Regions, Genetic / genetics
  • Saccharomyces cerevisiae / cytology
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae / ultrastructure
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Sequence Homology, Amino Acid*
  • Stress, Physiological*
  • Transcription, Genetic


  • MPV17 protein, human
  • Membrane Proteins
  • Mitochondrial Proteins
  • SYM1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins