title: Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator.
abstract: 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.
authors.affiliation: Department of Genetics, Biology of Microorganisms, Anthropology and Evolution, University of Parma, Parma 43100, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dallabona
authors.forename: René Massimiliano
authors.initials: RM
authors.lastname: Marsano
authors.forename: Paola
authors.initials: P
authors.lastname: Arzuffi
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mancini
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
authors.forename: Iliana
authors.initials: I
authors.lastname: Ferrero
authors.forename: Claudia
authors.initials: C
authors.lastname: Donnini
mesh_terms: D000483:Alleles; D015152:Blotting, Northern; D015153:Blotting, Western; D002952:Citric Acid Cycle / Q000235:genetics; D004734:Energy Metabolism; D018628:Gene Dosage / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D016153:Genes, Suppressor; D005816:Genetic Complementation Test; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009024:Morphogenesis; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000254:growth & development / Q000648:ultrastructure; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013312:Stress, Physiological; D014158:Transcription, Genetic
chemical_list: C530370:MPV17 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C505195:SYM1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins