title: A mutation in a mitochondrial ABC transporter results in mitochondrial dysfunction through oxidative damage of mitochondrial DNA.
abstract: We have isolated a Saccharomyces cerevisiae mutant that shows an increased tendency to form cytoplasmic petites (respiration-deficient rho- or rho0 mutants) in response to treatment of cells growing on a solid medium with the DNA-damaging agent methyl methane-sulfonate or ultraviolet light. The mutation in this strain, atm1-1, was found to cause a single amino acid substitution in ATM1, a nuclear gene that encodes the mitochondrial ATP-binding cassette (ABC) transporter. When the mutant cells were grown in liquid glucose medium, they accumulated free iron within the mitochondria and at the same time gave rise to spontaneous cytoplasmic petite mutants, as seen previously in cells carrying a mutation in a gene homologous to the human gene responsible for Friedreich's ataxia. Analysis of the effects of free iron and malonic acid (an inhibitor of oxidative respiration in mitochondria) on the incidence of petites among the mutant cells indicated that spontaneous induction of petites was a consequence of oxidative stress rather than a direct effect of either a defect in the ATM1 gene or the accumulation of free iron. We observed an increase in the incidence of strand breaks in the mitochondrial DNA of the atm1-1 mutant cells. Furthermore, we found that rates of induction of petites and accumulation of strand breaks in mitochondrial DNA were enhanced in the atm1-1 mutant by the introduction of another mutation, mhr1-1, which results in a deficiency in mitochondrial DNA repair. These observations indicate that spontaneous induction of petites in the atm1-1 mutant is a consequence of oxidative damage to mitochondrial DNA mediated by enhanced accumulation of mitochondrial iron.
authors.affiliation: Cellular and Molecular Biology Laboratory, Riken Institute, Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Senbongi
authors.forename: F
authors.initials: F
authors.lastname: Ling
authors.forename: T
authors.initials: T
authors.lastname: Shibata
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D003433:Crosses, Genetic; D004249:DNA Damage; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D005816:Genetic Complementation Test; D007501:Iron / Q000378:metabolism; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008928:Mitochondria / Q000235:genetics*; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D014466:Ultraviolet Rays
chemical_list: C091561:ATM1 protein, S cerevisiae; D018528:ATP-Binding Cassette Transporters; D004272:DNA, Mitochondrial; D005656:Fungal Proteins; D009153:Mutagens; D029701:Saccharomyces cerevisiae Proteins; D008741:Methyl Methanesulfonate; D007501:Iron