title: Complete loss-of-function of the heart/muscle-specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy.
abstract: Multiple mitochondrial DNA deletions are associated with clinically heterogeneous disorders transmitted as mendelian traits. Dominant missense mutations were found in the gene encoding the heart and skeletal muscle-specific isoform of the adenine nucleotide translocator (ANT1) in families with autosomal dominant progressive external opthalmoplegia and in a sporadic patient. We herein report on a sporadic patient who presented with hypertrophic cardiomyopathy, mild myopathy with exercise intolerance and lactic acidosis but no ophthalmoplegia. A muscle biopsy showed the presence of numerous ragged-red fibers, and Southern blot analysis disclosed multiple deletions of muscle mitochondrial DNA. Molecular analysis revealed a C to A homozygous mutation at nucleotide 368 of the ANT1 gene. The mutation converted a highly conserved alanine into an aspartic acid at codon 123 and was absent in 500 control individuals. This is the first report of a recessive mutation in the ANT1 gene. The clinical and biochemical features are different from those found in dominant ANT1 mutations, resembling those described in ANT1 knockout mice. No ATP uptake was measured in proteoliposomes reconstituted with protein extracts from the patient's muscle. The equivalent mutation in AAC2, the yeast ortholog of human ANT1, resulted in a complete loss of transport activity and in the inability to rescue the severe Oxidative Phosphorylation phenotype displayed by WB-12, an AAC1/AAC2 defective strain. Interestingly, exposure to reactive oxygen species (ROS) scavengers dramatically increased the viability of the WB-12 transformant, suggesting that increased redox stress is involved in the pathogenesis of the disease and that anti-ROS therapy may be beneficial to patients.
authors.affiliation: Department of Pharmaco-Biology, Laboratory of Biochemistry and Molecular Biology, University of Bari, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Palmieri
authors.forename: Simona
authors.initials: S
authors.lastname: Alberio
authors.forename: Isabella
authors.initials: I
authors.lastname: Pisano
authors.forename: Tiziana
authors.initials: T
authors.lastname: Lodi
authors.forename: Mija
authors.initials: M
authors.lastname: Meznaric-Petrusa
authors.forename: Janez
authors.initials: J
authors.lastname: Zidar
authors.forename: Antonella
authors.initials: A
authors.lastname: Santoro
authors.forename: Pasquale
authors.initials: P
authors.lastname: Scarcia
authors.forename: Flavia
authors.initials: F
authors.lastname: Fontanesi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Lamantea
authors.forename: Iliana
authors.initials: I
authors.lastname: Ferrero
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002470:Cell Survival; D004272:DNA, Mitochondrial / Q000235:genetics; D004579:Electron Transport; D006801:Humans; D051379:Mice; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009206:Myocardium / Q000473:pathology*; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D033741:Adenine Nucleotide Translocator 1; D004272:DNA, Mitochondrial; C112225:PET9 protein, S cerevisiae; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D000226:Mitochondrial ADP, ATP Translocases