title: Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease.
abstract: A point mutation in the Drosophila gene that codes for the major adult isoform of adenine nuclear translocase (ANT) represents a model for human diseases that are associated with ANT insufficiency [stress-sensitive B(1) (sesB(1))]. We characterized the organismal, bioenergetic and molecular phenotype of sesB(1) flies then tested strategies to compensate the mutant phenotype. In addition to developmental delay and mechanical-stress-induced seizures, sesB(1) flies have an impaired response to sound, defective male courtship, female sterility and curtailed lifespan. These phenotypes, excluding the latter two, are shared with the mitoribosomal protein S12 mutant, tko(25t). Mitochondria from sesB(1) adults showed a decreased respiratory control ratio and downregulation of cytochrome oxidase. sesB(1) adults exhibited ATP depletion, lactate accumulation and changes in gene expression that were consistent with a metabolic shift towards glycolysis, characterized by activation of lactate dehydrogenase and anaplerotic pathways. Females also showed downregulation of many genes that are required for oogenesis, and their eggs, although fertilized, failed to develop to the larval stages. The sesB(1) phenotypes of developmental delay and mechanical-stress-induced seizures were alleviated by an altered mitochondrial DNA background. Female sterility was substantially rescued by somatic expression of alternative oxidase (AOX) from the sea squirt Ciona intestinalis, whereas AOX did not alleviate developmental delay. Our findings illustrate the potential of different therapeutic strategies for ANT-linked diseases, based on alleviating metabolic stress.
authors.affiliation: BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
authors.forename: Suvi
authors.initials: S
authors.lastname: Vartiainen
authors.affiliation: BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
authors.forename: Shanjun
authors.initials: S
authors.lastname: Chen
authors.affiliation: BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
authors.forename: Jack
authors.initials: J
authors.lastname: George
authors.affiliation: BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
authors.forename: Tea
authors.initials: T
authors.lastname: Tuomela
authors.affiliation: BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland.
authors.forename: Kaisa R
authors.initials: KR
authors.lastname: Luoto
authors.affiliation: Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
authors.forename: Kevin M C
authors.initials: KM
authors.lastname: O'Dell
authors.affiliation: BioMediTech and Tampere University Hospital, FI-33014 University of Tampere, Finland. Research Program of Molecular Neurology, FI-00014 University of Helsinki, Finland. howard.t.jacobs@uta.fi.
authors.forename: Howard T
authors.initials: HT
authors.lastname: Jacobs
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics*; D005260:Female; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics*; D008969:Molecular Sequence Data; D010085:Oxidative Phosphorylation; D010641:Phenotype; D017354:Point Mutation
chemical_list: D033741:Adenine Nucleotide Translocator 1; D004247:DNA
keywords: Adenine nucleotide translocase; Alternative oxidase; Mitochondrial biogenesis; Mitochondrial disease