Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease

• Published in: Disease models & mechanisms 2014-06, Vol.7 (6), p.635-648
• Main Authors: Vartiainen, Suvi, Chen, Shanjun, George, Jack, Tuomela, Tea, Luoto, Kaisa R, O'Dell, Kevin M C, Jacobs, Howard T
• Format: Article
• Language: English
• Subjects: Adenine nucleotide translocase; Adenine Nucleotide Translocator 1 - genetics; Alternative oxidase; Amino Acid Sequence; Animals; Base Sequence; Biosynthesis; Cardiomyopathy; Convulsions & seizures; Defects; Disease; Disease Models, Animal; DNA; Drosophila - genetics; Female; Females; Genes; Genotype & phenotype; Insects; Kinases; Male; Metabolism; Mitochondria; Mitochondrial biogenesis; Mitochondrial disease; Mitochondrial Diseases - genetics; Mitochondrial DNA; Molecular Sequence Data; Mutation; Oxidative Phosphorylation; Pathology; Phenotype; Physiology; Point Mutation; Proteins
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.016527

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.