Phenotypic rescue of a Drosophila model of mitochondrial ANT1 disease

Abstract

Abstract A point mutation (stress-sensitive B1, sesB1 in the Drosophila gene coding for the major adult isoform of the adenine nuclear translocase (ANT) represents a model for human diseases associated with ANT insufficiency. We characterized the organismal, bioenergetic and molecular phenotype of sesB1, then tested strategies to compensate the mutant phenotype. In addition to developmental delay and bang-sensitivity, sesB1 manifests impaired response to sound, defective male courtship, female sterility and curtailed lifespan. These phenotypes, apart from the last two, are shared with the tko25t mutant in mitoribosomal protein S12. Mitochondria from sesB1 adults showed a decreased respiratory control ratio and downregulation of cytochrome oxidase. sesB1 adults exhibited ATP depletion, lactate accumulation, and changes in gene expression consistent with a metabolic shift towards glycolysis, with activation of lactate dehydrogenase and anaplerotic pathways. Females also showed downregulation of many genes required for oogenesis, and their eggs, though fertilized, failed to develop to the larval stages. The sesB1 phenotypes of developmental delay and bang-sensitivity were alleviated by altered mtDNA background. Female sterility was substantially rescued by somatic expression of the alternative oxidase (AOX) from Ciona intestinalis, whereas AOX did not alleviate developmental delay. Our findings illustrate the potential of different therapeutic strategies for ANT-linked diseases, based on increasing mitochondrial bioenergy production, or on alleviating metabolic stress.