AAA ATPases linking mitochondria with microtubule processing in flies and yeast

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DESCRIPTION (provided by applicant): Mitochondria, the organelles in which food energy is harnessed into usable ATP form, are moved and shaped to fulfill different energy needs within specialized cells. Many human genetic neurodegenerative disorders are associated with defects of mitochondrial dynamics. Drosophila melanogaster spermatogenesis is an ideal model system for genetic dissection of conserved mechanisms of mitochondrial morphogenesis, since mitochondria undergo dramatic shaping during sperm development. After meiosis, all mitochondria in a Drosophila spermatid normally fuse into two giant mitochondrial derivatives that interwrap precisely and intricately to form a spherical structure called the Nebenkern, which then unfurls and elongates along the growing sperm tail. The main focus is to elucidate molecular mechanisms underlying mitochondrial shaping, as a way to characterize genes whose human homologs might underlie mitochondrial dysfunction. We previously identified the Drosophila nmd gene (no mitochondrial derivative) as required for aggregation of mitochondria during spermatogenesis. The Nmd gene product is an AAA ATPase related to microtubule-severing proteins spastin and katanin, though unlike those relatives, Nmd is unique in its localization to both mitochondria and centrosomes/basal bodies. A paralog of Nmd, CG4701, is required for mitochondrial shaping later in spermatogenesis. Both paralogs seem to be required also for male meiotic cytokinesis, perhaps through effects on the meiotic spindle. A yeast ortholog exists but has not been well characterized. Since various observations initially suggest a conserved role for Nmd family members in both mitochondrial shaping and microtubule processing, the primary emphasis in the proposed research is to determine genetically and biochemically the interactions between these mitochondrial AAA ATPases (in both flies and yeast) and microtubules and other structures. These gene products are homologous to human protein ATAD1 which is important in neurons for internalization of receptors but about which little else is known. ATAD1 may be a good candidate for another version of spastic paraplegia that maps in the same region of the genome. Our work will allow for important insight into the molecular roles of this human gene in health and disease. As a final aim, the genes defective in two male sterile Drosophila strains with related phenotypes to nmd and CG4701 will be identified, allowing identification of further gene families that may ultimately be associated with human mitochondrial neuropathies, myopathies, and infertility syndromes. PUBLIC HEALTH RELEVANCE: Defects of mitochondrial shaping and movement underlie many neurodegenerative diseases and may be associated with premature aging as well as infertility. Elucidation of molecular mechanisms by which mitochondrial shaping is mediated by fly and yeast mitochondrial proteins related to those implicated in hereditary spastic paraplegia will enable characterization of related functions in humans. These efforts may provide a deeper understanding of mitochondria-related disorders and set the stage for the design of treatments.