Maintenance of normal mitochondrial morphology and mitchondrial DNA (mtDNA) is critical for the survival of most eukaryotic cells. Although changes in mitochondrial morphology, copy number and mtDNA content are associated with a variety of human diseases and the aging process, little is known about the molecular mechanisms that control aspects of mitochondrial behavior. The long-term objective os this proposal is to understand the role the Mgm1p GTPase plays in sustaining wild-type mitochondrial dynamics in the budding yeast, Saccharomyces cerevisiae. Mutations in MGM1 disrupt wild-type mitochondrial morphology, induce mtDNA loss and reduce the transport of mitochondria to daughter cells during division. In this application I propose: l) to generate and analyze a panel of novel temperature-sensitive alleles of MGM1 (mgml-ts), 2) to isolate and analyze second-site suppressors of mgml-ts alleles, and 3) to clone and characterize the genes and proteins defined by these second-site suppressors. These experiments will identify Mgmlp domains important for function and will also identify new genes that act in the same genetic pathway as MGM1. Since human cells express an Mgm1p homologue, understanding Mgmlp function in yeast should ultimately provide insight into mitochondrial behavior in mammalian cells.
