Mitochondria are dynamic organelles whose morphology and function are regulated by opposing fission and fusion. Using funds provided by this grant, my laboratory demonstrated that a dynamin-related GTPase called Dnm1 controls mitochondrial fission in budding yeast. Dnm1 defines a conserved family of mitochondrial GTPases with important but poorly understood functions in cell physiology and human health. The human homolog of yeast Dnm1 is called Drp1. Studies performed in mammals and cell lines suggest that Drp1 plays critical roles in maintaining mitochondrial function, mitochondrial fragmentation during apoptosis, and generation of mitochondrial fragments for autophagy. Based on these findings, molecules that regulate mitochondrial fission are potential targets for inhibitory drugs that reduce mitochondrial fragmentation and unwanted cell death, including the apoptotic death of cardiac cells after stroke or the neuronal cell death associated with a variety of neuropathies. This proposal focuses on the fission machinery of budding yeast, which serves as the prototype for mitochondrial fission machineries in all eukaryotes, including humans. This field has matured to the stage where the major questions are focused on how Dnm1 and its binding partners work together to elicit fission with the proper spatial and temporal control. To progress beyond this stage, it is critical to obtain a better mechanistic and structural understanding of how components of the Dnm1 fission complex interact and assemble, and how these interactions affect fission activity. The studies described here are designed to obtain this mechanistic and structural information. With this knowledge in hand, we will generate and test specific models for the regulation of Dnm1 assembly and fission complex activity.
The proposed studies will advance mechanistic and structural understanding of the molecules that regulate mitochondrial fission using yeast as a model system. This core mitochondrial fission machinery includes the Dnm1 GTPase, Mdv1/Caf4 adaptors, and the Fis1 membrane anchor. The results will be relevant to human development and health, as these proteins have human homologs including human Drp1 (yeast Dnm1 homolog) and its membrane receptor human Fis1 (yeast Fis1 homolog). Human Drp1 plays critical roles in maintaining mitochondrial function, mitochondrial fragmentation during apoptosis, and generation of mitochondrial fragments for autophagy. A mutation in Drp1 was recently linked to the death of an infant 37 days after birth. Experiments in this application take advantage of the sophisticated tools available in yeast to probe the mechanism of fission complex assembly and activity. What is learned from these studies will allow scientists and clinicians to manipulate the activities of these molecules for the benefit of human health
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