MECHANISMS OF MITOCHONDRIAL FISSION

University Of Utah, Salt Lake City UT

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Abstract

The basic molecular machinery controlling mitochondrial fission is conserved from yeast to humans. We are using genetic, biochemical and structural approaches to understand the mechanism of mitochondrial fission in budding yeast. We previously identified a dynamin-related GTPase called Dnmlp. Dnmlp cycles from the cytoplasm onto the outer mitochondrial membrane where it forms Mitochondrial Fission Complexes (MFCs) that divide mitochondrial compartments into smaller units. A second protein, Mdv1p associates with Dnmlp and is required for activation of MFCs. We recently identified a third fission protein on the outer mitochondrial membrane called Fislp. Fis1p.independently recruits Dnmlp and Mdvlp to the mitochondrial membrane and plays a critical role in assembly of functional MFCs. Additional Dnm1p-Dnm1p, Dnmlp- Mdvlp and Mdv1p-Mdv1p interactions play a role in membrane recruitment and MFC assembly. The studies proposed here are aimed at understanding the temporal and physical interactions that underlie Mdvlp and Dnmlp membrane recruitment and MFC assembly. Specifically, we propose to: 1) test the hypothesis that the NTE (N-Terminal Extension) of Mdvlp interacts with the binding pocket of the Fislp TPR fold, 2) map residues in Fislp required for Dnmlp membrane recruitment and MFC assembly, 3) solve the solution structure of yeast Fislp and the Fis1p-Mdv1p binding site complex, and 4) define the role of different Dnmlp molecular interactions in pre-and post-MFC assembly events. Some of the interactions we will identify and characterize are potential targets for inhibitors that block mitochondrial fission. In a clinical setting, such inhibitors could be used to reduce or prevent mitochondrial-mediated cell damage or death resulting from drug treatment, trauma or disease.