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 Dnm1p. Dnm1p 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 Dnm1p and is required for activation of MFCs. We recently identified a third fission protein on the outer mitochondrial membrane called Fis1p. Fis1p independently recruits Dnm1p and Mdv1p to the mitochondrial membrane and plays a critical role in assembly of functional MFCs. Additional Dnm1p-Dnm1p, Dnm1p- Mdv1p 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 Mdv1p and Dnm1p membrane recruitment and MFC assembly. Specifically, we propose to: 1) test the hypothesis that the NTE (N-Terminal Extension) of Mdv1p interacts with the binding pocket of the Fis1p TPR fold, 2) map residues in Fis1p required for Dnm1p membrane recruitment and MFC assembly, 3) solve the solution structure of yeast Fis1p and the Fis1p-Mdv1p binding site complex, and 4) define the role of different Dnm1p 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053466-11
Application #
7008530
Study Section
Special Emphasis Panel (ZRG1-SSS-U (04))
Program Officer
Poodry, Clifton A
Project Start
1996-02-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
11
Fiscal Year
2006
Total Cost
$321,171
Indirect Cost
Name
University of Utah
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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