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.

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053466-17
Application #
8541023
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Ainsztein, Alexandra M
Project Start
1996-02-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
17
Fiscal Year
2013
Total Cost
$385,468
Indirect Cost
$126,764
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Kalia, Raghav; Wang, Ray Yu-Ruei; Yusuf, Ali et al. (2018) Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature 558:401-405
Nguyen, Tammy T; Oh, Sang S; Weaver, David et al. (2014) Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc Natl Acad Sci U S A 111:E3631-40
Lewandowska, Agnieszka; Macfarlane, Jane; Shaw, Janet M (2013) Mitochondrial association, protein phosphorylation, and degradation regulate the availability of the active Rab GTPase Ypt11 for mitochondrial inheritance. Mol Biol Cell 24:1185-95
Bui, Huyen T; Shaw, Janet M (2013) Dynamin assembly strategies and adaptor proteins in mitochondrial fission. Curr Biol 23:R891-9
Koirala, Sajjan; Guo, Qian; Kalia, Raghav et al. (2013) Interchangeable adaptors regulate mitochondrial dynamin assembly for membrane scission. Proc Natl Acad Sci U S A 110:E1342-51
Bui, Huyen T; Karren, Mary A; Bhar, Debjani et al. (2012) A novel motif in the yeast mitochondrial dynamin Dnm1 is essential for adaptor binding and membrane recruitment. J Cell Biol 199:613-22
Guo, Qian; Koirala, Sajjan; Perkins, Edward M et al. (2012) The mitochondrial fission adaptors Caf4 and Mdv1 are not functionally equivalent. PLoS One 7:e53523
Cohen, Mickael M; Amiott, Elizabeth A; Day, Adam R et al. (2011) Sequential requirements for the GTPase domain of the mitofusin Fzo1 and the ubiquitin ligase SCFMdm30 in mitochondrial outer membrane fusion. J Cell Sci 124:1403-10
Koirala, Sajjan; Bui, Huyen T; Schubert, Heidi L et al. (2010) Molecular architecture of a dynamin adaptor: implications for assembly of mitochondrial fission complexes. J Cell Biol 191:1127-39
Shaw, Janet M; Winge, Dennis R (2009) Shaping the mitochondrion: mitochondrial biogenesis, dynamics and dysfunction. Conference on Mitochondrial Assembly and Dynamics in Health and Disease. EMBO Rep 10:1301-5

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