Mitochondria are dynamic organelles that continually fuse and divide. The balance between these opposing processes controls the morphology of mitochondria. Most importantly, these processes also play a central role in regulating the physiology of mitochondria. Fusion enables content mixing between mitochondria, maintains mitochondrial DNA levels, and preserves respiratory function. Fission is an important component of apoptosis. Disruptions in these pathways are associated with neurodegenerative disease and early lethality in humans. Our long-term objective is to address the following major gaps in our understanding of mitochondrial fission and fusion in mammals. First, it is unknown how the fission machinery is recruited to the mitochondrial surface during division. Second, it is unknown how the fusion and fission pathways interact to regulate mitochondrial function in intact tissues. Third, we need to develop better tools to study mitochondrial dynamics in tissues, rather than relying solely on studies from cultured cells. To address these gaps, we will use a combination of mouse and cellular studies. In the first aim, we use mouse mutants deficient in two proteins--Mff and Fis1--important for mitochondrial fission. Mff and Fis1 are mitochondrial outer membrane proteins that are the best candidates for recruiting the fission machinery to mitochondria, and cellular studies of our mouse mutants will allow a definitive test of this hypothesis. In addition, phenotypic analysis of these mutants will reveal whether Mff and Fis1 have tissue-specific roles in mitochondrial fission. In the second aim, we will genetically combine these mutations with mutations in fusion genes to understand how fission and fusion pathways interact to control mitochondrial function. In the third aim, we develop a mouse model that allows mitochondrial dynamics to be tracked easily in tissues. This new mouse model will broadly facilitate investigations of mitochondrial dynamics, including the study of the mouse mutants generated from this proposal.

Public Health Relevance

Because they generate energy for human cells, mitochondria are particularly important for muscle and nerve function. Our proposal will lead to fundamental knowledge about how the fusion and division of mitochondria regulate their function. This knowledge has important health implications because the major neurodegenerative diseases - including Parkinson's, Huntington's, and Alzheimer's diseases - involve mitochondrial dysfunction and may be alleviated by control of mitochondrial dynamics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062967-12
Application #
8443825
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
2001-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
12
Fiscal Year
2013
Total Cost
$322,967
Indirect Cost
$123,605
Name
California Institute of Technology
Department
None
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Mishra, Prashant; Chan, David C (2014) Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 15:634-46
Chan, Nickie C; den Besten, Willem; Sweredoski, Michael J et al. (2014) Degradation of the deubiquitinating enzyme USP33 is mediated by p97 and the ubiquitin ligase HERC2. J Biol Chem 289:19789-98
Mishra, Prashant; Carelli, Valerio; Manfredi, Giovanni et al. (2014) Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab 19:630-41
Losón, Oliver C; Liu, Raymond; Rome, Michael E et al. (2014) The mitochondrial fission receptor MiD51 requires ADP as a cofactor. Structure 22:367-77
Marinov, Georgi K; Wang, Yun E; Chan, David et al. (2014) Evidence for site-specific occupancy of the mitochondrial genome by nuclear transcription factors. PLoS One 9:e84713
Ngo, Huu B; Lovely, Geoffrey A; Phillips, Rob et al. (2014) Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nat Commun 5:3077
Carelli, Valerio; Chan, David C (2014) Mitochondrial DNA: impacting central and peripheral nervous systems. Neuron 84:1126-42
Loson, Oliver C; Song, Zhiyin; Chen, Hsiuchen et al. (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659-67
Wang, Yun E; Marinov, Georgi K; Wold, Barbara J et al. (2013) Genome-wide analysis reveals coating of the mitochondrial genome by TFAM. PLoS One 8:e74513
Zhang, Yan; Chan, Nickie C; Ngo, Huu B et al. (2012) Crystal structure of mitochondrial fission complex reveals scaffolding function for mitochondrial division 1 (Mdv1) coiled coil. J Biol Chem 287:9855-61

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