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.
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.
|Liu, Raymond; Chan, David C (2017) OPA1 and cardiolipin team up for mitochondrial fusion. Nat Cell Biol 19:760-762|
|Fahrner, Jill A; Liu, Raymond; Perry, Michael Scott et al. (2016) A novel de novo dominant negative mutation in DNM1L impairs mitochondrial fission and presents as childhood epileptic encephalopathy. Am J Med Genet A 170:2002-11|
|Toyama, Erin Quan; Herzig, Sébastien; Courchet, Julien et al. (2016) Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351:275-281|
|Chen, Hsiuchen; Ren, Shuxun; Clish, Clary et al. (2015) Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy. J Cell Biol 211:795-805|
|Mishra, Prashant; Varuzhanyan, Grigor; Pham, Anh H et al. (2015) Mitochondrial Dynamics is a Distinguishing Feature of Skeletal Muscle Fiber Types and Regulates Organellar Compartmentalization. Cell Metab 22:1033-44|
|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|
|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|
|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|
|Carelli, Valerio; Chan, David C (2014) Mitochondrial DNA: impacting central and peripheral nervous systems. Neuron 84:1126-42|
|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|
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