The mitochondrion plays a key role in energy production, prevention of oxidative damage and regulation of cell death. Consequently, mitochondrial dysfunction contributes to a broad range of muscular and neural disorders, including Parkinson's, deafness-dystonia syndrome, and Leigh's syndrome. Furthermore, the first connection between a defect in mitochondrial protein import and an inherited disease was made in patients with Mohr-Tranebjaerg syndrome/deafness-dystonia syndrome (MTS);this is caused by mutations in one of the small Tim proteins (DDP1, Tim8 in S. cerevisiae). Key players in assembly of DDP1 are proteins Erv1, a sulfhydryl oxidase, and Mia40. Thus, delineation of DDP1 assembly is pertinent to understanding the molecular basis of deafness-dystonia syndrome. My proposed research centers on characterization of an import pathway into the mitochondrial intermembrane space (IMS) that is redox regulated and is required for the assembly of DDP1.1 propose (1) to identify Erv1 interacting proteins including substrates and partner proteins, and (2) to reconstitute the disulfide exchange reaction with Erv1, Mia40 and potential partner proteins. This pathway in the IMS has only been identified in the past three years and thus, a complete knowledge of this import pathway and its components would aid in development of potential treatments and therapies for deafness-dystonia syndrome and other devastating mitochondrial diseases. Additionally, import pathways should be better characterized because they might serve as delivery systems for therapeutic compounds. Lastly, my proposed studies in the model yeast, which is amenable to biochemistry and genetics, will provide the basis for future studies in mammalian systems because import is largely conserved between yeast and mammals. This project is important to public health because defective mitochondria contribute to a broad range of neurodegenerative and muscular diseases as well as aging.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F05-J (20))
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Fabian, Miles
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Neal, Sonya E; Dabir, Deepa V; Wijaya, Juwina et al. (2017) Osm1 facilitates the transfer of electrons from Erv1 to fumarate in the redox-regulated import pathway in the mitochondrial intermembrane space. Mol Biol Cell 28:2773-2785
Dabir, Deepa V; Hasson, Samuel A; Setoguchi, Kiyoko et al. (2013) A small molecule inhibitor of redox-regulated protein translocation into mitochondria. Dev Cell 25:81-92
Bourens, Myriam; Dabir, Deepa V; Tienson, Heather L et al. (2012) Role of twin Cys-Xaa9-Cys motif cysteines in mitochondrial import of the cytochrome C oxidase biogenesis factor Cmc1. J Biol Chem 287:31258-69