Defects in the mitochondrion, the energy-producing unit of the cell, lead to a wide range neural and muscular diseases caused by decreased energy production, free radical damage, and perturbations to apoptotic pathways. The protein import pathways of the mitochondrion mediate the import and assembly of proteins from the cytosol. The X-linked disease Mohr-Tranebjaerg syndrome or deafness-dystonia syndrome is caused by a specific defect in the import of inner membrane proteins. The goal of this proposal is to investigate the mechanism of protein import into the mitochondrion in the experimental model, the budding yeast Saccharomyces cerevisiae. Components of this import pathway include the soluble Tim8p-Tim13p and Tim9p-Tim10p complexes in the intermembrane space and the TIM22 complex (Tim12p, Tim18p, Tim22p, and Tim54p) in the inner membrane. The objective of this research is to define the molecule mechanisms of protein import with a combined biochemical, biophysical, and genetic approach. Specifically, the mechanism by which the Tim8p-Tim13p and Tim9p-Tim10p complexes are assembled and subsequently escort the substrates to the inner membrane will be elucidated. In addition, a chemical-genetic approach will be utilized to identify small molecule effectors that may modulate the import pathway, with the long-term goal of developing therapeutics for deafness-dystonia syndrome and other mitochondrial disorders. Moreover, the link between mitochondrial protein assembly and degradation pathways will be investigated in our yeast models. The proposed project will expand fundamental knowledge about the mechanism of protein insertion into the mitochondrial inner membrane, extending present studies that have focused generally on the mechanism by which proteins reach soluble compartments of the mitochondrion. This research will impact public health because these mechanistic studies will provide insight into how defects in mitochondrial biogenesis lead to diseases such as deafness-dystonia syndrome, Friedreich's ataxia, and Parkinson's and Alzheimer's disease, which are caused by mitochondrial dysfunction. The goal of this research is to use our yeast models in a chemical-genetic approach to identify small molecule effectors, which in the long-term may lay the groundwork for developing new tools to understand how mitochondrial defects lead to human diseases and new therapeutic approaches to develop drugs that will modulate mitochondrial function. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061721-08
Application #
7426846
Study Section
Cell Structure and Function (CSF)
Program Officer
Shapiro, Bert I
Project Start
2000-09-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
8
Fiscal Year
2008
Total Cost
$328,450
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Yien, Yvette Y; Shi, Jiahai; Chen, Caiyong et al. (2018) FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity. J Biol Chem 293:19797-19811
Steffen, Janos; Koehler, Carla M (2018) ER-mitochondria contacts: Actin dynamics at the ER control mitochondrial fission via calcium release. J Cell Biol 217:15-17
Steffen, Janos; Vashisht, Ajay A; Wan, Jijun et al. (2017) Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria. Mol Biol Cell 28:600-612
Miyata, Non; Tang, Zhiye; Conti, Michael A et al. (2017) Adaptation of a Genetic Screen Reveals an Inhibitor for Mitochondrial Protein Import Component Tim44. J Biol Chem 292:5429-5442
Sangwan, Smriti; Zhao, Anni; Adams, Katrina L et al. (2017) Atomic structure of a toxic, oligomeric segment of SOD1 linked to amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A 114:8770-8775
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
Thangamani, Shankar; Maland, Matthew; Mohammad, Haroon et al. (2017) Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway. Front Cell Infect Microbiol 7:4
Filipuzzi, Ireos; Steffen, Janos; Germain, Mitchel et al. (2017) Stendomycin selectively inhibits TIM23-dependent mitochondrial protein import. Nat Chem Biol 13:1239-1244
Wan, Jijun; Steffen, Janos; Yourshaw, Michael et al. (2016) Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia. Brain 139:2877-2890
Lu, Ya-Wen; Galbraith, Laura; Herndon, Jenny D et al. (2016) Defining functional classes of Barth syndrome mutation in humans. Hum Mol Genet 25:1754-70

Showing the most recent 10 out of 55 publications