Progressive mitochondrial oxidative damage and dysfunction is fundamental to the pathogenesis of many human diseases. Using a yeast model system, we have shown that the novel protein Lifespan-associated Mitochondrial Stress-responsive 1 (Lms1) is recruited to mitochondria under conditions of mitochondrial stress. When Lms1 is depleted, oxidative stress induces loss of respiratory function and markedly accelerated loss of viability over time. Lms1 associates in vivo with Cdc48, an ATPase integral to the retrotranslocation and degradation of proteins from the endoplasmic reticulum (ERAD pathway). These observations have been extended to C. elegans, wherein knockdown of Lms1 leads to peroxide sensitivity and decreased lifespan and oxidative stress induces cytosol to mitochondria translocation. We propose that Lms1 is a component of an important pan-eukaryotic system for protection from the lethal effects of oxidative stress and mitochondrial dysfunction. We hypothesize that it senses mitochondrial stress and, through Cdc48 recruitment, enacts the degradation of misfolded or damaged mitochondrial protein. We hereby propose to determine: I) The mechanisms regulating Lms1 mitochondrial translocation. We will determine: 1) the location and specificity of the mitochondrial dysfunction signal;2) how this signal is relayed to Lms1;and 3) the identity of the Lms1 mitochondrial receptor. II) The function of Lms1 in preserving mitochondrial activity and viability. We will: 1) comprehensively identify the components of the Lms1- Cdc48 complex;2) determine the nature and regulation of the Lms1-Cdc48 interaction;and 3) understand the mitochondrial defect observed in the lms1 mutant. III) Lms1 regulation and function in mammals. We will: 1) examine mammalian Lms1 regulation and function using cultured cells;and 2) using an Lms1-/- mouse, determine the physiological role of this protein in maintaining mitochondrial function, particularly in cardiomyocytes.

Public Health Relevance

Many human diseases are caused by a progressive deterioration of the function of mitochondria. We have discovered a widespread cellular system that acts to prevent this type of deterioration and have shown that it protects both yeast and nematodes from certain types of damage. We suggest that it will be equally important in humans and propose to further understand its biochemical and physiological role.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087346-04
Application #
8213729
Study Section
Cell Structure and Function (CSF)
Program Officer
Krasnewich, Donna M
Project Start
2009-03-09
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$295,010
Indirect Cost
$98,990
Name
University of Utah
Department
Biochemistry
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Heo, Jin-Mi; Rutter, Jared (2011) Ubiquitin-dependent mitochondrial protein degradation. Int J Biochem Cell Biol 43:1422-6
Heo, Jin-Mi; Livnat-Levanon, Nurit; Taylor, Eric B et al. (2010) A stress-responsive system for mitochondrial protein degradation. Mol Cell 40:465-80
Rutter, Jared; Winge, Dennis R; Schiffman, Joshua D (2010) Succinate dehydrogenase - Assembly, regulation and role in human disease. Mitochondrion 10:393-401
Hao, Huai-Xiang; Khalimonchuk, Oleh; Schraders, Margit et al. (2009) SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325:1139-42