This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Epidemiological studies have linked exposure to environmental factors such as pesticides and heavy metals to increased risk of neurodegenerative disorders, cancer and overall mortality. Although there is considerable data in support of the contention that mitochondrial dysfunction and damage play an important part in these processes, there is little information about the role of environmental factors in mitochondrial damage, underlying molecular mechanisms, and correlation with disease development and progression. Numerous studies have demonstrated that in most of the cases either reactive oxygen species (ROS) generation or the response to oxidative stress is aberrant. We hypothesize that even minor change in mitochondrial function may lead to an imbalance in electron transport, formation of reactive oxygen species and oxidative stress. In response, a small number of """"""""stressor specific"""""""" molecules are altered in either concentration or structure, resulting in activation of a specific stress defense response that prevents irreversible damage and cellular malfunction. These changes affect primarily mitochondrial proteins and lipid composition of mitochondrial membranes, and can be used as potential biomarkers of mitochondrial dysfunction. Our approach will exploit cutting-edge metabolomic and proteomic technologies in tractable yeast and cell culture models to provide broader system-level analyses of the effects of environmental stressors on mitochondrial function. Understanding these effects will provide critical new insight into the molecular mechanisms associated with their toxicities. The knowledge gained in the yeast and cell culture systems will be extended to and validated in a mammalian (rodent) model. The overall goal of this proposal is to develop and define biomarkers of mitochondrial dysfunction resulting from various environmental stressors. Our objective is to identify biomarkers of protein oxidation using various environmental stressors and well-characterized model systems that enable us to precisely and reproducibly monitor the effects of protein oxidation and alternation over time.
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