Mitochondrial Anti-Oxidant Factors and Redox Status

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DESCRIPTION (provided by applicant) Oxidative stress presents a danger to the cell in the form of reactive oxygen species (ROS) that can damage cellular components. ROS can be generated by environmental sources such as hyperoxia and redox-active chemicals, as well as by endogenous sources such as enzymatic redox reactions. Most of the ROS in the eukaryotic cell is generated in the mitochondrion, an essential organelle involved in diverse cellular functions. Given its vital role in the cell, along with its potential to generate damaging molecules, it is not surprising that mitochondrial defects are associated with a variety of neurodegenerative diseases, aging, and cancer. However, the mechanisms for combating oxidative damage in this organelle are poorly understood. It is therefore critical to identify anti-oxidant systems that specifically function to alleviate oxidative stress in mitochondria and to examine their connection with cytosolic systems. Using the yeast Saccharomyces cerevisiae as a model system, these issues will be addressed by characterizing mitochondrial anti-oxidant systems and uncovering the mechanisms for maintaining mitochondrial versus cytosolic redox balance. Initial results have indicated that the anti-oxidant factor glutathione reductase is targeted to both the mitochondria and the cytosol by an alternative translation mechanism. Future studies will address whether this dual localization mechanism dictates the distribution of two other anti-oxidant factors, a glutaredoxin and a methionine sulfoxide reductase (aim 1). The function of these two proteins in the mitochondria and/or the cytosol will be addressed by examining the physiological effects of altered expression of these proteins (aim 2). Finally, the role these anti-oxidant factors play in maintaining redox balance in the mitochondria versus the cytosol will be determined by monitoring the oxidation state of key redox cofactors and assessing markers of oxidative damage (aim 3). Overall, these studies will address how mitochondria maintain redox balance in the face of endogenous stresses and environmental insults.