The mitochondrion represents a target of reactive oxygen stress and mitochondrial DNA appears to be an early and sensitive marker of this stress. Many human diseases are associated with reactive oxygen, including cancer, heart disease and neurodegenerative diseases. Mitochondria are essential organelles for generating ATP during oxidative phosphorylation. The mitochondrial DNA encodes 13 polypeptides, eleven are involved in electron transport and two serve as subunits of ATP synthase. Damage to mitochondrial DNA is repaired, but prolonged oxidant treatment results in persistent mtDNA damage, loss of mitochondrial function, increase in p21Waf1/CIP, and apoptosis. These observations suggest that mitochondrial injury, specifically DNA damage, is important for reactive oxygen- induced toxicity. We are testing the hypothesis that reactive oxygen species (ROS) generated in the mitochondria result in mtDNA damage, which in turn causes the release of more ROS (O2-?, H2O2, and OH?) that lead to further mitochondrial decline and many degenerative diseases associated with aging. We are studying this hypothesis using a murine model of Parkinsons disease in which mice are treated with MPTP, a complex I inhibitor. Future experiments will address the fate of mRNA stability in mitochondria from cells treated with ROS. Thus, one of the consequences of mitochondrial DNA damage would be the loss of transcription and subsequent alterations in the electron transport chain which could lead to further increases in ROS. - Apoptosis, ATP Synthesis, Caspase Assays, DNA Damage Repair, DNA, Recombinant DNA, Mitochondria Mitchondria, mRNA, Mitchondria, Northern Analysis Quantitative Polymerase Chain Reaction Reactive Oxygen Species

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