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 had previously confirmed this hypothesis using a murine model of Parkinson's disease in which mice are treated with MPTP, a complex I inhibitor. We are continuing these experiments using 3-nitropropionic acid, a complex II inhibitor which produces brain lesions in rodents similar to those observed with Huntington's Disease. We are also examing the role of mitochondrial iron as a partner in Fenton-chemistry-induced mtDNA damage using two different approaches described in more detail below: frataxin mutations in yeast and telomerase expression in human cells
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