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DNA Repair & Mitochondrial Damage Group
Figure 4: hTERT targeted to the mitochondria by an N-terminal leader sequence impacting the mtDNA after oxidative stress.
The mitochondrion (Figure 4) represents a target of reactive oxygen and mitochondrial DNA (mtDNA) 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 mtDNA encodes 13 polypeptides, 11 involved in electron transport and two serving as subunits of ATP synthase. Damage to mtDNA is repaired, but prolonged oxidant treatment results in persistent mtDNA damage, loss of mitochondrial function and apoptosis. These observations suggest that mtDNA damage is important in the toxicity induced by reactive oxygen species (ROS) such as superoxide, hydrogen peroxide and the hydroxyl radical. The group is testing the hypothesis that ROS generated in the mitochondria result in mtDNA damage, which in turn causes the release of more ROS that lead to further mitochondrial decline and many degenerative diseases associated with aging. The group is currently analyzing how mitochondria repair DNA double strand breaks using cellular extracts and in vivo models. |
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