Since our initial demonstration that mitochondrial DNA (mtDNA) mutations can result in Type II diabetes, considerable evidence has accumulated supporting the hypothesis that Type II diabetes is the product of inherited partial mitochondrial oxidative phosphorylation (OXPHOS) deficiency which inhibitsthe mitochondrial metabolism of calories and increases mitochondrial production of reactive oxygen species (ROS). The oxidative stress form the ROS further erodes mitochondrial function in both target tissues and in pancreatic p cells, leading to insulin resistance, loss of insulin secretion, and (3 cells apoptosis. To further clarify the role of mtDNA mutations in Type II diabetes, we propose to identify the inherited mtDNA mutations causing diabetes in a number of maternally inherited diabetes pedigrees. We will then use the cybrid transfer technique to place these mutations onto hepatic and pancreatic cell nuclear backgrounds and then the characterize these cybrid cell lines for the biochemical defects assoiated with the mtDNA mutations. These same cell lines with then be treated with metallopophyrin superoxide dismutase (SOD) mimetics to determine with these catalytic antioxidants can reduce ameliorate the biochemical defect caused by the mtDNA mutation. In addition, we will study mice with inherited defects in mitochondrial antioxidant defenses (Sod2) and in OXPHOS ATP production (Antl &Ant2) to correlate the development of diabetes with the age-related decline in mitochondrial function and the accumulation of somatic mtDNA mutations in both insulin target and insulin secreting tissues. These mice will also be treated with the metalloporphyrinmimetics to determine if these drugs will then delay the development of the symptoms and the accumulation of the somatic mtDNA mutations.
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