For the past 22 years, our """"""""Mitochondria! Inborn Errors of Metabolism"""""""" research project has been testing the hypothesis that: Genetic variants in the mitochondrial genome play an important role in the etiology of human disease. This research has resulted in the identification of the first inherited mitochondrial DMA (mtDNA) disease;characterization of the regional human mtDNA population variation throughout the World;demonstration that a subset of this variation has been adaptive and influences disease predisposition today;indicated that the accumulation of somatic mtDNA mutations may be the aging clock;shown that mtDNA mutations are important in cancer;developed the first mouse models for nuclear DNA (nDNA) and mtDNA mitochondrial disease;and demonstrated the importance of mitochondrial energy production, reactive oxygen species generation (ROS), and initiation of apoptosis in the pathophysiology of mitochondrial disease. These observations have led to the corollary hypothesis that: The pathophysiology of mitochondrial disease results from the interplay between energy deficiency, ROS production and altered redox state, and their effects on cell growth and apoptosis in tissues and organs. In the current resubmission, we propose to continue to investigate this pathophysiological hypothesis of mitochondrial disease through three experimental comparisons. First, we will create and compare mice with a severe versus mild oxidative phosphorylaton (OXPHOS) defects by introducing mutations into the nDNA- encoded subunit genes of respiratory complex I. Second, we will create and compare mice with different severity mtDNA mutations at different levels of heteroplasmy. Third, we will compare mice that are heteroplasmic for two """"""""normal"""""""" mtDNAs (NZB versus 129) with mice that are homoplasmic for the 129 mtDNA, both on a B6 nDNA background. We have already discovered that the heteroplasmic mice have a reduced fecundity, reduced life span, increased cancer rate, and increased mtDNA mutation and recombination rates. Since no deleterious mtDNA mutation has been introduced into these heteroplasmic mice, the pathological consequences of the heteroplasmy would appear to have a physiological basis. For each set of experiments we will compare mitochondrial energy output, ROS production, and redox status, and examine tissue and organ cell loss and/or neoplastic transformation. We predict that severe mitochondrial defects will cause acute neonatal disease primarily do to energetic failure, while mild chronic OXPHOS defects will result in delayed-onset degenerative disease and/or cancer primarily as a consequence of increased ROS production and altered cellular redox signaling.
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