Over the past ten years the molecular genetic basis of several rare mitochondrial DNA (mtDNA) disorders has been elucidated. However, the role of mtDNA damage and repair in common diseases remains largely unknown. Lung mtDNA may be at great risk as a result of the oxidative environment during oxygen metabolism and during application of therapeutic interventions such as breathing high oxygen concentrations. The partial reduction of oxygen to reactive species in combination with a newly described biochemistry involving nitrogen centered reactive species may occur in close proximity to mtDNA. Published data indicated that hyperoxia results in mitochondrial morphologic changes in lung endothelium and epithelium. The observed morphologic charges correlate with alterations in biochemical and metabolic function of the mitochondria. However, the effect of hyperoxia on lung mtDNA is virtually unexplored. Therefore, the major goal of this application is to determine the mechanisms of oxidative modification of lung mtDNA by reactive species. The proposed studies will establish the role of mtDNA damage and repair in lung cellular mitochondrial function and will be extended to examine the consequences on lung mtDNA after exposure to hyperoxia and hyperoxia with therapeutic levels of nitric oxide. Mitochondrial DNA damage will be determined and quantified by several end-point assays and will be correlated with mitochondrial function. Overall, the studies proposed in this application will establish mechanisms of oxidative mtDNA damage and determine whether mtDNA damage is part of the pathogenic mechanism of hyperoxic lung injury.
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