Mitochondrial DNA Repair Processes In Oxidative Stress And Aging

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Mitochondrial dysfunction is recognized as an important contributing factor for aging and age-related degeneration. We and others are investigating the relationship between nuclear DNA damage and mitochondrial dysfunction. Like the nuclear compartment, mitochondria also have a stress response. How DNA repair deficiencies contribute to altered nucleus to mitochondria signaling and mitochondrial dysfunction is being studied. Mitochondria are vital for cellular energy supply and intracellular signaling after stress. One component of that stress response is mitophagy, the clearance of dysfunctional or superfluous mitochondria. Importantly, the faithful execution of mitophagy contributes to mitochondrial DNA maintenance. Thus here, we aimed to investigate how mitophagy is regulated after acute DNA damage. Our results show that mitophagy increases after DNA damage in primary fibroblasts, murine neurons and Caenorhabditis elegans neurons. Further we showed that modulation of mitophagy after DNA damage is independent of the type of DNA damage stimuli used and that the protein Spata18 is an important player in this process. Knockdown of Spata18, a p53 regulated protein, suppresses mitophagy, disturbs mitochondrial Ca2+ homeostasis, affects ATP production, and attenuates DNA repair. Importantly, mitophagy after DNA damage is a vital cellular response to maintain mitochondrial functions and DNA repair. In other studies, we are continuing to investigate mitochondrial DNA repair proteins and their regulation. Additionally, we are investigating the regulation of mitophagy in various disease states.