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. We find that certain DNA repair disorders with neurodegeneration like Cockayne Syndrome, Xeroderma pigmentosum group A (XPA) and Ataxia Telangiectasia (A-T) have a mitochondrial phenotype characterized by increased mitochondrial membrane potential, increased reactive oxygen species generation and decreased mitophagy, the degradation pathway for abnormal mitochondria. This mitochondrial stress response appears to be initiated by persistent activation of PARP1 leading to diminished cellular NAD+ levels. The mitochondrial abnormalities also correlate with inhibition of the NAD+-SIRT1-PGC-alpha axis. PARPs, the target proteins they PARylate, and the cofactor NAD+ play critical roles in the nucleus to mitochondria signaling cascade, which is linked to mitochondrial dysfunction. We showed that these mitochondrial phenotypes can be partially rescued by PARP1 inhibitors or NAD+ precursors in various experimental systems and species, suggesting an evolutionarily conserved mechanism. We are pursuing pharmacological modulation of the nuclear-mitochondrial signaling network which we believe will be a promising novel approach for the prevention and treatment of age-associated diseases. Current research shows that inhibition of PARP1, activation of SIRT1 or restoration of NAD+ using NAD+ precursors like nicotinamide riboside or nicotinamide mononucleotide, all normalize mitochondrial phenotypes. Aprataxin (APTX) is an enzyme in the base excision repair (BER) pathway that removes 5AMP groups from DNA ends. These adducts are created as a result of abortive ligation or base modifications. People with mutations in APTX develop ataxia with oculomotor apraxia type 1 (AOA1) and it is a progressive spinocerebellar ataxia. APTX functions in both nuclear and mitochondrial DNA stability, however, mitochondrial function has not been well characterized in AOA1 cells. We found that APTX deficiency impairs mitochondrial morphology, network formation, and mitophagy. Thus, we surveyed genes that modulate mitochondrial morphology and found that OPA1 expression was impaired in APTX-deficient cells. This works strengthens the associations between defective DNA repair and mitochondrial alterations and further corroborates that mitochondrial dysfunction is a characteristic of an increasing number of genetically diverse neurodegenerative disorders.