Mitochondrial DNA Repair Processes In Oxidative Stress And Aging

线粒体功能障碍被认为是衰老和年龄相关变性的重要因素。我们和其他人正在研究核DNA损伤和线粒体功能障碍之间的关系。我们发现某些神经退行性DNA修复疾病，如Cockayne综合征、着色性干皮病A组（XPA）和共济失调毛细血管扩张症（A- t）具有线粒体表型，其特征是线粒体膜电位增加、活性氧产生增加和线粒体自噬减少，线粒体自噬是异常线粒体的降解途径。这种线粒体应激反应似乎是由PARP1的持续激活引发的，导致细胞NAD+水平降低。线粒体异常也与NAD+- sirt1 - pgc - α轴的抑制相关。parp、parp修饰的靶蛋白和辅助因子NAD+在细胞核到线粒体的信号级联反应中起关键作用，这与线粒体功能障碍有关。我们发现，在各种实验系统和物种中，这些线粒体表型可以被PARP1抑制剂或NAD+前体部分拯救，这表明了一种进化保守的机制。我们正在寻求核线粒体信号网络的药理学调节，我们相信这将是预防和治疗年龄相关疾病的一种有前途的新方法。目前的研究表明，抑制PARP1，激活SIRT1或使用NAD+前体如烟酰胺核苷或烟酰胺单核苷酸恢复NAD+，都能使线粒体表型正常化。

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.