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性退化的重要促成因素。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。 像核隔室一样，线粒体也有应激反应。目前正在研究DNA修复缺陷如何改变细胞核到线粒体的信号传导和线粒体功能障碍。 线粒体在应激后的细胞能量供应和细胞内信号转导中至关重要。这种应激反应的一个组成部分是线粒体自噬，即清除功能失调或多余的线粒体。重要的是，线粒体自噬的忠实执行有助于线粒体DNA的维持。因此，在这里，我们的目的是研究如何线粒体自噬是在急性DNA损伤后调节。我们的研究结果表明，原代成纤维细胞，小鼠神经元和秀丽隐杆线虫神经元的DNA损伤后，线粒体自噬增加。此外，我们表明，DNA损伤后的线粒体自噬的调制是独立的DNA损伤刺激的类型，蛋白Spata 18是在这个过程中的重要球员。Spata 18是一种p53调节蛋白，其敲低可抑制线粒体自噬，扰乱线粒体Ca 2+稳态，影响ATP产生，并减弱DNA修复。重要的是，DNA损伤后的线粒体自噬是维持线粒体功能和DNA修复的重要细胞反应。 在其他研究中，我们正在继续研究线粒体DNA修复蛋白及其调控。此外，我们正在研究各种疾病状态下线粒体自噬的调节。

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.