Mitochondrial DNA Repair Processes In Oxidative Stress And Aging

氧化应激和衰老中的线粒体 DNA 修复过程

• 批准号: 10471691
• 负责人: Vilhelm A Bohr
• 金额: $ 62.25万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471691
• 关键词: Aging; Bioenergetics; Cell Death; Cell Nucleus; DNA Damage; DNA Polymerase beta; DNA Repair; DNA Repair Disorder; Electron Transport; Failure; Health; Individual; Investigation; Lead; Mitochondria; Mitochondrial DNA; Morphology; Mutation; Nuclear; Nucleotides; Oxidative Stress; Polymerase; Process; Reactive Oxygen Species; Reporting; Signal Transduction; System; age related; biological adaptation to stress; improved; mitochondrial dysfunction; oxidative DNA damage; oxidative damage

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 have their own DNA repair and stress response systems. Previously, we reported the unexpected finding that DNA polymerase Beta (PolB) was present in mitochondria and could contribute to DNA repair in that compartment. Upon further investigation, we compared PolB and Polymerase Gamma (PolG), the replicative polymerase for mitochondrial DNA, on DNA repair substrates and intermediates. We reported that DNA PolB was more proficient at single-nucleotide gap filling and extracts lacking PolB are severely deficient in processing BER intermediates. Moving forward, we are investigating how DNA repair deficiencies contributes to altered nucleus-to-mitochondria signaling and mitochondrial dysfunction is being studied.

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，线粒体有自己的DNA修复和应激反应系统。 此前，我们报道了一个意想不到的发现，即DNA聚合酶β（PolB）存在于线粒体中，并可能有助于该隔室中的DNA修复。在进一步的研究中，我们比较了PolB和聚合酶γ（PolG），线粒体DNA的复制聚合酶，DNA修复底物和中间体。我们报告说DNA PolB更擅长单核苷酸缺口填充，而缺乏PolB的提取物在处理BER中间体方面严重不足。展望未来，我们正在研究DNA修复缺陷如何导致细胞核与线粒体信号传导的改变，并且正在研究线粒体功能障碍。