SELECTIVE MITOCHONDRIAL AUTOPHAGY IN THE MAINTENANCE OF GENOME STABILITY

选择性线粒体自噬维持基因组稳定性

• 批准号: 7963177
• 负责人: JIN WANG
• 金额: $ 17.02万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7963177
• 关键词: Autophagocytosis; Autophagosome; Biological Markers; Candidate Disease Gene; Cells; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; Event; Family member; Gene Mutation; Genes; Genome Stability; Genomic Instability; Impairment; Iron; Lead; Libraries; Maintenance; Malignant Neoplasms; Membrane Potentials; Mitochondria; Mitochondrial DNA; Modality; Molecular; Mus; Nuclear; Nucleotides; Organelles; Play; Prevention; Production; Proteins; Proteomics; Quality Control; RNA Interference; Reactive Oxygen Species; Role; Screening procedure; Sulfur; Testing; Tissues; Tumor Suppression; erythroid differentiation; insight; mitochondrial autophagy; mitochondrial dysfunction; mitochondrial membrane; novel; prevent; public health relevance; therapeutic development; tumorigenesis

DESCRIPTION (provided by applicant): Autophagy has emerged as a novel mechanism for tumor suppression. It has been postulated that defective autophagy leads to the accumulation of damaged proteins or organelles, resulting in genome instability and cancer. We have observed that a Bcl-2 family member, Nix, is required for selective autophagy of mitochondria that have lost mitochondrial membrane potential. Dysfunctional mitochondria can produce reactive oxygen species to cause DNA damage. However, it is unclear whether selective mitochondrial autophagy is important for preventing damages to mitochondrial and nuclear DNA. We hypothesize that selective mitochondrial autophagy plays a critical role in mitochondrial quality control. Accumulation of dysfunctional mitochondria due to defective autophagy may cause increases in DNA damage, leading to genome instability. We propose 1) to determine the role for mitochondrial autophagy in protecting genome stability; 2) to characterize the molecular mechanisms of specific recognition of dysfunctional mitochondria by autophagosomes. This study may help to reveal molecular events of autophagy as novel biomarkers for mitochondrial quality control in the protection against genome instability and cancer. PUBLIC HEALTH RELEVANCE: Narrative This study seeks to identify the molecular events in autophagy as novel biomarkers in mitochondrial quality control and the prevention of genome instability.

描述（申请人提供）：自噬已成为一种新的肿瘤抑制机制。据推测，有缺陷的自噬会导致受损蛋白质或细胞器的积累，从而导致基因组不稳定和癌症。我们观察到Bcl-2家族成员Nix是失去线粒体膜电位的线粒体选择性自噬所必需的。功能失调的线粒体可以产生活性氧导致DNA损伤。然而，选择性线粒体自噬对于防止线粒体和核DNA损伤是否重要尚不清楚。我们假设选择性线粒体自噬在线粒体质量控制中起着关键作用。由于自噬缺陷引起的功能失调线粒体的积累可能导致DNA损伤增加，从而导致基因组不稳定。我们建议1)确定线粒体自噬在保护基因组稳定性中的作用；2)研究自噬体特异性识别功能异常线粒体的分子机制。这项研究可能有助于揭示自噬的分子事件作为线粒体质量控制的新生物标志物，在防止基因组不稳定和癌症方面发挥作用。