SELECTIVE MITOCHONDRIAL AUTOPHAGY IN THE MAINTENANCE OF GENOME STABILITY

描述（由申请人提供）：自噬已成为肿瘤抑制的一种新机制。据推测，有缺陷的自噬导致受损蛋白质或细胞器的积累，导致基因组不稳定和癌症。我们已经观察到Bcl-2家族成员Nix是已经失去线粒体膜电位的线粒体的选择性自噬所必需的。功能失调的线粒体可产生活性氧，导致DNA损伤。然而，目前还不清楚选择性线粒体自噬是否对防止线粒体和核DNA损伤很重要。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。由于有缺陷的自噬而导致的功能失调的线粒体的积累可能导致DNA损伤的增加，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）表征自噬体特异性识别功能障碍线粒体的分子机制。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，以防止基因组不稳定和癌症。 公共卫生相关性：本研究旨在确定自噬中的分子事件作为线粒体质量控制和预防基因组不稳定性的新型生物标志物。

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.