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

基本信息

批准号：
8089250
负责人：
JIN WANG
金额：
$ 19.81万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-12-31
项目状态：
已结题

项目摘要

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（由申请人提供）：自噬已成为肿瘤抑制的新机制。据推测，自噬有缺陷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性和癌症。我们已经观察到，损失线粒体膜电位的线粒体的选择性自噬所必需的Bcl-2家族成员NIX是必需的。功能失调的线粒体会产生活性氧，从而引起DNA损伤。但是，尚不清楚选择性线粒体自噬是否对于防止损害线粒体和核DNA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关键作用。由于自噬缺陷引起的线粒体功能障碍的积累可能会导致DNA损伤增加，从而导致基因组不稳定性。我们建议1）确定线粒体自噬在保护基因组稳定性方面的作用； 2）表征自噬体对线粒体功能障碍线粒体的特异性识别的分子机制。这项研究可能有助于揭示自噬的分子事件，作为保护基因组不稳定性和癌症的线粒体质量控制的新生物标志物。公共卫生相关性：叙事本研究旨在将自噬中的分子事件确定为线粒体质量控制和预防基因组不稳定性的新生物标志物。