线粒体ROS调控线粒体分裂/融合偏移在衰老自噬抑制中的作用及机制研究

Reactive oxygen species (ROS) are closely related to aging, in which ROS could regulate aging by multiple mechanisms. Autophagy is a process of cell metabolism, clearance of damaged organelles and macromolecules, so as to achieve self -renewal. Autophagy has been demonstrated playing critical role in the anti-aging process. A large number of literatures have shown that ROS could activate autophagy. However, in our previous studies, we found that the ROS level increased significantly while the autophagy (including mitophagy) level decreased greatly with aging. This paradoxical phenomenon of high level ROS accompanied with low level autophagy, is contrary to the current knowledge of ROS inducing autophagy. We also found, in our previous study, the mitochondrial ROS induced the imbalance of mitochondrial dynamics with the increased protein levels of mitofusins (Mfns) as well as transcript factor PGC-1β. Based on these findings and the latest literatures, we bring up a hypothesis: mitochondrial ROS increase Mfns levels by regulating PGC-1β, resulting in the imbalance of mitochondrial dynamics, and finally leading to the inhibition of mitophagy (autophagy). In the present study, we will employ the natural aging models both in vivo and in vitro. The modern molecular biology techniques will be used to regulate the targeted proteins to demonstrate our hypothesis and make clear the detail molecular pathways. This study will benefit to understand the autophagy mechanism of aging, as well as the potential anti-aging strategy in the future.

活性氧（ROS）与衰老密切相关，能够通过多种机制调控衰老。自噬是细胞代谢、清除受损细胞器及大分子实现自我更新的一种过程，在抗衰老中发挥着不可或缺的重要作用。大量文献报道ROS能够激活自噬。但我们前期研究发现，衰老机体ROS水平显著升高，自噬（包括线粒体自噬）水平却显著降低。这种高水平ROS伴随着低水平自噬的矛盾现象与目前认知的ROS诱导自噬是相悖的。同时我们前期研究还发现，衰老过程中线粒体来源的ROS能够引起线粒体分裂/融合发生偏移，线粒体融合蛋白（Mfns）及上游调控因子PGC-1β表达水平显著增加。结合工作基础及进展我们提出了“线粒体ROS通过PGC-1β提高Mfns表达引起线粒体分裂/融合偏移最终抑制线粒体自噬”的科研设想。本项目拟采用细胞和动物自然衰老模型，运用现代分子生物学技术手段，证明该设想的正确并探讨其中的分子机制，对于阐明衰老的自噬机制以及潜在的抗衰老策略具有重要意义。

活性氧（ROS）与衰老密切相关，能够通过多种机制影响衰老。线粒体是ROS的最主要来源。自噬是细胞代谢、清除受损细胞器及大分子实现自我更新的一种过程，在抗衰老中发挥着不可或缺的重要作用。而线粒体自身也可以进行代谢调节，包括线粒体分裂/融合和线粒体自噬，从而调控线粒功能。因此我们猜测线粒体来源的ROS可能通过调控线粒体分裂/融合和自噬从而调控线粒体功能改善衰老。我们采用细胞和动物衰老模型和现代基因操作技术，针对线粒体关键抗氧化酶和线粒体代谢中关键靶分子进行干预，从而验证课题组提出的“线粒体ROS可能通过调控PGC-1β/Mfns进而调控自噬（线粒体自噬）和衰老”的科研设想。研究结果发现“线粒体ROS-PGC-1β/Mfns-自噬(线粒体自噬)”在衰老过程中是一个客观变化规律。调控线粒体ROS水平，能够调控PGC-1β、Mfns和自噬(线粒体自噬)，进而调控衰老。通过调控PGC-1β和Mfns可以调控线粒体分裂/融合以及自噬水平，改善线粒体ROS水平以及衰老状态。这些研究结果表明，调控线粒体ROS水平可以作为未来抗衰老的重要潜在靶点和策略，具有重要的理论和实际应用价值。