跨组织线粒体应激信号交流调控机体衰老研究进展

Inter-tissue communication of mitochondrial stress in aging

线粒体内蛋白质稳态的平衡对于细胞正常的生理功能非常关键。线粒体蛋白稳态失衡时,细胞会启动应激反应机制,即线粒体未折叠蛋白反应(mitochondrial unfolded protein response,UPR^(mt)),修复线粒体功能,平衡细胞内稳态。尽管线粒体的严重损伤对机体是有害的,但在线虫(Caenorhabditis elegans)、果蝇(Drosophila melanogaste)及小鼠(Mus musculus)中都有研究表明线粒体的轻微损伤可以通过激活UPR^(mt),促进寿命延长。有趣的是,在没有直接经历线粒体损伤的细胞或组织中,UPR^(mt)也能以非自主方式被诱导。不同组织间可以通过名为“mitokine”的细胞因子进行UPR^(mt)的跨组织调控,系统性地协调机体整体的压力适应能力和抗衰老能力。该调控机制与衰老相关神经退行性疾病、癌症等多种疾病密切相关,近年来有关研究与日俱增。本文系统总结了线粒体应激及其组织间通讯的机制,并介绍了跨组织线粒体应激交流信号“mitokine”调控衰老进程的最新研究进展,以期为跨组织信号调控和机体衰老等研究提供参考。

The protein homeostasis in mitochondria is critical for the normal physiological function of cells.To cope with mitochondrial stress,cells elicit specific stress response named mitochondrial unfolded protein response(UPR^(mt)),to maintain mitochondrial homeostasis and repair mitochondrial function.Although severe damage to mitochondria is detrimental,studies in worms,flies,and mice have shown that mild mitochondrial damage promotes longevity by activating UPR^(mt).Interestingly,UPR^(mt) can also be induced in a cell non-autonomous manner in cells or tissues which are not directly experiencing mitochondrial stress.The secreted molecules called“mitokine”are responsible for the mitochondrial stress communication between different tissues.This inter-tissue regulation of mitochondrial stress response systematically coordinates the adaptation ability which is closely associated with aging and a variety of diseases such as neurodegeneration and cancer.In this review,we summarize recent advances about inter-tissue mitochondrial stress communications,and introduce the current knowledge about the“mitokine”and its regulation on aging for further studies.