title: Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence.
abstract: Macroautophagy/autophagy has profound implications for aging. However, the true features of autophagy in the progression of aging remain to be clarified. In the present study, we explored the status of autophagic flux during the development of cell senescence induced by oxidative stress. In this system, although autophagic structures increased, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence and the activity of lysosomal proteolytic enzymes all decreased in senescent cells, indicating impaired autophagic flux with lysosomal dysfunction. The influence of autophagy activity on senescence development was confirmed by both positive and negative autophagy modulators; and MTOR-dependent autophagy activators, rapamycin and PP242, efficiently suppressed cellular senescence through a mechanism relevant to restoring autophagic flux. By time-phased treatment of cells with the antioxidant N-acetylcysteine (NAC), the mitochondria uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and ambroxol, a reagent with the effect of enhancing lysosomal enzyme maturation, we found that mitochondrial dysfunction plays an initiating role, while lysosomal dysfunction is more directly responsible for autophagy impairment and senescence. Interestingly, the effect of rapamycin on autophagy flux is linked to its role in functional revitalization of both mitochondrial and lysosomal functions. Together, this study demonstrates that autophagy impairment is crucial for oxidative stress-induced cell senescence, thus restoring autophagy activity could be a promising way to retard senescence.
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Haoran
authors: H
authors: Tai
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Zhe
authors: Z
authors: Wang
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Hui
authors: H
authors: Gong
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Xiaojuan
authors: X
authors: Han
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Jiao
authors: J
authors: Zhou
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Xiaobo
authors: X
authors: Wang
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Xiawei
authors: X
authors: Wei
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Yi
authors: Y
authors: Ding
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Ning
authors: N
authors: Huang
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Jianqiong
authors: J
authors: Qin
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Jie
authors: J
authors: Zhang
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Shuang
authors: S
authors: Wang
authors: b Wellcome Trust Center for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne , UK.
authors: Fei
authors: F
authors: Gao
authors: b Wellcome Trust Center for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne , UK.
authors: Zofia M
authors: ZM
authors: Chrzanowska-Lightowlers
authors: c Department of Clinical Medicine , Medical School of Nankai University , Tianjin , China.
authors: Rong
authors: R
authors: Xiang
authors: a Lab for Aging Research, Center of Gerontology and Geriatrics, State Key Laboratory of Biotherapy & Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University , Chengdu , China.
authors: Hengyi
authors: H
authors: Xiao
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D001343:Autophagy; D016922:Cellular Senescence / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D041681:NIH 3T3 Cells; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D058570:TOR Serine-Threonine Kinases; D000111:Acetylcysteine
keywords: autophagy; lysosomes; mitochondria; oxidative stress; rapamycin; senescence