Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence
Autor: | Zhe Wang, Haoran Tai, Yi Ding, Ning Huang, Hui Gong, Jianqiong Qin, Zofia M.A. Chrzanowska-Lightowlers, Xiaojuan Han, Shuang Wang, Jiao Zhou, Hengyi Xiao, Xiawei Wei, Fei Gao, Rong Xiang, Xiaobo Wang, Jie Zhang |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Sequestosome-1 Protein Senescence Mitochondrion Biology medicine.disease_cause Antioxidants Mice 03 medical and health sciences Adenosine Triphosphate Autophagy medicine Animals Humans Molecular Biology Cellular Senescence chemistry.chemical_classification Reactive oxygen species Microscopy Confocal TOR Serine-Threonine Kinases Proteolytic enzymes Hydrogen Peroxide Cell Biology Basic Research Paper Acetylcysteine Mitochondria Cell biology Oxidative Stress 030104 developmental biology chemistry NIH 3T3 Cells Lysosomes Reactive Oxygen Species Flux (metabolism) Oxidative stress Signal Transduction |
Zdroj: | Autophagy. 13:99-113 |
ISSN: | 1554-8635 1554-8627 |
Popis: | 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. |
Databáze: | OpenAIRE |
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