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Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence

Lookup NU author(s): Dr Fei Gao, Professor Zofia Chrzanowska-Lightowlers

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


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.


Publication metadata

Author(s): Tai HR, Wang Z, Gong H, Han XJ, Zhou J, Wang XB, Wei XW, Ding Y, Huang N, Qin JQ, Zhang J, Wang S, Gao F, Chrzanowska-Lightowlers ZM, Xiang R, Xiao HY

Publication type: Article

Publication status: Published

Journal: Autophagy

Year: 2017

Volume: 13

Issue: 1

Pages: 99-113

Print publication date: 01/01/2017

Online publication date: 28/10/2016

Acceptance date: 06/10/2016

ISSN (print): 1554-8627

ISSN (electronic): 1554-8635

Publisher: Taylor & Francis

URL: https://doi.org/10.1080/15548627.2016.1247143

DOI: 10.1080/15548627.2016.1247143


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