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Autophagy. 2017 Jan 2;13(1):99-113. doi: 10.1080/15548627.2016.1247143. Epub 2016 Oct 28.

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

Author information

1
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.
2
b Wellcome Trust Center for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne , UK.
3
c Department of Clinical Medicine , Medical School of Nankai University , Tianjin , China.

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.

KEYWORDS:

autophagy; lysosomes; mitochondria; oxidative stress; rapamycin; senescence

PMID:
27791464
PMCID:
PMC5240829
DOI:
10.1080/15548627.2016.1247143
[Indexed for MEDLINE]
Free PMC Article

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