Bronchial epithelial SIRT1 deficiency exacerbates cigarette smoke induced emphysema in mice through the FOXO3/PINK1 pathway

Abstract

Purpose: Cellular senescence and mitochondrial fragmentation are thought to be crucial components of the cigarette smoke(CS)-induced responses that contribute to the chronic obstructive pulmonary disease (COPD) development as a result of accelerated premature aging of the lung. Although there have been a few reports on the role of sirtuin 1(SIRT1) in mitochondrial homeostasis, senescence and inflammation, whether SIRT1/FOXO3/PINK1 signaling mediated mitophagy ameliorates cellular senescence in COPD is still unclear. This study aimed to ascertain whether SIRT1 regulates cellular senescence via FOXO3/PINK1-mediated mitophagy in COPD. Methods: To investigate the effect of CS exposure and SIRT1 deficiency on mitophagy and senescence in the lung, a SIRT1 knockout(KO) mouse model was used. Airway resistance, cellular senescence mitochondrial injury, mitophagy, cellular architecture and protein expression levels in lung tissues, from SIRT1 KO and wild-type(WT) COPD model mice exposed to CS for 6 months were examined by western blotting, histochemistry, immunofluorescence and transmission electron microscopy(TEM). Results: In CS exposed mice, SIRT1 deficiency exacerbated airway resistance and cellular senescence, increased FOXO3 acetylation and decreased PINK1 protein levels and attenuated mitophagy. Mechanistically, the damaging effect of SIRT1 deficiency on lung tissue was attributed to increased FOXO3 acetylation and decreased PINK1 levels, and attenuated mitophagy. In vitro, mitochondrial damage and cellular sensitivity in response to CS exposure were more severe in control cells than in cells treated with aSIRT1 activator. SIRT1 activation SIRT1 activation decreased FOXO3 acetylation and increased the protein levels of PINK1 and enhanced mitophagy. Conclusion: These results demonstrated that the detrimental effects of SIRT1 deficiency on cell senescence associated with insufficient mitophagy, and involved the FOXO3/PINK1 signaling pathway.

Keywords:

• COPD
• FOXO3
• mitophagy
• PINK1
• SIRT1

Acknowledgments

We thank Professor Yaqing Li for his guidance on the writing of this paper.

Declarations of interest

The authors declare that they have no competing interests.

Ethics approval and consent to participate

All animal experiments were approved by the Experimental Animal Ethics Committee of Hangzhou medical college and performed in accordance with the guidelines for the care and use of laboratory animals set by Zhejiang Industry University (Hangzhou, China).

Data availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Additional information

Funding

This work was funded by the National Natural Science Foundation of China (No. 8187010048).

Notes on contributors

Hui Jiang

DY and YJ conceived of the study. HJ and YL participated in design of the study and performed the experiments. HJ carried out the statistical analysis. DY helped in the interpretation of the data and coordination and drafted the manuscript. All authors read and approved the final manuscript.