Jiang Hui, Jiang Yaona, Xu Yuanri, Yuan Dong, Li Yaqing
Department of Clinical Medicine, Medical College of Soochow University, Suzhou, Jiangsu, China.
Department of Internal Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.
Exp Lung Res. 2022 Feb 8:1-16. doi: 10.1080/01902148.2022.2037169.
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. : 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). : 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. : These results demonstrated that the detrimental effects of SIRT1 deficiency on cell senescence associated with insufficient mitophagy, and involved the FOXO3/PINK1 signaling pathway.
细胞衰老和线粒体碎片化被认为是香烟烟雾（CS）诱导反应的关键组成部分，由于肺部加速过早衰老，这些反应会导致慢性阻塞性肺疾病（COPD）的发展。尽管已有一些关于沉默调节蛋白1（SIRT1）在线粒体稳态、衰老和炎症中作用的报道，但SIRT1/FOXO3/PINK1信号介导的线粒体自噬是否能改善COPD中的细胞衰老仍不清楚。本研究旨在确定SIRT1是否通过FOXO3/PINK1介导的线粒体自噬在COPD中调节细胞衰老。：为了研究CS暴露和SIRT1缺乏对肺中线粒体自噬和衰老的影响，使用了SIRT1基因敲除（KO）小鼠模型。通过蛋白质印迹、组织化学、免疫荧光和透射电子显微镜（TEM）检查了暴露于CS 6个月的SIRT1 KO和野生型（WT）COPD模型小鼠肺组织中的气道阻力、细胞衰老、线粒体损伤、线粒体自噬、细胞结构和蛋白质表达水平。：在暴露于CS的小鼠中，SIRT1缺乏加剧了气道阻力和细胞衰老，增加了FOXO3乙酰化，降低了PINK1蛋白水平，并减弱了线粒体自噬。从机制上讲，SIRT1缺乏对肺组织的损害作用归因于FOXO3乙酰化增加、PINK1水平降低以及线粒体自噬减弱。在体外，对照细胞对CS暴露的线粒体损伤和细胞敏感性比用SIRT1激活剂处理的细胞更严重。SIRT1激活降低了FOXO3乙酰化，增加了PINK1蛋白水平，并增强了线粒体自噬。：这些结果表明，SIRT1缺乏对与线粒体自噬不足相关的细胞衰老具有有害影响，并且涉及FOXO3/PINK1信号通路。
