Cigarette smoke (CS)-induced accumulation of mitochondrial damage has been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Mitophagy plays a crucial role in eliminating damaged mitochondria, and is governed by the PINK1 (PTEN induced putative protein kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway. Although both increased PINK1 and reduced PRKN have been implicated in COPD pathogenesis in association with mitophagy, there are conflicting reports for the role of mitophagy in COPD progression. To clarify the involvement of PRKN-regulated mitophagy in COPD pathogenesis, prkn knockout (KO) mouse models were used. To illuminate how PINK1 and PRKN regulate mitophagy in relation to CS-induced mitochondrial damage and cellular senescence, overexpression and knockdown experiments were performed in airway epithelial cells (AEC). In comparison to wild-type mice, prkn KO mice demonstrated enhanced airway wall thickening with emphysematous changes following CS exposure. AEC in CS-exposed prkn KO mice showed accumulation of damaged mitochondria and increased oxidative modifications accompanied by accelerated cellular senescence. In vitro experiments showed PRKN overexpression was sufficient to induce mitophagy during CSE exposure even in the setting of reduced PINK1 protein levels, resulting in attenuation of mitochondrial ROS production and cellular senescence. Conversely PINK1 overexpression failed to recover impaired mitophagy caused by PRKN knockdown, indicating that PRKN protein levels can be the rate-limiting factor in PINK1-PRKN-mediated mitophagy during CSE exposure. These results suggest that PRKN levels may play a pivotal role in COPD pathogenesis by regulating mitophagy, suggesting that PRKN induction could mitigate the progression of COPD. Abbreviations: AD: Alzheimer disease; AEC: airway epithelial cells; BALF: bronchoalveolar lavage fluid; AKT: AKT serine/threonine kinase; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; COPD: chronic obstructive pulmonary disease; CS: cigarette smoke; CSE: CS extract; CXCL1: C-X-C motif chemokine ligand 1; CXCL8: C-X-C motif chemokine ligand 8; HBEC: human bronchial epithelial cells; 4-HNE: 4-hydroxynonenal; IL: interleukin; KO: knockout; LF: lung fibroblasts; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; 8-OHdG: 8-hydroxy-2'-deoxyguanosine; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PCD: programmed cell death; PFD: pirfenidone; PIK3C: phosphatidylinositol-4:5-bisphosphate 3-kinase catalytic subunit; PINK1: PTEN induced putative kinase 1; PTEN: phosphatase and tensin homolog; RA: rheumatoid arthritis; ROS: reactive oxygen species; SA-GLB1/β-Gal: senescence-associated-galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SNP: single nucleotide polymorphism; TNF: tumor necrosis factor.

中文翻译：

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慢性阻塞性肺病发病过程中PRKN调节的细胞吞噬作用和细胞衰老。

香烟烟雾（CS）引起的线粒体损伤累积已广泛涉及慢性阻塞性肺疾病（COPD）发病机理。线粒体在消除受损的线粒体中起着关键作用，并受PINK1（PTEN诱导的假定蛋白激酶1）-PRKN（帕金丁RBR E3泛素蛋白连接酶）途径的控制。尽管PINK1的增加和PRKN的减少均与线粒体吞噬有关，但与COPD发病有关，但关于线粒体吞噬在COPD进展中的作用有相互矛盾的报道。为了阐明PRKN调控的线粒体在COPD发病机理中的作用，使用了prkn基因敲除（KO）小鼠模型。为了阐明PINK1和PRKN如何调节CS诱导的线粒体损伤和细胞衰老相关的线粒体吞噬，在气道上皮细胞（AEC）中进行过表达和敲低实验。与野生型小鼠相比，prkn KO小鼠在CS暴露后表现出气管壁增厚，气肿改变。暴露于CS的prkn KO小鼠中的AEC显示出受损的线粒体积聚并伴随着加速的细胞衰老而增加了氧化修饰。体外实验表明，即使在PINK1蛋白水平降低的情况下，PRKN过表达也足以诱导CSE暴露期间的线粒体吞噬，从而导致线粒体ROS产生和细胞衰老的减弱。相反，PINK1过表达未能恢复由PRKN敲低引起的受损的自噬，这表明在CSE暴露期间PRKN蛋白水平可能是PINK1-PRKN介导的自噬的速率限制因素。这些结果表明，PRKN水平可能通过调节线粒体在COPD发病中起关键作用，表明PRKN的诱导可以减轻COPD的进展。缩写：AD：阿尔茨海默氏病；AEC：气道上皮细胞；BALF：支气管肺泡灌洗液；AKT：AKT丝氨酸/苏氨酸激酶；CALCOCO2 / NDP52：钙结合和卷曲螺旋结构域2；CDKN1A：细胞周期蛋白依赖性激酶抑制剂1A；CDKN2A：细胞周期蛋白依赖性激酶抑制剂2A；COPD：慢性阻塞性肺疾病；CS：香烟烟雾；CSE：CS提取物；CXCL1：CXC基序趋化因子配体1；CXCL8：CXC基序趋化因子配体8；HBEC：人支气管上皮细胞；4-HNE：4-羟基壬烯; IL：白介素；KO：淘汰赛；LF：肺成纤维细胞；LPS：脂多糖；MAP1LC3 / LC3：微管相关蛋白1轻链3；MTOR：雷帕霉素激酶的机械靶 8-OHdG：8-羟基-2'-脱氧鸟苷；OPTN：optineurin；PRKN：parkin RBR E3泛素蛋白连接酶；PCD：程序性细胞死亡；PFD：吡非尼酮；PIK3C：磷脂酰肌醇-4：5-双磷酸3-激酶催化亚基；PINK1：PTEN诱导推定激酶1；PTEN：磷酸酶和张力蛋白同源物；RA：类风湿关节炎；ROS：活性氧；SA-GLB1 /β-Gal：衰老相关的半乳糖苷酶，β1；SASP：与衰老相关的分泌表型；SNP：单核苷酸多态性；TNF：肿瘤坏死因子。磷酸酶和张力蛋白同源物；RA：类风湿关节炎；ROS：活性氧；SA-GLB1 /β-Gal：衰老相关的半乳糖苷酶，β1；SASP：与衰老相关的分泌表型；SNP：单核苷酸多态性；TNF：肿瘤坏死因子。磷酸酶和张力蛋白同源物；RA：类风湿关节炎；ROS：活性氧；SA-GLB1 /β-Gal：衰老相关的半乳糖苷酶，β1；SASP：与衰老相关的分泌表型；SNP：单核苷酸多态性；TNF：肿瘤坏死因子。