title: Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease.
abstract: Cigarette smoke (CS)-induced cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The molecular mechanism by which CS induces cellular senescence is unknown. Here, we show that CS stress (exposure of primary lung cells to CS extract 0.2-0.75% with a half-maximal inhibitory concentration of ∼0.5%) led to impaired mitophagy and perinuclear accumulation of damaged mitochondria associated with cellular senescence in both human lung fibroblasts and small airway epithelial cells (SAECs). Impaired mitophagy was attributed to reduced Parkin translocation to damaged mitochondria, which was due to CS-induced cytoplasmic p53 accumulation and its interaction with Parkin. Impaired Parkin translocation to damaged mitochondria was also observed in mouse lungs with emphysema (6 months CS exposure, 100 mg TPM/m(3)) as well as in lungs of chronic smokers and patients with COPD. Primary SAECs from patients with COPD also exhibited impaired mitophagy and increased cellular senescence via suborganellar signaling. Mitochondria-targeted antioxidant (Mito-Tempo) restored impaired mitophagy, decreased mitochondrial mass accumulation, and delayed cellular senescence in Parkin-overexpressing cells. In conclusion, defective mitophagy leads to CS stress-induced lung cellular senescence, and restoring mitophagy delays cellular senescence, which provides a promising therapeutic intervention in chronic airway diseases.
authors: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA.
authors: Tanveer
authors: T
authors: Ahmad
authors: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA.
authors: Isaac K
authors: IK
authors: Sundar
authors: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA.
authors: Chad A
authors: CA
authors: Lerner
authors: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA.
authors: Janice
authors: J
authors: Gerloff
authors: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA.
authors: Ana M
authors: AM
authors: Tormos
authors: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA hongwei_yao@urmc.rochester.edu irfan_rahman@urmc.rochester.edu.
authors: Hongwei
authors: H
authors: Yao
authors: Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA hongwei_yao@urmc.rochester.edu irfan_rahman@urmc.rochester.edu.
authors: Irfan
authors: I
authors: Rahman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016022:Case-Control Studies; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D063306:Mitophagy / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000975:Antioxidants; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: DNA damage; Parkin; Pink1; perinuclear mitochondrial clustering; reactive oxygen species