Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease.

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.

Ahmad T ，Sundar IK ，Lerner CA ，Gerloff J ，Tormos AM ，Yao H ，Rahman I ... -  《-》

PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis.

Araya J ，Tsubouchi K ，Sato N ，Ito S ，Minagawa S ，Hara H ，Hosaka Y ，Ichikawa A ，Saito N ，Kadota T ，Yoshida M ，Fujita Y ，Utsumi H ，Kobayashi K ，Yanagisawa H ，Hashimoto M ，Wakui H ，Ishikawa T ，Numata T ，Kaneko Y ，Asano H ，Yamashita M ，Odaka M ，Morikawa T ，Nishimura SL ，Nakayama K ，Kuwano K ... -  《-》

PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis.

Ito S ，Araya J ，Kurita Y ，Kobayashi K ，Takasaka N ，Yoshida M ，Hara H ，Minagawa S ，Wakui H ，Fujii S ，Kojima J ，Shimizu K ，Numata T ，Kawaishi M ，Odaka M ，Morikawa T ，Harada T ，Nishimura SL ，Kaneko Y ，Nakayama K ，Kuwano K ... -  《-》

Dysregulation of mitochondrial complexes and dynamics by chronic cigarette smoke exposure Utilizing MitoQC reporter mice.

Cigarette smoke (CS) is known to cause impaired mitophagy and mitochondrial dysregulation in the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. Mitochondrial complexes and dynamics are affected by acute CS exposure in lung epithelium and mouse lung. We hypothesize that chronic CS exposure (4 months) will induce lung mitochondrial dysregulation and abnormal mitophagy. In this study, we employed the mitoQC reporter mice, a mitochondrial reporter strain, which can reflect the mitophagy based on the fluorescence-tagged mitochondria. Chronic CS exposure induced lung inflammatory cell infiltration, airspace enlargement, and lung cellular senescence. We showed the higher occurrence of mitophagy (GFP/mCherry) in the lung cells by CS exposure, associated with more mitochondrial fluorescence signals (GFP+/mCherry+). After chronic CS exposure, the mitochondrial complexes and function related genes were inhibited, while protein levels of complexes I and III slightly changed. Additionally, chronic CS exposure down-regulated most of the mitochondrial dynamic markers at gene expression level, included mitochondrial fusion/fission and mitochondrial translocate/transfer markers. For the markers related to mitophagy, Pink1 and Parkin, decreased gene and protein levels of Parkin, and decreased gene expression of Pink1, were identified in the CS exposure group. Hence, CS-induced mitophagy is mediated by Pink1-Parkin independent mechanism. Thus, we have shown that the chronic CS epxosure dysregulated mitochondrial complexes and dynamics and induced mitophagy, using the state-of-the art mitoQC reporter mouse model. Our results suggested that dysregulated mitochondrial function and dynamics are associated with CS-induced lung injury and phenotypic development of chronic lung diseases, such as COPD/ emphysema.

Wang Q ，Unwalla H ，Rahman I 《-》

Cigarette smoke-induced autophagy impairment accelerates lung aging, COPD-emphysema exacerbations and pathogenesis.

Vij N ，Chandramani-Shivalingappa P ，Van Westphal C ，Hole R ，Bodas M ... -  《-》