Abstract
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.