Cigarette smoke exposure disrupts the molecular regulation of mitochondrial metabolism in human bronchial and alveolar epithelial cells

Abstract

Mitochondrial dysfunction in bronchial and alveolar epithelial cells has been implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Although abnormalities in mitochondrial morphology and function in response to exposure of these cells to cigarette smoke (CS) have been described, it is unclear to what extent the pathways regulating mitochondrial content and function (i.e. mitochondrial biogenesis vs mitophagy) are impacted. Therefore, in the present study, the abundance of key constituents of mitochondrial metabolic pathways as well as transcript and protein levels of key molecules controlling mitochondrial biogenesis and mitophagy were investigated in whole lung homogenates and in primary bronchial epithelial cells (PBECs; PLUC facility MUMC+) from COPD and non-COPD subjects (n=5-8/group). In addition, PBECs from non-COPD subjects were exposed to CS extract or CS in submerged cultures or in an air-liquid interface system respectively. We observed that the expression of constituents of mitochondrial metabolic pathways, including the Krebs cycle, fatty acid β-oxidation and the electron transport chain, was significantly different in COPD patients compared to non-COPD subjects. This was associated with significant decreases in the abundance of key regulators of mitochondrial biogenesis and with increased expression levels of components of the mitophagy machinery. Moreover, these alterations were, at least in part, recapitulated by exposure of PBECs to CS components. In conclusion, CS exposure disrupts the molecular regulation of mitochondrial metabolism in epithelial cells of the human airways and lung.