Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells.

Cigarette smoke is the main risk factor for chronic obstructive pulmonary disease (COPD). Exposure of cells to cigarette smoke induces an initial adaptive cellular stress response involving increased oxidative stress and induction of inflammatory signaling pathways. Exposure of mitochondria to cellular stress alters their fusion/fission dynamics. While mild stress induces a pro-survival response termed stress induced mitochondrial hyperfusion, severe stress results in mitochondrial fragmentation and mitophagy. In the present study, we analyzed the mitochondrial response to mild and non-toxic doses of cigarette smoke extract (CSE) in alveolar epithelial cells. We characterized mitochondrial morphology, expression of mitochondrial fusion and fission genes, markers of mitochondrial proteostasis as well as mitochondrial functions such as membrane potential and oxygen consumption. Murine lung epithelial (MLE)12, as well as primary mouse alveolar epithelial cells revealed pronounced mitochondrial hyperfusion upon treatment with CSE, accompanied by increased expression of the mitochondrial fusion protein mitofusin (MFN) 2 and increased metabolic activity. We did not observe any alterations in mitochondrial proteostasis, i.e. induction of the mitochondrial unfolded protein response or mitophagy. Therefore, our data indicate an adaptive pro-survival response of mitochondria of alveolar epithelial cells to non-toxic concentrations of CSE. A hyperfused mitochondrial network, however, renders the cell more vulnerable to additional stress such as sustained cigarette smoke exposure. As such cigarette smoke induced mitochondrial hyperfusion - although being part of a beneficial adaptive stress response in the first place - may contribute to the pathogenesis of COPD