title: Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells.
abstract: 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. Whereas mild stress induces a prosurvival 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 nontoxic 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 and primary mouse alveolar epithelial cells revealed pronounced mitochondrial hyperfusion upon treatment with CSE, accompanied by increased expression of the mitochondrial fusion protein mitofusin 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 prosurvival response of mitochondria of alveolar epithelial cells to nontoxic 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 part of a beneficial adaptive stress response in the first place, may contribute to the pathogenesis of COPD.
authors.affiliation: Comprehensive Pneumology Center (CPC), University Hospital Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Member of the German Center for Lung Research (DZL), Germany.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Ballweg
authors.affiliation: Comprehensive Pneumology Center (CPC), University Hospital Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Member of the German Center for Lung Research (DZL), Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Mutze
authors.affiliation: Comprehensive Pneumology Center (CPC), University Hospital Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Member of the German Center for Lung Research (DZL), Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: Comprehensive Pneumology Center (CPC), University Hospital Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Member of the German Center for Lung Research (DZL), Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: Comprehensive Pneumology Center (CPC), University Hospital Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Member of the German Center for Lung Research (DZL), Germany silke.meiners@helmholtz-muenchen.de.
authors.forename: Silke
authors.initials: S
authors.lastname: Meiners
mesh_terms: D000818:Animals; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000096:biosynthesis; D007249:Inflammation / Q000139:chemically induced; D008168:Lung / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects*; D063306:Mitophagy / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000648:ultrastructure; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000648:ultrastructure; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D014026:Nicotiana / Q000009:adverse effects*; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D012906:Smoke; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse
keywords: chronic obstructive pulmonary disease; emphysema; proteostasis; stress-induced mitochondrial hyperfusion