Ballweg Korbinian, Mutze Kathrin, Königshoff Melanie, Eickelberg Oliver, Meiners Silke
Comprehensive Pneumology Center (CPC), University Hospital Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Member of the German Center for Lung Research (DZL), Germany.
Comprehensive Pneumology Center (CPC), University Hospital Ludwig-Maximilians University, Helmholtz Zentrum München, Munich, Member of the German Center for Lung Research (DZL), Germany
Am J Physiol Lung Cell Mol Physiol. 2014 Dec 1;307(11):L895-907. doi: 10.1152/ajplung.00180.2014. Epub 2014 Oct 17.
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.
香烟烟雾是慢性阻塞性肺疾病（COPD）的主要危险因素。细胞暴露于香烟烟雾会引发初始适应性细胞应激反应，包括氧化应激增加和炎症信号通路的诱导。线粒体暴露于细胞应激会改变其融合/裂变动态。轻度应激会诱导一种称为应激诱导的线粒体过度融合的促生存反应，而严重应激则会导致线粒体碎片化和线粒体自噬。在本研究中，我们分析了肺泡上皮细胞中线粒体对轻度和无毒剂量香烟烟雾提取物（CSE）的反应。我们对线粒体形态、线粒体融合和裂变基因的表达、线粒体蛋白质稳态的标志物以及线粒体功能（如膜电位和氧消耗）进行了表征。小鼠肺上皮（MLE）12细胞和原代小鼠肺泡上皮细胞在用CSE处理后显示出明显的线粒体过度融合，同时线粒体融合蛋白线粒体融合素2的表达增加且代谢活性增强。我们未观察到线粒体蛋白质稳态有任何改变，即未观察到线粒体未折叠蛋白反应或线粒体自噬的诱导。因此，我们的数据表明肺泡上皮细胞线粒体对无毒浓度的CSE具有适应性促生存反应。然而，过度融合的线粒体网络会使细胞更容易受到额外应激的影响，例如持续暴露于香烟烟雾中。因此，香烟烟雾诱导的线粒体过度融合虽然最初是有益的适应性应激反应的一部分，但可能会导致COPD的发病机制。
