Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells

Abstract

Ballweg K, Mutze K, Königshoff M, Eickelberg O, Meiners S. Cigarette smoke extract affects mitochondrial function in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 307: L895-L907, 2014. First published October 17, 2014 doi:10.1152/ajplung.00180.2014.-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 stressinduced 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. chronic obstructive pulmonary disease; emphysema; proteostasis; stress-induced mitochondrial hyperfusion CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is one of the leading causes of death worldwide. It is characterized by progressive and irreversible airflow limitation (4, 44). In the Western world, the main risk factor for development of COPD is cigarette smoke (CS) (4, 44), which is a complex mixture of thousands of injurious agents and reactive oxidants (7,33,44). Exposure of lung epithelial cells to CS initiates an adaptive cell response, such as induction of autophagy, impaired proteasome function, and proinflammatory and oxidative responses (7,33,35).Mitochondria are crucial cellular organelles for cellular energetics, signaling, and apoptosis. Differences in cellular energy demands or cellular stress rapidly alter mitochondrial behavior mainly by changing mitochondrial fusion and fission dynamics (5, 9, 26). Mitochondrial hyperfusion provides a stress-resolving mechanism for the cell, as elongated mitochondria are pr...

Hallmarks of the ageing lung

“…While there is no doubt that increased ROS level and disturbed anti-oxidant protection contributes to the onset and progression of COPD [92], the exchange of mitochondrial function beyond its role as ROS generators is not yet solved. Recent data indicate that cigarette smoke alters mitochondrial structure and function but this appears to depend upon cell type and extent of damage [93,94]. A recent study strongly indicates the disposal of smoke-damaged mitochondria via the PINK1/Parkin-mediated autophagy route as PINK1 knock-out mice were protected against mitochondrial dysfunction and smoke-induced emphysema formation [95].…”

Mitochondria in lung disease

“…mitochondrial OXPHOS (15,16), whereas treatment with nontoxic doses of CS increases mitochondrial metabolic activity (17,18), inducing a metabolic shift from glucose (glycolysis) to palmitate (β-oxidation) metabolism (18). Loss of acetyl-CoA and the Krebs cycle intermediate succinate is observed in basal cells of smokers (19).…”

“…35 and Figure 2). Hyperfusion has been documented in COPD and in lung cancer (17,18,37,38), whereas loss of fusion, specifically loss of MFN2, has been associated with lung cancer (38) and PH (39). The role of mitochondrial fission and fusion in lung cancer may be microenvironment specific; increased fission may allow cancer cells to proliferate rapidly and invade the surrounding tissue, while increased fusion may allow for cell survival during times of stress or drug toxicity (27).…”

Smoking and interstitial lung diseases

“…However, autophagy is supposedly specific to cell type and, thus, in alveolar macrophages in COPD patients, there appears to be a selective defect in autophagy resulting in impaired clearance of damaged and dysfunctional mitochondria [69]. After treatment with cigarette smoke, recent studies have shown altered mitochondrial structure (elongation) and function in alveolar epithelial cells [70], and in primary bronchial epithelial cells [71]. By contrast, HARA et al [72] demonstrated mitochondrial fragmentation in primary human bronchial epithelial cells upon stimulation with cigarette smoke extract for 48 h. It has been suggested that while mitochondria initially adapt to cigarette smoke and oxidative stress by altering their structure, this may be not beneficial in the long term due to a resultant decrease in mitophagy [70].…”

“…After treatment with cigarette smoke, recent studies have shown altered mitochondrial structure (elongation) and function in alveolar epithelial cells [70], and in primary bronchial epithelial cells [71]. By contrast, HARA et al [72] demonstrated mitochondrial fragmentation in primary human bronchial epithelial cells upon stimulation with cigarette smoke extract for 48 h. It has been suggested that while mitochondria initially adapt to cigarette smoke and oxidative stress by altering their structure, this may be not beneficial in the long term due to a resultant decrease in mitophagy [70]. Recently, AHMAD et al [73] proposed a pathway of smoke-induced cellular senescence due to impaired mitophagy.…”