Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells

Abstract

BackgroundCigarette smoking is the major risk factor for COPD, leading to chronic airway inflammation. We hypothesized that cigarette smoke induces structural and functional changes of airway epithelial mitochondria, with important implications for lung inflammation and COPD pathogenesis.MethodsWe studied changes in mitochondrial morphology and in expression of markers for mitochondrial capacity, damage/biogenesis and fission/fusion in the human bronchial epithelial cell line BEAS-2B upon 6-months from ex-smoking COPD GOLD stage IV patients to age-matched smoking and never-smoking controls.ResultsWe observed that long-term CSE exposure induces robust changes in mitochondrial structure, including fragmentation, branching and quantity of cristae. The majority of these changes were persistent upon CSE depletion. Furthermore, long-term CSE exposure significantly increased the expression of specific fission/fusion markers (Fis1, Mfn1, Mfn2, Drp1 and Opa1), oxidative phosphorylation (OXPHOS) proteins (Complex II, III and V), and oxidative stress (Mn-SOD) markers. These changes were accompanied by increased levels of the pro-inflammatory mediators IL-6, IL-8, and IL-1β. Importantly, COPD primary bronchial epithelial cells (PBECs) displayed similar changes in mitochondrial morphology as observed in long-term CSE-exposure BEAS-2B cells. Moreover, expression of specific OXPHOS proteins was higher in PBECs from COPD patients than control smokers, as was the expression of mitochondrial stress marker PINK1.ConclusionThe observed mitochondrial changes in COPD epithelium are potentially the consequence of long-term exposure to cigarette smoke, leading to impaired mitochondrial function and may play a role in the pathogenesis of COPD.

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

“…Our results showing mitochondrial dysfunction in fibroblasts from COPD patients even at nonsenescent passage are consistent with data published in the literature showing that bronchial epithelial cells from COPD patients exhibited swollen, elongated mitochondria with fragmentation, and disruption of cristae (Hoffmann et al, 2013). Since fibroblasts were isolated from lung samples of patients suffering from lung cancer, a cancer‐related fibroblast phenotype could explain the differences between COPD and control smokers.…”

“…However, we think this possibility unlikely because: (a) Smoker controls and COPD patients suffered from similar cancer histological types, (b) biopsies were harvested at a distance from the tumor and were verified to be free of malignant cells, and (c) primary cultures of lung fibroblasts did not exhibit Cancer Associated Fibroblasts markers (data not shown). Cigarette smoke can trigger mitochondrial dysfunction in COPD fibroblasts since lung epithelial cells and fibroblasts exposed to cigarette smoke exhibit an increase in mitochondrial ROS, reduced ATP levels, and changes in mitochondria structure (Ahmad et al, 2015), (Hoffmann et al, 2013). However, other factors probably contribute to mitochondrial dysfunction in COPD cells since in the present study, the smoking history of COPD and control smokers was similar.…”

PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis

“…Although PINK1 and PARK2 are both crucial for mitophagy, 30 a recent paper shows upregulation of PINK1 in COPD lung, which is interpreted as reflecting accumulation of mitochondrial damage. 26 Consistently, we observed modestly increased PINK1 levels in lung homogenates from COPD patients, whereas PARK2 levels were decreased and there was a positive correlation between PARK2 levels and percentage of FEV1/FVC (Fig. 5 and 6).…”

“…5A). 26 However, PINK1 demonstrated no significant correlation with percentage of forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) (Fig. 5B).…”

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).…”