Sirt3-MnSOD signaling pathway attenuates airway epithelial mitochondrial oxidative stress in chronic obstructive pulmonary disease

Abstract

Background: Mitochondrial oxidative stress in airway epithelial cells contributes to the pathogenesis of chronic obstructive pulmonary disease (COPD). Sirt3-MnSOD signaling pathway regulates mitochondrial oxidative stress, but its role in mitochondrial damage in COPD is unclear. Aims: This study investigated the role of Sirt3-MnSOD pathway in cigarette smoke induced mitochondrial damage in a rat COPD model and human airway epithelial cells. Methods: The COPD rat model was established by cigarette smoke exposure and LPS instillation, and airway epithelium structure and Sirt3-MnSOD pathway was studied. Human airway epithelial cells (BEAS-2B) were exposed to cigarette smoke extract (CSE), and transfeted with Sirt3 siRNA or Sirt3 plasmid, and the expression of Sirt3-MnSOD pathway and mitochondrial oxidation was determined. Results: Histology showed airway inflammation, alveolar space dilation, and airway epithelial mitochondrial damage in COPD rats. Sirt3 and MnSOD protein expression was significantly decreased in the airway epithelia of COPD rats. In BEAS-2B cells, CSE significantly decreased Sirt3 and MnSOD protein levels, and increased MnSOD acetylation in a concentration and time dependent manner. In CSE treated cells, Sirt3 siRNA significantly increased MnSOD acetylation, and mitochondria oxidation stress. In contrast, Sirt3 overexpression significantly decreased MnSOD acetylation, and protected mitochondria from oxidative damage in CSE treated BEAS-2B cells. Conclusions: The data suggest that Sirt3 attenuates CSE-induced mitochondrial oxidative stress in the airway epithelia via deacetylating MnSOD, and may provide a novel therapeutic target for COPD.