Involvement of Mieap-mediated mitochondrial quality control in regulating cellular senescence during COPD pathogenesis

<bold>Background:</bold> Cellular senescence has been widely implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Enhanced release of mitochondrial reactive oxygen species (mtROS) resulting from accumulation of damaged mitochondria can be responsible for accelerated cellular senescence, which is attributed to disorganized mitochondrial quality control (MQC). Mitochondria-eating protein (Mieap) is a novel p53 regulated protein, and recent findings suggest that Mieap is participated in MQC. However, the involvement of Mieap-regulated MQC in COPD pathogenesis remains unclear. <bold>Aims and objectives:</bold> To elucidate the involvement of Mieap-mediated MQC in cigarette smoke (CS)-induced cellular senescence in human bronchial epithelial cells (HBEC) and emphysematous change in COPD mouse models. <bold>Methods:</bold> The regulatory role of Mieap in CS extract (CSE)-induced mtROS release, the change of oxygen consumption rate (OCR), and cellular senescence was examined in HBEC and in long term CS-exposure mouse models. Mieap expression levels in COPD samples were evaluated. <bold>Results:</bold> Mieap knockdown enhanced CSE-induced mtROS production and cellular senescence in HBEC. Flux analyzer showed that both CS exposure and Mieap knockdown decreased OCR. Mieap knockout mice exhibited exaggeration of emphysematous change compared to wild-type mice after 6 months CS exposure. Mieap expression levels were significantly reduced in COPD lungs compared to nonsmoker and non-COPD smoker lungs. <bold>Conclusions:</bold> Reduced Mieap expression levels might be involved in the mechanisms for perturbation of MQC and accelerated cellular senescence during COPD pathogenesis.