Unfolded protein responses disrupt mitochondrial homeostasis and damage epithelium in COPD pathogenesis

<bold>Background:</bold> Chronic obstructive pulmonary disease (COPD) manifests through repeated airway lesions triggered by various stressors and impaired wound repair mechanisms. Cigarette smoke disrupts mitochondrial functions, with mitochondrial unfolded protein responses (UPR^mt) serving as vital cellular stress reactions for maintaining mitochondrial homeostasis. However, the precise role of UPR^mt in COPD pathogenesis remains unclear. <bold>Objectives:</bold> This study aims to investigate whether impaired UPR^mt in COPD contributes to alveolar epithelial damage and COPD progression. <bold>Methods:</bold> We evaluated UPR^mt gene expression (<italic>LONP1</italic>, <italic>HSPA9</italic>, <italic>HSPD1</italic>, <italic>HSPE1</italic>) in lung tissues from COPD patients, cigarette smoke-exposed mouse models, and Beas-2B epithelial cells. Additionally, we explored the UPR^mt modulation effect on mitochondrial dysfunction and epithelial damage using the UPR^mt inhibitor KRIBB11 and the UPR^mt agonist Nicotinamide Riboside <italic>in vitro</italic>. <bold>Results:</bold> Our findings reveal significant downregulation of UPR^mt gene expression in human and mouse COPD lungs. Similarly, exposure to cigarette smoke extract (CSE) reduced UPR^mt gene expression in Beas-2B cells. Inhibition of UPR^mt in Beas-2B cells heightened CSE-induced mitochondrial reactive oxygen species (ROS) production and necroptosis from increased expression of RIP1 and RIP3 while enhanced UPR^mt aided in mitochondrial ROS clearance and restored cell viability. <bold>Conclusions:</bold> Our results suggest that UPR^mt pathway inhibition occurs in COPD and may contribute to pathogenesis by increasing susceptibility to cigarette smoke-induced epithelial cell damage through mitochondrial homeostasis disturbance. UPR^mt may be a promising therapeutic target for COPD.