D108-04 Mitochondrial Ribosomal Protein MRPS17 Confers Protection Against Cigarette Smoke-Induced Ferroptosis in Bronchial Epithelial Cells

Abstract Introduction The pathogenesis of chronic obstructive pulmonary disease (COPD) is primarily driven by cigarette smoke (CS)-induced oxidative stress. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has been identified as a key mechanism in airway epithelial injury. However, the mitochondrial regulatory mechanisms involved in this process remain largely unclear. Methods An in vitro bronchial epithelial cell injury model was established using cigarette smoke extract (CSE) treatment. Integrated proteomic and transcriptomic analyses were employed to identify mitochondrial ribosomal protein S17 (MRPS17) as a potential key regulator. MRPS17 expression was modulated via lentivirus-mediated overexpression and RNA interference. Mitochondrial ultrastructure was observed by transmission electron microscopy, mitochondrial membrane potential (ΔΨm) was detected using the JC-1 fluorescent probe, lipid peroxidation levels were assessed with the C11-BODIPY 581/591 probe, and mitochondrial oxygen consumption rate was measured using the Seahorse XF Analyzer. Furthermore, GPX4 activity was determined to confirm the involvement of ferroptosis. Results MRPS17 expression was significantly downregulated in smoker-derived bronchial epithelial cells and CSE-exposed cells. Loss of MRPS17 function induced mitochondrial fragmentation, impaired oxidative phosphorylation capacity, led to excessive accumulation of reactive oxygen species (ROS) and lipid peroxidation, and ultimately triggered ferroptosis. Conversely, restoring MRPS17 expression effectively maintained mitochondrial network integrity, stabilized mitochondrial membrane potential, and significantly suppressed the ferroptosis process. Mechanistically, MRPS17 directly participates in regulating the translation of core catalytic subunits of the oxidative respiratory chain. MRPS17 deficiency significantly reduced the assembly efficiency of respiratory chain complexes, resulting in electron transport chain dysfunction, manifested as decreased oxidative phosphorylation coupling efficiency, insufficient ATP synthesis, collapsed mitochondrial membrane potential, and concomitant inhibition of GPX4 activity. Conclusion This study demonstrates that MRPS17 acts as a novel mitochondrial protective factor against CS-induced ferroptosis in bronchial epithelial cells. Its protective effect stems from the maintenance of mitochondrial function and cellular redox homeostasis. Therefore, targeting the MRPS17-mitochondrial function axis may represent a potential and promising therapeutic strategy for COPD intervention. This abstract is funded by: none