Modulation of cellular bioenergetics enhances CFTR-dependent chloride transport in human bronchial epithelium

Abstract Airway surface liquid (ASL) homeostasis depends on coordinated epithelial ion transport, with the cystic fibrosis transmembrane conductance regulator (CFTR) playing a central role in chloride secretion. Reduced CFTR activity contributes to ASL dehydration, impaired mucociliary clearance, and chronic airway inflammation. In the present study, we investigated whether modulation of cellular bioenergetics by a mitochondria-targeted conjugate 3a and the flavonoid luteolin enhances CFTR-mediated chloride transport in human bronchial epithelial HBE cells. CFTR activity was evaluated by Ussing chamber, while mitochondrial respiration, intracellular ATP and Ca²⁺ levels, reactive oxygen species (ROS) production, cell viability, and transepithelial electrical resistance (TEER) were assessed to characterize the cellular responses to treatment. Neither salinomycin nor conjugate 3a affected cell viability or ROS production, whereas luteolin significantly reduced intracellular ROS levels and enhanced epithelial barrier integrity. Conjugate 3a markedly increased mitochondrial oxygen consumption, intracellular ATP levels, cytosolic Ca²⁺ concentration, and CFTR-mediated chloride secretion, while the parent compound salinomycin produced no significant effects. Luteolin also enhanced CFTR activity and increased ATP and intracellular Ca²⁺ levels without stimulating mitochondrial respiration, suggesting a mechanism independent of enhanced oxidative metabolism. Our findings demonstrate that pharmacological modulation of mitochondrial function may represent a complementary strategy to improve epithelial ion transport and restore airway surface hydration in diseases associated with impaired CFTR function.