Mitochondrial uncoupling proteins protect human airway epithelial ciliated cells from oxidative damage

Apical cilia on epithelial cells defend the lung by propelling pathogens and particulates out of the respiratory airways. Ciliated cells produce ATP that powers cilia beating by densely grouping mitochondria just beneath the apical membrane. However, this efficient localization comes at a cost because electrons leaked during oxidative phosphorylation react with molecular oxygen to form superoxide, and thus, the cluster of mitochondria creates a hotspot for oxidant production. The relatively high oxygen concentration overlying airway epithelia further intensifies the risk of generating superoxide. Thus, airway ciliated cells face a unique challenge of producing harmful levels of oxidants. However, surprisingly, highly ciliated epithelia produce less reactive oxygen species (ROS) than epithelia with few ciliated cells. Compared to other airway cell types, ciliated cells express high levels of mitochondrial uncoupling proteins, UCP2 and UCP5. These proteins decrease mitochondrial protonmotive force and thereby reduce production of ROS. As a result, lipid peroxidation, a marker of oxidant injury, decreases. However, mitochondrial uncoupling proteins exact a price for decreasing oxidant production; they decrease the fraction of mitochondrial respiration that generates ATP. These findings indicate that ciliated cells sacrifice mitochondrial efficiency in exchange for safety from damaging oxidation. Employing uncoupling proteins to prevent oxidant production, instead of relying solely on antioxidants to decrease postproduction oxidant levels, may offer an advantage for targeting a local area of intense ROS generation. Significance Motile cilia protruding from airway epithelial cells propel pathogens out of the lungs. Respiratory ciliated cells have an efficient supply chain that provides ATP to power cilia beating; the producers of ATP (mitochondria) are clustered just beneath the consumers (cilia) and an abundant supply (oxygen) in air covering the cells. But a byproduct of this organization, reactive oxygen species (ROS), pose the risk of injury. Human airway ciliated cells balance the requirement for energy and the potential for oxidant injury with mitochondrial uncoupling proteins, which decrease mitochondrial efficiency but minimize ROS production. Improved understanding of airway metabolism may yield benefit for people challenged by localized hyperoxia because of treatment with inhaled oxygen.