Department of Internal Medicine, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
Department of Molecular Physiology and Biophysics, Pappajohn Biomedical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
Proc Natl Acad Sci U S A. 2024 Mar 5;121(10):e2318771121. doi: 10.1073/pnas.2318771121. Epub 2024 Feb 28.
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.
上皮细胞顶端的纤毛通过将病原体和颗粒物从呼吸道中推出，从而保护肺部。纤毛细胞通过将大量的线粒体密集地排列在顶膜下方来产生驱动纤毛运动的 ATP。然而，这种有效的定位是有代价的，因为在线粒体氧化磷酸化过程中泄漏的电子与分子氧反应形成超氧化物，因此，线粒体簇会产生大量的氧化剂。覆盖在气道上皮细胞上方的相对较高的氧气浓度进一步加剧了生成超氧化物的风险。因此，气道纤毛细胞面临着产生有害水平氧化剂的独特挑战。然而，令人惊讶的是，高度纤毛化的上皮细胞产生的活性氧（ROS）比纤毛细胞较少的上皮细胞少。与其他气道细胞类型相比，纤毛细胞表达高水平的线粒体解偶联蛋白 UCP2 和 UCP5。这些蛋白降低了线粒体质子动力并减少 ROS 的生成。因此，脂质过氧化（氧化损伤的标志物）减少。然而，线粒体解偶联蛋白降低了 ROS 的产生，也降低了生成 ATP 的线粒体呼吸的比例。这些发现表明，纤毛细胞牺牲了线粒体的效率，以换取免受氧化损伤的安全。利用解偶联蛋白来防止氧化剂的产生，而不是仅仅依靠抗氧化剂来降低氧化剂的产生后水平，可能为靶向 ROS 生成强烈的局部区域提供优势。
