Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
J Cell Sci. 2021 Feb 25;134(4):jcs257162. doi: 10.1242/jcs.257162.
Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive pulmonary disease (COPD), which is impacted by cigarette smoking and has no therapeutic options. We utilized a high-copy cDNA library genetic selection approach in the amoeba to identify genetic protectors to cigarette smoke. Members of the mitochondrial ADP/ATP transporter family adenine nucleotide translocase (ANT) are protective against cigarette smoke in and human bronchial epithelial cells. Gene expression of ANT2 is reduced in lung tissue from COPD patients and in a mouse smoking model, and overexpression of ANT1 and ANT2 resulted in enhanced oxidative respiration and ATP flux. In addition to the presence of ANT proteins in the mitochondria, they reside at the plasma membrane in airway epithelial cells and regulate airway homeostasis. ANT2 overexpression stimulates airway surface hydration by ATP and maintains ciliary beating after exposure to cigarette smoke, both of which are key functions of the airway. Our study highlights a potential for upregulation of ANT proteins and/or of their agonists in the protection from dysfunctional mitochondrial metabolism, airway hydration and ciliary motility in COPD.This article has an associated First Person interview with the first author of the paper.
气道水合作用和纤毛功能对于气道稳态至关重要，在慢性阻塞性肺疾病（COPD）中会失调，而 COPD 受吸烟影响且尚无治疗选择。我们利用变形虫中的高拷贝 cDNA 文库遗传选择方法来鉴定针对香烟烟雾的遗传保护因子。线粒体 ADP/ATP 转运蛋白家族腺嘌呤核苷酸转位酶（ANT）的成员在和人支气管上皮细胞中对香烟烟雾具有保护作用。COPD 患者肺组织和小鼠吸烟模型中的 ANT2 基因表达减少，而 ANT1 和 ANT2 的过表达导致氧化呼吸和 ATP 通量增强。除了线粒体中存在 ANT 蛋白外，它们还存在于气道上皮细胞的质膜上，并调节气道稳态。ANT2 的过表达通过 ATP 刺激气道表面水合作用，并在暴露于香烟烟雾后维持纤毛运动，这两者都是气道的关键功能。我们的研究强调了上调 ANT 蛋白及其激动剂在保护 COPD 中功能失调的线粒体代谢、气道水合作用和纤毛运动方面的潜力。本文有该论文第一作者的相关第一人称采访。
