Characterization of mitochondrial function in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function
Characterization of mitochondrial function in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function
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DOI：
10.1007/s10863-016-9663-y
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发表时间：
2016-06-01
影响因子：
3
通讯作者：
Reshkin, Stephan Joel
中科院分区：
文献类型：
--
作者：
Atlante, Anna;Favia, Maria;Reshkin, Stephan Joel
支持囊性纤维化（CF）中发生氧化应激的证据已得到充分证实，文献表明氧化应激与线粒体功能障碍密不可分。在这里，我们已经表征了线粒体功能，特别是在F508 del-CFTR等位基因纯合或稳定表达wt-CFTR的气道细胞中氧化磷酸化和ROS产生的步骤。我们发现CF细胞的耗氧量、Delta I生成、腺嘌呤核苷酸转运体依赖的ADP/ATP交换以及线粒体复合物I和IV的活性受损，而线粒体ROS产生和膜脂质过氧化增加。重要的是，用小分子VX-809和4，6，4 '-三甲基当归素处理CF细胞，其通过拯救F508 del CFTR依赖性氯化物分泌而充当F508 del CFTR的“校正剂”，同时每sS对wt-CFTR细胞中的线粒体功能没有影响，显著改善了所有上述线粒体参数，接近在表达wt-CFTR的气道细胞中发现的值。这项关于线粒体生物能量学的新研究为未来的研究提供了一个跳板，以进一步了解线粒体参与CF的分子机制，并确定主要负责F508 del-CFTR依赖性线粒体损伤的蛋白质，从而揭示CF治疗的潜在新靶点。
Evidence supporting the occurrence of oxidative stress in Cystic Fibrosis (CF) is well established and the literature suggests that oxidative stress is inseparably linked to mitochondrial dysfunction. Here, we have characterized mitochondrial function, in particular as it regards the steps of oxidative phosphorylation and ROS production, in airway cells either homozygous for the F508del-CFTR allele or stably expressing wt-CFTR. We find that oxygen consumption, Delta I generation, adenine nucleotide translocator-dependent ADP/ATP exchange and both mitochondrial Complex I and IV activities are impaired in CF cells, while both mitochondrial ROS production and membrane lipid peroxidation increase. Importantly, treatment of CF cells with the small molecules VX-809 and 4,6,4'-trimethylangelicin, which act as "correctors" for F508del CFTR by rescuing the F508del CFTR-dependent chloride secretion, while having no effect per sS on mitochondrial function in wt-CFTR cells, significantly improved all the above mitochondrial parameters towards values found in the airway cells expressing wt-CFTR. This novel study on mitochondrial bioenergetics provides a springboard for future research to further understand the molecular mechanisms responsible for the involvement of mitochondria in CF and identify the proteins primarily responsible for the F508del-CFTR-dependent mitochondrial impairment and thus reveal potential novel targets for CF therapy.