The impairment of the CFTR channel activity, a cAMP-activated chloride (Cl⁻) channel responsible for cystic fibrosis (CF), has been associated with a variety of mitochondrial alterations such as modified gene expression, impairment in oxidative phosphorylation, increased reactive oxygen species (ROS), and a disbalance in calcium homeostasis. The mechanisms by which these processes occur in CF are not fully understood. Previously, we demonstrated a reduced MTND4 expression and a failure in the mitochondrial complex I (mCx-I) activity in CF cells. Here we hypothesized that the activity of CFTR might modulate the mitochondrial fission/fusion balance, explaining the decreased mCx-I. The mitochondrial morphology and the levels of mitochondrial dynamic proteins MFN1 and DRP1 were analysed in IB3−1 CF cells, and S9 (IB3−1 expressing wt-CFTR), and C38 (IB3−1 expressing a truncated functional CFTR) cells. The mitochondrial morphology of IB3−1 cells compared to S9 and C38 cells showed that the impaired CFTR activity induced a fragmented mitochondrial network with increased rounded mitochondria and shorter branches. Similar results were obtained by using the CFTR pharmacological inhibitors CFTR(inh)-172 and GlyH101 on C38 cells. These morphological changes were accompanied by modifications in the levels of the mitochondrial dynamic proteins MFN1, DRP1, and p(616)-DRP1. IB3−1 CF cells treated with Mdivi-1, an inhibitor of mitochondrial fission, restored the mCx-I activity to values similar to those seen in S9 and C38 cells. These results suggest that the mitochondrial fission/fusion balance is regulated by the CFTR activity and might be a potential target to treat the impaired mCx-I activity in CF.

CFTR 通道活性受损，cAMP 激活的氯化物 (Cl ^-) 通道负责囊性纤维化 (CF)，已与各种线粒体改变有关，例如基因表达修饰、氧化磷酸化受损、活性氧 (ROS) 增加和钙稳态失衡。这些过程在 CF 中发生的机制尚不完全清楚。以前，我们证明了 CF 细胞中 MTND4 表达降低和线粒体复合物 I (mCx-I) 活性失败。在这里，我们假设 CFTR 的活性可能会调节线粒体裂变/融合平衡，从而解释了 mCx-I 的降低。在IB3-1 CF细胞和S9（表达wt-CFTR的IB3-1）和C38（表达截短的功能性CFTR的IB3-1）细胞中分析线粒体形态和线粒体动态蛋白MFN1和DRP1的水平。与 S9 和 C38 细胞相比，IB3-1 细胞的线粒体形态表明，受损的 CFTR 活性诱导了线粒体网络碎片化，线粒体圆形增加，分支更短。通过在 C38 细胞上使用 CFTR 药理学抑制剂 CFTR(inh)-172 和 GlyH101 获得了类似的结果。这些形态变化伴随着线粒体动态蛋白 MFN1、DRP1 和 p(616)-DRP1 水平的改变。用线粒体裂变抑制剂 Mdivi-1 处理的 IB3-1 CF 细胞将 mCx-I 活性恢复到与在 S9 和 C38 细胞中观察到的值相似的值。这些结果表明线粒体裂变/融合平衡受 CFTR 活性调节，可能是治疗 CF 中受损的 mCx-I 活性的潜在目标。