CFTR chloride channel activity modulates the mitochondrial morphology in cultured epithelial cells

GARCÍA, ROCÍO; CLAUZURE, MARIÁNGELES; JARA, RAQUEL; DE LOS ÁNGELES AGUILAR, MARÍA; SANTA-COLOMA, TOMÁS A.; FALDUTI, CAMILA; MASSIP-COPIZ, MARÍA M.; VALDIVIESO, ÁNGEL G.

INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELLULAR BIOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2021 vol. 135

1357-2725

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.