Characterization of mitochondrial function in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function
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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, ΔΨ 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 sè 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.
KeywordsCystic fibrosis CFTR Correctors Mitochondria Oxidative phosphorylation ROS
Adenine nucleotide translocator
- ATP D.S.
ATP detecting system
Airway cells homozygous for the F508del-CFTR allele
Cystic fibrosis transmembrane conductance regulator
Mitochondrial membrane potential
Electron transport chain
Airway cells stably expressing wt-CFTR
Mitochondrial respiratory chain
Superoxide anion radical
Reactive oxygen species
This research was supported by Italian Cystic Fibrosis Research Foundation FFC#1/2015 Project: “Relationship between mitochondria and F508del-CFTR in Cystic Fibrosis” to A.A.
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