title: Characterization of mitochondrial function in cells with impaired cystic fibrosis transmembrane conductance regulator (CFTR) function.
abstract: 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.
authors.affiliation: Institute of Biomembrane and Bioenergetics - CNR, Via G. Amendola 165/A, 70126, Bari, Italy. a.atlante@ibbe.cnr.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Atlante
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70126, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Favia
authors.affiliation: Institute of Biomembrane and Bioenergetics - CNR, Via G. Amendola 165/A, 70126, Bari, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bobba
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70126, Bari, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Guerra
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70126, Bari, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Casavola
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Via E. Orabona 4, 70126, Bari, Italy.
authors.forename: Stephan Joel
authors.initials: SJ
authors.lastname: Reshkin
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D011564:Furocoumarins / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D009154:Mutation; D012137:Respiratory System / Q000166:cytology
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; D002712:Chlorides; D011564:Furocoumarins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor; C041621:4,4',6-trimethylangelicin
keywords: CFTR; Correctors; Cystic fibrosis; Mitochondria; Oxidative phosphorylation; ROS