Mitochondrial oxidative stress in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice

Am J Respir Cell Mol Biol. 2006 Nov;35(5):579-86. doi: 10.1165/rcmb.2005-0473OC. Epub 2006 Jun 8.


Cystic fibrosis is a fatal genetic disorder involving dysfunction of the cystic fibrosis transmembrane regulator protein (CFTR) resulting in progressive respiratory failure. Previous studies indicate that CFTR regulates cellular glutathione (GSH) transport and that dysfunctional CFTR is associated with chronic pulmonary oxidative stress. The cause and the source of this oxidative stress remain unknown. The current study examines the role of the mitochondria in CFTR-mediated pulmonary oxidative stress. Mitochondrial GSH levels and markers of DNA and protein oxidation were assessed in the lung mitochondria from CFTR-knockout mice. In addition, in vitro models using human CFTR-sufficient and -deficient lung epithelial cells were also employed. Mitochondrial GSH levels were found to be decreased up to 85% in CFTR-knockout mice, and 43% in human lung epithelial cells deficient in CFTR. A concomitant 29% increase in the oxidation of mitochondrial DNA, and a 30% loss of aconitase activity confirmed the existence of a mitochondrial oxidative stress. Flow cytometry revealed significantly elevated levels of cellular reactive oxygen species (ROS) in CFTR-deficient human lung cells. These studies suggest that dysfunctional CFTR leads to an increase in the level of ROS and mitochondrial oxidative stress. This oxidative stress, however, appears to be a consequence of lower mitochondrial GSH levels and not increased oxidation of GSH. Further studies are needed to determine how CFTR deficiency contributes to mitochondrial oxidative stress and the role this plays in CFTR-mediated lung pathophysiology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aconitate Hydratase / metabolism
  • Animals
  • Biomarkers / metabolism
  • Cell Fractionation
  • Cell Line
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Fumarate Hydratase / metabolism
  • Glutathione / metabolism
  • Humans
  • Lung / cytology
  • Lung / metabolism*
  • Mice
  • Mice, Inbred CFTR
  • Mitochondria / chemistry
  • Mitochondria / metabolism*
  • Oxidative Stress*
  • Reactive Oxygen Species / metabolism
  • Respiratory Mucosa / cytology


  • Biomarkers
  • Reactive Oxygen Species
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Fumarate Hydratase
  • Aconitate Hydratase
  • Glutathione