CFTR-PTEN-dependent mitochondrial metabolic dysfunction promotes Pseudomonas aeruginosa airway infection

Sci Transl Med. 2019 Jul 3;11(499):eaav4634. doi: 10.1126/scitranslmed.aav4634.


Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor best known for regulating cell proliferation and metabolism. PTEN forms a complex with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the plasma membrane, and this complex is known to be functionally impaired in CF. Here, we demonstrated that the combined effect of PTEN and CFTR dysfunction stimulates mitochondrial activity, resulting in excessive release of succinate and reactive oxygen species. This environment promoted the colonization of the airway by Pseudomonas aeruginosa, bacteria that preferentially metabolize succinate, and stimulated an anti-inflammatory host response dominated by immune-responsive gene 1 (IRG1) and itaconate. The recruitment of myeloid cells induced by these strains was inefficient in clearing the infection and increased numbers of phagocytes accumulated under CFTR-PTEN axis dysfunction. This central metabolic defect in mitochondrial function due to impaired PTEN activity contributes to P. aeruginosa infection in CF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxy-Lyases / metabolism
  • Colony Count, Microbial
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • HCT116 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunity
  • Interleukin-1beta / metabolism
  • Lung / immunology
  • Lung / microbiology*
  • Mice, Inbred C57BL
  • Middle Aged
  • Mitochondria / metabolism*
  • Oxidants / metabolism
  • Oxidative Stress
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / metabolism*
  • Pseudomonas Infections / metabolism*
  • Pseudomonas aeruginosa / isolation & purification
  • Reactive Oxygen Species / metabolism
  • Succinates / metabolism


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-1beta
  • Oxidants
  • Reactive Oxygen Species
  • Succinates
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • PTEN Phosphohydrolase
  • ACOD1 protein, human
  • Carboxy-Lyases