Research ArticleCystic Fibrosis

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

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Science Translational Medicine  03 Jul 2019:
Vol. 11, Issue 499, eaav4634
DOI: 10.1126/scitranslmed.aav4634

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Feeding Pseudomonas

Why patients with cystic fibrosis (CF) are susceptible to infection by Pseudomonas aeruginosa is poorly understood. Riquelme, Lozano, and Moustafa et al. found that the dysfunctional PTEN seen in CF ultimately repressed the activity of mitochondrial succinate dehydrogenase, leading to increased secretion of succinate into airways in a mouse model of the disease. P. aeruginosa readily metabolized this succinate, promoting airway colonization by this bacterium (but not Staphylococcus aureus) in the mice. Continued adaptation to succinate was observed in longitudinal isolates from a patient with CF. Succinate-adapted P. aeruginosa suppressed the immune response in human monocytes and mice, which may help explain the persistence of this infection in patients with CF.


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.

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