TY - JOUR
T1 - Pseudomonas aeruginosa Induced Host Epithelial Cell Mitochondrial Dysfunction
AU - Maurice, Nicholas M.
AU - Bedi, Brahmchetna
AU - Yuan, Zhihong
AU - Goldberg, Joanna B.
AU - Koval, Michael
AU - Hart, C. Michael
AU - Sadikot, Ruxana T.
N1 - Funding Information:
The work was supported by the Department of Veterans Affairs (VA; 2I01BX001786 Merit Review Award to RTS, Veterans Integrated Services Network (VISN) 7 Research Development Award (RDA) to NMM) and by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH; T32HL116271 to NMM). R01 HL144478 from National Institute of Health to Dr. RTS and DMG. The contents of this report do not represent the views of the VA, the NIH, or the US Government. This electron microscopy study was supported by the Robert P. Apkarian Integrated Electron Microscopy Core, which is subsidized by the Emory University School of Medicine and the Emory College of Arts and Sciences. The JEOL JEM-1400 120kV TEM was supported by the NIH (S10 RR025679). We are grateful to Osric A. Forrest for his invaluable assistance with FACS analysis and Hong Yi for her assistance with TEM.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The pathogenicity of P. aeruginosa is dependent on quorum sensing (QS), an inter-bacterial communication system that can also modulate host biology. The innate immune function of the lung mucosal barrier is dependent on proper mitochondrial function. The purpose of this study was to define the mechanism by which bacterial factors modulate host lung epithelial cell mitochondrial function and to investigate novel therapies that ameliorate this effect. 3-oxo-C12-HSL disrupts mitochondrial morphology, attenuates mitochondrial bioenergetics, and induces mitochondrial DNA oxidative injury. Mechanistically, we show that 3-oxo-C12-HSL attenuates expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, antioxidant defense, and cellular respiration, and its downstream effectors in both BEAS-2B and primary lung epithelial cells. Overexpression of PGC-1α attenuates the inhibition in cellular respiration caused by 3-oxo-C12-HSL. Pharmacologic activation of PGC-1α restores barrier integrity in cells treated with 3-oxo-C12-HSL. These data demonstrate that the P. aeruginosa QS molecule, 3-oxo-C12-HSL, alters mitochondrial pathways critical for lung mucosal immunity. Genetic and pharmacologic strategies that activate the PGC-1α pathway enhance host epithelial cell mitochondrial function and improve the epithelial innate response to P. aeruginosa. Therapies that rescue PGC-1α function may provide a complementary approach in the treatment of P. aeruginosa infection.
AB - The pathogenicity of P. aeruginosa is dependent on quorum sensing (QS), an inter-bacterial communication system that can also modulate host biology. The innate immune function of the lung mucosal barrier is dependent on proper mitochondrial function. The purpose of this study was to define the mechanism by which bacterial factors modulate host lung epithelial cell mitochondrial function and to investigate novel therapies that ameliorate this effect. 3-oxo-C12-HSL disrupts mitochondrial morphology, attenuates mitochondrial bioenergetics, and induces mitochondrial DNA oxidative injury. Mechanistically, we show that 3-oxo-C12-HSL attenuates expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, antioxidant defense, and cellular respiration, and its downstream effectors in both BEAS-2B and primary lung epithelial cells. Overexpression of PGC-1α attenuates the inhibition in cellular respiration caused by 3-oxo-C12-HSL. Pharmacologic activation of PGC-1α restores barrier integrity in cells treated with 3-oxo-C12-HSL. These data demonstrate that the P. aeruginosa QS molecule, 3-oxo-C12-HSL, alters mitochondrial pathways critical for lung mucosal immunity. Genetic and pharmacologic strategies that activate the PGC-1α pathway enhance host epithelial cell mitochondrial function and improve the epithelial innate response to P. aeruginosa. Therapies that rescue PGC-1α function may provide a complementary approach in the treatment of P. aeruginosa infection.
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U2 - 10.1038/s41598-019-47457-1
DO - 10.1038/s41598-019-47457-1
M3 - Article
C2 - 31417101
AN - SCOPUS:85070742579
SN - 2045-2322
VL - 9
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 11929
ER -