Abstract
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.
Highlights
The pathogenicity of P. aeruginosa depends in large part on its genetic flexibility made possible by a complex genome and arsenal of virulence factors
Mitochondrial morphology is tightly regulated by dynamic mitochondrial quality control mechanisms including mitochondrial biogenesis, mitophagy, fusion, and fission
Previous research has demonstrated that the quorum sensing (QS) molecule, 3-oxo-C12-HSL, activates the apoptotic pathway in a variety of cell types[20,21,22] and causes mitochondrial membrane permeabilization in fibroblasts[20], but little is known about their specific effects on lung epithelial cells
Summary
The pathogenicity of P. aeruginosa depends in large part on its genetic flexibility made possible by a complex genome and arsenal of virulence factors. QS is a central virulence factor that allows P. aeruginosa to coordinate expression of genes important to adaptation to the environment. This mechanism enables the bacteria to regulate genes in a density-dependent manner through the production of acyl homoserine lactones, small diffusible molecules that act as auto-inducers[3]. Cellular stresses that increase demand for ATP or disrupt the OXPHOS pathway can cause increased ROS generation and overwhelm antioxidant defenses This can lead to further disruption of mitochondrial metabolic processes, endoplasmic reticulum Ca2+ release, cell death, damage of mitochondrial DNA (mtDNA), and promotion of inflammatory signaling[13]
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