PON2 mediates mitochondrial dysfunction in tracheal epithelial cells in response to a quorum sensing molecule N-(-3-oxododecanoyl)-l-homoserine lactone.

Autor:	Whitt AG; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, U.S.A.; Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, U.S.A., Meng S; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, U.S.A.; Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, U.S.A., Jin JZ; Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, U.S.A., Conroy LR; Department of Neuroscience, College of Medicine, University of Kentucky, Lexington, KY, U.S.A.; Markey Cancer Center, University of Kentucky, Lexington, KY, U.S.A., McNally LA; Diabetes and Obesity Center, Division of Environmental Medicine, Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KY, U.S.A., Burlison JA; Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, U.S.A., Hill BG; Diabetes and Obesity Center, Division of Environmental Medicine, Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KY, U.S.A.; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, U.S.A., Clem BF; Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, U.S.A.; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, U.S.A., White C; Department of Physiology and Biophysics, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, U.S.A., Li C; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, U.S.A.; Experimental Therapeutics Group, Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, U.S.A.
Jazyk:	angličtina
Zdroj:	The Biochemical journal [Biochem J] 2022 Oct 14; Vol. 479 (19), pp. 2013-2034.
DOI:	10.1042/BCJ20220100
Abstrakt:	The opportunistic bacterium Pseudomonas aeruginosa secretes the quorum-sensing molecule N-(3-oxododecanoyl)-l-homoserine lactone (C12) to co-ordinate gene expression profiles favorable for infection. Recent studies have demonstrated that high concentrations of C12 impair many aspects of host cell physiology, including mitochondrial function and cell viability. The cytotoxic effects of C12 are mediated by the lactonase enzyme, Paraoxonase 2 (PON2), which hydrolyzes C12 to a reactive metabolite. However, the influence of C12 on host cell physiology at concentrations observed in patients infected with P. aeruginosa is largely unknown. Since the primary site of P. aeruginosa infections is the mammalian airway, we sought to investigate how PON2 modulates the effects of C12 at subtoxic concentrations using immortalized murine tracheal epithelial cells (TECs) isolated from wild-type (WT) or PON2-knockout (PON2-KO) mice. Our data reveal that C12 at subtoxic concentrations disrupts mitochondrial bioenergetics to hinder cellular proliferation in TECs expressing PON2. Subtoxic concentrations of C12 disrupt normal mitochondrial network morphology in a PON2-dependent manner without affecting mitochondrial membrane potential. In contrast, higher concentrations of C12 depolarize mitochondrial membrane potential and subsequently trigger caspase signaling and apoptotic cell death. These findings demonstrate that different concentrations of C12 impact distinct aspects of host airway epithelial cell physiology through PON2 activity in mitochondria. (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
Databáze:	MEDLINE
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