Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxo-dodecanoyl)-L-homoserine lactone triggers mitochondrial dysfunction and apoptosis in neutrophils through calcium signaling.

Abstract:

:Pseudomonas aeruginosa is an opportunistic pathogen that utilizes the quorum-sensing (QS) process to regulate the production of different virulence factors and biofilm. N-3-oxo-dodecanoyl-L-homoserine lactone (C12) is a key QS molecule of P. aeruginosa which interacts with the mammalian immune cells and modulates their function. Here, we investigated the molecular mechanism of C12-induced apoptosis in neutrophils. Our data show that C12 causes apoptosis in neutrophils through an elevation in cytosolic and mitochondrial Ca2+ levels. Besides, C12 induces phosphatidylserine (PS) exposure, mitochondrial membrane potential (MMP) depolarization, mitochondrial permeability transition pore (MPTP) formation and mitochondrial reactive oxygen species (mROS) generation. C12-induced rise in intracellular Ca2+ level is majorly contributed by endoplasmic reticulum store through the activation of inositol 1, 4, 5-triphosphate receptor. Intracellular calcium chelation inhibited C12-induced mitochondrial dysfunction and apoptosis. Further, inhibition of mitochondrial Ca2+ uniporter by ruthenium red or Ru360 abrogated C12-induced mitochondrial Ca2+ uptake, MMP loss, MPTP opening, mROS production, and PS exposure. These mechanistic insights are expected to provide a better understanding of the role of C12 in P. aeruginosa pathogenesis.

journal_name

Med Microbiol Immunol

authors

Singh PK,Yadav VK,Kalia M,Sharma D,Pandey D,Agarwal V

doi

10.1007/s00430-019-00631-8

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

855-868

issue

6

eissn

0300-8584

issn

1432-1831

pii

10.1007/s00430-019-00631-8

journal_volume

208

pub_type

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