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.

中文翻译：

---

铜绿假单胞菌群体感应分子N-（3-氧代十二烷酰基）-L-高丝氨酸内酯通过钙信号触发中性粒细胞的线粒体功能障碍和凋亡。

铜绿假单胞菌是一种机会病原体，它利用群体感应（QS）过程来调节不同毒力因子和生物膜的产生。N -3-氧代十二烷酰基-1-高丝氨酸内酯（C12）是铜绿假单胞菌的关键QS分子，它与哺乳动物的免疫细胞相互作用并调节其功能。在这里，我们研究了中性粒细胞中C12诱导凋亡的分子机制。我们的数据表明C12通过增加胞质和线粒体Ca ²⁺引起中性粒细胞凋亡水平。此外，C12还诱导了磷脂酰丝氨酸（PS）的暴露，线粒体膜电位（MMP）的去极化，线粒体通透性转换孔（MPTP）的形成和线粒体活性氧（mROS）的产生。C12诱导的细胞内Ca ²⁺水平升高主要是通过肌醇1、4、5-三磷酸受体的激活引起的内质网存储。细胞内钙螯合抑制C12诱导的线粒体功能障碍和细胞凋亡。此外，钌红或Ru360抑制线粒体Ca ²⁺单向转运体，废除了C12诱导的线粒体Ca ²⁺摄取，MMP丢失，MPTP开放，mROS产生和PS暴露。这些机制的见解有望使人们更好地了解C12在铜绿假单胞菌发病机理中的作用。