A Conserved Mitochondrial Surveillance Pathway Is Required for Defense against Pseudomonas aeruginosa

In the arms race of bacterial pathogenesis, bacteria produce an array of toxins and virulence factors that disrupt host processes while hosts respond with immune countermeasures. One key virulence mediator of the ubiquitous, opportunistic, extracellular pathogen Pseudomonas aeruginosa is the iron-binding siderophore pyoverdin (PMID:10722571;PMID: 8550201). The mechanisms used by pyoverdin to acquire iron from the host remain incompletely elucidated. Here we demonstrate that mitochondria represent an important target for iron acquisition and that exposure to this toxin results in loss of mitochondrial membrane potential, altered mitochondrial dynamics, and mitophagy in both Caenorhabditis elegans and mammalian cells. We also show that animal mitophagy protects the consequences of siderophore activity, conferring resistance to pyoverdin-mediated host killing. In C. elegans, the conserved autophagic genes bec-1/BECN1 and lgg-1/LC3, and the mitophagic regulator pink-1/PINK1 are required for iron chelator-elicited mitochondrial turnover and provide protection against iron sequestration by P. aeruginosa, likely by ameliorating the mitochondrial damage. While autophagic mechanisms have been implicated in the destruction of intracellular bacteria via a process called xenophagy (PMID: 24005326), our findings represent the first report of resistance to an extracellular pathogen being conferred by authentic autophagic activity that targets host organelles.在细菌致病的军备竞赛中，细菌会产生一系列毒素与毒力因子以破坏宿主生理过程，而宿主则会启动免疫防御对策与之抗衡。广泛存在的机会性胞外致病菌铜绿假单胞菌（Pseudomonas aeruginosa）的关键毒力介导因子之一，是结合铁离子的铁载体绿脓杆菌素（pyoverdin）（文献编号：PMID:10722571；PMID:8550201）。目前，绿脓杆菌素从宿主体内夺取铁离子的具体机制尚未完全阐明。本研究证实，线粒体是绿脓杆菌素夺取铁离子的重要靶标；在秀丽隐杆线虫（Caenorhabditis elegans）与哺乳动物细胞中，暴露于该毒素会引发线粒体膜电位丧失、线粒体动力学改变以及线粒体自噬（mitophagy）。本研究同时发现，动物体内的线粒体自噬可拮抗铁载体介导的损伤，使宿主对绿脓杆菌素诱导的宿主死亡产生抗性。在秀丽隐杆线虫中，保守的自噬基因bec-1/BECN1与lgg-1/LC3，以及线粒体自噬调控因子pink-1/PINK1，参与铁螯合剂诱导的线粒体周转过程，并可通过缓解线粒体损伤，对抗铜绿假单胞菌介导的铁离子螯合作用。尽管此前已有研究表明，自噬机制可通过一种被称为异体吞噬（xenophagy）的过程清除胞内细菌（文献编号：PMID:24005326），但本研究首次报道，靶向宿主细胞器的功能性自噬活性可赋予宿主对抗胞外致病菌的抗性。