title: Mitophagy confers resistance to siderophore-mediated killing by Pseudomonas aeruginosa.
abstract: In the arms race of bacterial pathogenesis, bacteria produce an array of toxins and virulence factors that disrupt core host processes. Hosts mitigate the ensuing damage by responding with immune countermeasures. The iron-binding siderophore pyoverdin is a key virulence mediator of the human pathogen Pseudomonas aeruginosa, but its pathogenic mechanism has not been established. Here we demonstrate that pyoverdin enters Caenorhabditis elegans and that it is sufficient to mediate host killing. Moreover, we show that iron chelation disrupts mitochondrial homeostasis and triggers mitophagy both in C. elegans and mammalian cells. Finally, we show that mitophagy provides protection both against the extracellular pathogen P. aeruginosa and to treatment with a xenobiotic chelator, phenanthroline, in C. elegans. Although autophagic machinery has been shown to target intracellular bacteria for degradation (a process known as xenophagy), our report establishes a role for authentic mitochondrial autophagy in the innate immune defense against P. aeruginosa.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; and Department of Genetics, Harvard Medical School, Boston, MA 02115.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Kirienko
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; and Department of Genetics, Harvard Medical School, Boston, MA 02115.
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Ausubel
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; and Department of Genetics, Harvard Medical School, Boston, MA 02115 ruvkun@molbio.mgh.harvard.edu.
authors.forename: Gary
authors.initials: G
authors.lastname: Ruvkun
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D005453:Fluorescence; D057809:HEK293 Cells; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007501:Iron / Q000378:metabolism; D018613:Microscopy, Confocal; D063306:Mitophagy / Q000187:drug effects* / Q000276:immunology; D009842:Oligopeptides / Q000378:metabolism / Q000633:toxicity*; D010618:Phenanthrolines; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D017262:Siderophores / Q000378:metabolism / Q000633:toxicity*
chemical_list: D009842:Oligopeptides; D010618:Phenanthrolines; D017262:Siderophores; C042453:pyoverdin; D007501:Iron
keywords: C. elegans; Pseudomonas; innate immunity; mitophagy; siderophore