title: Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation.
abstract: Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside the cells in blood in various pathologies. Platelets are abundant in blood where they promote hemostasis. Although lacking a nucleus, platelets contain functional mitochondria. On activation, platelets produce extracellular vesicles known as microparticles. We hypothesized that activated platelets could also release their mitochondria. We show that activated platelets release respiratory-competent mitochondria, both within membrane-encapsulated microparticles and as free organelles. Extracellular mitochondria are found in platelet concentrates used for transfusion and are present at higher levels in those that induced acute reactions (febrile nonhemolytic reactions, skin manifestations, and cardiovascular events) in transfused patients. We establish that the mitochondrion is an endogenous substrate of secreted phospholipase A2 IIA (sPLA2-IIA), a phospholipase otherwise specific for bacteria, likely reflecting the ancestral proteobacteria origin of mitochondria. The hydrolysis of the mitochondrial membrane by sPLA2-IIA yields inflammatory mediators (ie, lysophospholipids, fatty acids, and mtDNA) that promote leukocyte activation. Two-photon microscopy in live transfused animals revealed that extracellular mitochondria interact with neutrophils in vivo, triggering neutrophil adhesion to the endothelial wall. Our findings identify extracellular mitochondria, produced by platelets, at the midpoint of a potent mechanism leading to inflammatory responses.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
authors.forename: Luc H
authors.initials: LH
authors.lastname: Boudreau
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Duchez
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cloutier
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Psychiatrie et Neurosciences, Quebec, QC, Canada;
authors.forename: Denis
authors.initials: D
authors.lastname: Soulet
authors.affiliation: Département de Biologie, Université Laval, Quebec, QC, Canada;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Martin
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA;
authors.forename: James
authors.initials: J
authors.lastname: Bollinger
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Psychiatrie et Neurosciences, Quebec, QC, Canada;
authors.forename: Alexandre
authors.initials: A
authors.lastname: Paré
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
authors.forename: Matthieu
authors.initials: M
authors.lastname: Rousseau
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA;
authors.forename: Gajendra S
authors.initials: GS
authors.lastname: Naika
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
authors.forename: Tania
authors.initials: T
authors.lastname: Lévesque
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
authors.forename: Cynthia
authors.initials: C
authors.lastname: Laflamme
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
authors.forename: Geneviève
authors.initials: G
authors.lastname: Marcoux
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 7275, Centre National de la Recherche Scientifique-Université Nice Sophia Antipolis, Valbonne, France;
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Richard W
authors.initials: RW
authors.lastname: Farndale
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
authors.forename: Marc
authors.initials: M
authors.lastname: Pouliot
authors.affiliation: Etablissement Français du Sang Auvergne-Loire and Université de Lyon, Saint-Etienne, France;
authors.forename: Hind
authors.initials: H
authors.lastname: Hamzeh-Cognasse
authors.affiliation: Etablissement Français du Sang Auvergne-Loire and Université de Lyon, Saint-Etienne, France;
authors.forename: Fabrice
authors.initials: F
authors.lastname: Cognasse
authors.affiliation: Etablissement Français du Sang Auvergne-Loire and Université de Lyon, Saint-Etienne, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Garraud
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, and Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Peter A
authors.initials: PA
authors.lastname: Nigrovic
authors.affiliation: Département de Biologie, Université Laval, Quebec, QC, Canada;
authors.forename: Helga
authors.initials: H
authors.lastname: Guderley
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Psychiatrie et Neurosciences, Quebec, QC, Canada;
authors.forename: Steve
authors.initials: S
authors.lastname: Lacroix
authors.affiliation: Research and Development, Héma-Québec, Quebec, QC, Canada; and.
authors.forename: Louis
authors.initials: L
authors.lastname: Thibault
authors.affiliation: The Keenan Research Center in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Semple
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA;
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
authors.forename: Eric
authors.initials: E
authors.lastname: Boilard
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005434:Flow Cytometry; D054501:Group II Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D015539:Platelet Activation; D012283:Rickettsia prowazekii / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D054501:Group II Phospholipases A2; C516287:PLA2G2A protein, human; C516288:Pla2g2a protein, mouse
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