title: Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense.
abstract: Macrophages tightly scale their core metabolism after being activated, but the precise regulation of the mitochondrial electron-transport chain (ETC) and its functional implications are currently unknown. Here we found that recognition of live bacteria by macrophages transiently decreased assembly of the ETC complex I (CI) and CI-containing super-complexes and switched the relative contributions of CI and CII to mitochondrial respiration. This was mediated by phagosomal NADPH oxidase and the reactive oxygen species (ROS)-dependent tyrosine kinase Fgr. It required Toll-like receptor signaling and the NLRP3 inflammasome, which were both connected to bacterial viability-specific immune responses. Inhibition of CII during infection with Escherichia coli normalized serum concentrations of interleukin 1β (IL-1β) and IL-10 to those in mice treated with dead bacteria and impaired control of bacteria. We have thus identified ETC adaptations as an early immunological-metabolic checkpoint that adjusts innate immune responses to bacterial infection.
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.|Institute for Regenerative Medicine and Biotherapies, Institut National pour la Santé et la Recherche Médicale, U1183, Montpellier, France.
authors.forename: Johan
authors.initials: J
authors.lastname: Garaude
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acín-Pérez
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Sarai
authors.initials: S
authors.lastname: Martínez-Cano
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Michel
authors.initials: M
authors.lastname: Enamorado
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité Hospital Berlin, Berlin, Germany.
authors.forename: Matteo
authors.initials: M
authors.lastname: Ugolini
authors.affiliation: Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.
authors.forename: Estanislao
authors.initials: E
authors.lastname: Nistal-Villán
authors.affiliation: Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervás-Stubbs
authors.affiliation: Unidad de Inflamación y Cirugía Experimental, Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria-Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Pelegrín
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité Hospital Berlin, Berlin, Germany.
authors.forename: Leif E
authors.initials: LE
authors.lastname: Sander
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.|Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Enríquez
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sancho
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D004927:Escherichia coli Infections / Q000276:immunology*; D048168:Escherichia coli K12 / Q000276:immunology*; D006790:Host-Parasite Interactions; D007113:Immunity, Innate / Q000235:genetics; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D045222:Electron Transport Chain Complex Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D016753:Interleukin-10