title: Regulation of oxidative stress by methylation-controlled J protein controls macrophage responses to inflammatory insults.
abstract: Mitochondria contribute to macrophage immune function through the generation of reactive oxygen species, a byproduct of the mitochondrial respiratory chain. MCJ (also known as DnaJC15) is a mitochondrial inner membrane protein identified as an endogenous inhibitor of respiratory chain complex I. Here we show that MCJ is essential for the production of tumor necrosis factor by macrophages in response to a variety of Toll-like receptor ligands and bacteria, without affecting their phagocytic activity. Loss of MCJ in macrophages results in increased mitochondrial respiration and elevated basal levels of reactive oxygen species that cause activation of the JNK/c-Jun pathway, lead to the upregulation of the TACE (also known as ADAM17) inhibitor TIMP-3, and lead to the inhibition of tumor necrosis factor shedding from the plasma membrane. Consequently, MCJ-deficient mice are resistant to the development of fulminant liver injury upon lipopolysaccharide administration. Thus, attenuation of the mitochondrial respiratory chain by MCJ in macrophages exquisitely regulates the response of macrophages to infectious insults.
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst Proteomics Unit.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Navasa
authors.affiliation: Proteomics Unit.
authors.forename: Itziar
authors.initials: I
authors.lastname: Martín
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Iglesias-Pedraz
authors.affiliation: Metabolomics Unit, CIC bioGUNE.
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
authors.affiliation: Proteomics Unit.
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Atondo
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst.
authors.forename: Hooman
authors.initials: H
authors.lastname: Izadi
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst.
authors.forename: Furkan
authors.initials: F
authors.lastname: Ayaz
authors.affiliation: Metabolomics Unit, CIC bioGUNE.
authors.forename: Sara
authors.initials: S
authors.lastname: Fernández-Álvarez
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington.
authors.forename: Ketki
authors.initials: K
authors.lastname: Hatle
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst.
authors.forename: Abhigyam
authors.initials: A
authors.lastname: Som
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington.
authors.forename: Oliver
authors.initials: O
authors.lastname: Dienz
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Osborne
authors.affiliation: Metabolomics Unit, CIC bioGUNE Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Technology Park of Bizkaia, Derio Biochemistry and Molecular Biology Department, University of the Basque Country.
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincón
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst Proteomics Unit Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Anguita
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D004579:Electron Transport; D016758:Genes, jun; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C582292:Mcj protein, mouse; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D019717:Tissue Inhibitor of Metalloproteinase-3; D051193:Toll-Like Receptors; D048069:Tumor Necrosis Factors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: MCJ; TACE activity; TIMP-3; TNF shedding; macrophage; reactive oxygen species