Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity
Juan Tur,
Selma Pereira-Lopes,
Tania Vico,
Eros A. Marín,
Juan P. Muñoz,
Maribel Hernández-Alvarez,
Pere-Joan Cardona,
Antonio Zorzano,
Jorge Lloberas,
Antonio Celada
Affiliations
Juan Tur
Macrophage Biology Group, Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
Selma Pereira-Lopes
Macrophage Biology Group, Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
Tania Vico
Macrophage Biology Group, Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
Eros A. Marín
Macrophage Biology Group, Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
Juan P. Muñoz
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
Maribel Hernández-Alvarez
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
Pere-Joan Cardona
Unitat de tuberculosi experimental, Institut Germans Trias i Pujol, Badalona, Spain
Antonio Zorzano
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08036 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
Jorge Lloberas
Macrophage Biology Group, Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; Corresponding author
Antonio Celada
Macrophage Biology Group, Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; Corresponding author
Summary: Mitofusin 2 (Mfn2) plays a major role in mitochondrial fusion and in the maintenance of mitochondria-endoplasmic reticulum contact sites. Given that macrophages play a major role in inflammation, we studied the contribution of Mfn2 to the activity of these cells. Pro-inflammatory stimuli such as lipopolysaccharide (LPS) induced Mfn2 expression. The use of the Mfn2 and Mfn1 myeloid-conditional knockout (KO) mouse models reveals that Mfn2 but not Mfn1 is required for the adaptation of mitochondrial respiration to stress conditions and for the production of reactive oxygen species (ROS) upon pro-inflammatory activation. Mfn2 deficiency specifically impairs the production of pro-inflammatory cytokines and nitric oxide. In addition, the lack of Mfn2 but not Mfn1 is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. Mfn2floxed;CreLysM mice fail to be protected from Listeria, Mycobacterium tuberculosis, or LPS endotoxemia. These results reveal an unexpected contribution of Mfn2 to ROS production and inflammation in macrophages.