The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages
Dino Gobelli,
Pablo Serrano-Lorenzo,
María J. Esteban-Amo,
Julia Serna,
M. Teresa Pérez-García,
Antonio Orduña,
Alexis A. Jourdain,
Miguel Á. Martín-Casanueva,
Miguel Á. de la Fuente,
María Simarro
Affiliations
Dino Gobelli
Department of Cell Biology, Histology and Pharmacology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain; Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain
Pablo Serrano-Lorenzo
Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain; Mitochondrial Disorders Laboratory, Clinical Biochemistry Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
María J. Esteban-Amo
Department of Cell Biology, Histology and Pharmacology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain; Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain
Julia Serna
Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain; Department of Biochemistry and Molecular Biology and Physiology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain
M. Teresa Pérez-García
Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain; Department of Biochemistry and Molecular Biology and Physiology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain
Antonio Orduña
Division of Microbiology, Hospital Clínico of Valladolid, 47003 Valladolid, Spain; Department of Microbiology, University of Valladolid, 47005 Valladolid, Spain
Alexis A. Jourdain
Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, Switzerland
Miguel Á. Martín-Casanueva
Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain; Mitochondrial Disorders Laboratory, Clinical Biochemistry Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain
Miguel Á. de la Fuente
Department of Cell Biology, Histology and Pharmacology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain; Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain
María Simarro
Department of Cell Biology, Histology and Pharmacology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain; Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain; Corresponding author
Summary: The functions of macrophages are tightly regulated by their metabolic state. However, the role of the mitochondrial electron transport chain (ETC) in macrophage functions remains understudied. Here, we provide evidence that the succinate dehydrogenase (SDH)/complex II (CII) is required for respiration and plays a role in controlling effector responses in macrophages. We find that the absence of the catalytic subunits Sdha and Sdhb in macrophages impairs their ability to effectively stabilize HIF-1α and produce the pro-inflammatory cytokine IL-1β in response to LPS stimulation. We also arrive at the novel result that both subunits are essential for the LPS-driven production of IL-10, a potent negative feedback regulator of the macrophage inflammatory response. This phenomenon is explained by the fact that the absence of Sdha and Sdhb leads to the inhibition of Stat3 tyrosine phosphorylation, caused partially by the excessive accumulation of mitochondrial reactive oxygen species (mitoROS) in the knockout cells.
