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

doi:10.1016/j.isci.2023.107473

The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages

iScience. 2023 Jul 25;26(8):107473. doi: 10.1016/j.isci.2023.107473. eCollection 2023 Aug 18.

Authors

Dino Gobelli^{1

2}, Pablo Serrano-Lorenzo^{3

4

5}, María J Esteban-Amo^{1

2}, Julia Serna^{2

6}, M Teresa Pérez-García^{2

6}, Antonio Orduña^{7

8}, Alexis A Jourdain⁹, Miguel Á Martín-Casanueva^{3

4

5}, Miguel Á de la Fuente^{1

2}, María Simarro^{1

2}

Affiliations

¹ Department of Cell Biology, Histology and Pharmacology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain.
² Unit of Excellence Institute of Biomedicine and Molecular Genetics (IBGM), University of Valladolid and Spanish National Research Council (CSIC), 47003 Valladolid, Spain.
³ Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain.
⁴ Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain.
⁵ Mitochondrial Disorders Laboratory, Clinical Biochemistry Department, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.
⁶ Department of Biochemistry and Molecular Biology and Physiology, Faculty of Medicine, University of Valladolid, 47005 Valladolid, Spain.
⁷ Division of Microbiology, Hospital Clínico of Valladolid, 47003 Valladolid, Spain.
⁸ Department of Microbiology, University of Valladolid, 47005 Valladolid, Spain.
⁹ Department of Immunobiology, Faculty of Biology and Medicine, University of Lausanne, 1011 Lausanne, Switzerland.

Abstract

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.

Keywords: Biological sciences; Cell biology; Immunology; Molecular biology.