Macrophage Biology Group, Department of Cell Biology, Physiology and Immunology, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain.
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.
Cell Rep. 2020 Aug 25;32(8):108079. doi: 10.1016/j.celrep.2020.108079.
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. Mfn2 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.
线粒体融合蛋白 2（Mfn2）在线粒体融合和维持线粒体-内质网接触位点方面发挥着重要作用。鉴于巨噬细胞在炎症中起着重要作用，我们研究了 Mfn2 对这些细胞活性的贡献。促炎刺激物，如脂多糖（LPS），诱导 Mfn2 的表达。使用 Mfn2 和 Mfn1 骨髓细胞条件性敲除（KO）小鼠模型表明，Mfn2 但不是 Mfn1，对于线粒体呼吸对应激条件的适应以及在促炎激活时产生活性氧（ROS）是必需的。Mfn2 缺乏特异性地损害促炎细胞因子和一氧化氮的产生。此外，缺乏 Mfn2 但不是 Mfn1 与自噬、细胞凋亡、吞噬作用和抗原处理的功能障碍有关。Mfn2 小鼠不能免受李斯特菌、结核分枝杆菌或 LPS 内毒素血症的保护。这些结果揭示了 Mfn2 在巨噬细胞中产生 ROS 和炎症中的意外作用。
