ABSTRACT

MFN2 (mitofusin 2) is required for mitochondrial fusion and for mitochondria-endoplasmic reticulum interaction. Using myeloid-conditional KO mice models, we found that MFN2 but not MFN1 is a prerequisite for the adaptation of mitochondrial respiration to stress conditions as well as for the production of reactive oxygen species (ROS). The deficient ROS production in the absence of MFN2 impairs the induction of cytokines and nitric oxide, and is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. The lack of MFN2 in macrophages causes an impaired response in a model of non-septic inflammation in mice, as well as a failure in protection from Listeria, Mycobacterium tuberculosis or LPS endotoxemia. These results reveal an unexpected role of MFN2 to ROS production in macrophages affecting natural and acquired immunity and the immune response.

摘要

MFN2（mitofusin 2）是线粒体融合和线粒体-内质网相互作用所必需的。使用骨髓条件性 KO 小鼠模型，我们发现 MFN2 而不是 MFN1 是线粒体呼吸适应压力条件以及产生活性氧 (ROS) 的先决条件。在没有 MFN2 的情况下，ROS 产生不足会损害细胞因子和一氧化氮的诱导，并与功能失调的自噬、细胞凋亡、吞噬作用和抗原加工有关。巨噬细胞中 MFN2 的缺乏导致小鼠非感染性炎症模型的反应受损，以及对李斯特菌、结核分枝杆菌的保护失败或 LPS 内毒素血症。这些结果揭示了 MFN2 对巨噬细胞中 ROS 产生的意外作用，影响自然和获得性免疫以及免疫反应。