Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
Department of Agricultural & Biological Engineering, Purdue University, West Lafayette, IN 47907, USA.
J Cell Sci. 2020 Sep 4;133(17):jcs248880. doi: 10.1242/jcs.248880.
Neutrophils rely on glycolysis for energy production. How mitochondria regulate neutrophil function is not fully understood. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (MFN2) regulates neutrophil homeostasis and chemotaxis -deficient neutrophils are released from the hematopoietic tissue, trapped in the vasculature in zebrafish embryos, and not capable of chemotaxis. Consistent with this, human neutrophil-like cells that are deficient for MFN2 fail to arrest on activated endothelium under sheer stress or perform chemotaxis on 2D surfaces. Deletion of MFN2 results in a significant reduction of neutrophil infiltration to the inflamed peritoneal cavity in mice. Mechanistically, MFN2-deficient neutrophil-like cells display disrupted mitochondria-ER interaction, heightened intracellular Ca levels and elevated Rac activation after chemokine stimulation. Restoring a mitochondria-ER tether rescues the abnormal Ca levels, Rac hyperactivation and chemotaxis defect resulting from MFN2 depletion. Finally, inhibition of Rac activation restores chemotaxis in MFN2-deficient neutrophils. Taken together, we have identified that MFN2 regulates neutrophil migration via maintaining the mitochondria-ER interaction to suppress Rac activation, and uncovered a previously unrecognized role of MFN2 in regulating cell migration and the actin cytoskeleton.This article has an associated First Person interview with the first authors of the paper.
中性粒细胞依赖糖酵解产生能量。线粒体如何调节中性粒细胞功能尚不完全清楚。在这里，我们报告说，线粒体外膜蛋白 Mitofusin 2（MFN2）调节中性粒细胞的稳态和趋化作用——缺乏 MFN2 的中性粒细胞从造血组织中释放出来，被困在斑马鱼胚胎的脉管系统中，并且不能趋化。与此一致的是，缺乏 MFN2 的人中性粒细胞样细胞在切应力下不能在激活的内皮细胞上停止，也不能在 2D 表面上进行趋化。MFN2 的缺失导致小鼠炎症性腹膜腔中中性粒细胞浸润显著减少。在机制上，MFN2 缺陷的中性粒细胞样细胞在趋化因子刺激后显示出线粒体-内质网相互作用破坏、细胞内 Ca 水平升高和 Rac 激活升高。恢复线粒体-内质网连接可挽救由于 MFN2 缺失导致的异常 Ca 水平、Rac 过度激活和趋化作用缺陷。最后，抑制 Rac 激活可恢复 MFN2 缺陷中性粒细胞的趋化作用。总之，我们已经确定 MFN2 通过维持线粒体-内质网相互作用来抑制 Rac 激活来调节中性粒细胞迁移，并揭示了 MFN2 在调节细胞迁移和肌动蛋白细胞骨架中的先前未被认识的作用。本文有该论文第一作者的相关第一人称采访。
