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 in vivo. Mfn2-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 Ca²⁺ levels and elevated Rac activation after chemokine stimulation. Restoring a mitochondria–ER tether rescues the abnormal Ca²⁺ 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.

中性粒细胞依靠糖酵解来产生能量。线粒体如何调节中性粒细胞功能尚不完全清楚。在这里，我们报道线粒体外膜蛋白 Mitofusin 2 (MFN2)在体内调节中性粒细胞稳态和趋化性。Mfn2缺陷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，并且不具有趋化性。与此一致的是，缺乏 MFN2 的人类中性粒细胞样细胞无法在纯粹应力下停滞在活化的内皮上，也无法在 2D 表面上进行趋化。删除 MFN2 会导致小鼠发炎腹腔的中性粒细胞浸润显着减少。从机制上讲，MFN2 缺陷的中性粒细胞样细胞在趋化因子刺激后表现出线粒体与 ER 相互作用中断、细胞内 Ca ²⁺水平升高以及 Rac 激活升高。恢复线粒体-ER 系链可以挽救异常的 Ca ²⁺水平、Rac 过度激活和 MFN2 耗竭导致的趋化性缺陷。最后，抑制 Rac 激活可恢复 MFN2 缺陷的中性粒细胞的趋化性。综上所述，我们发现 MFN2 通过维持线粒体 - ER 相互作用来抑制 Rac 激活，从而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以前未被认识的作用。

本文与该论文的第一作者进行了相关的第一人称采访。