Mitofusin 2 regulates neutrophil adhesive migration via suppressing Rac activation

Mitochondrial membrane potential is required for neutrophil migration, although the mechanism remains unclear. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (Mfn2) regulates neutrophil homeostasis in vivo. Mfn2-deficient neutrophils are released from the hematopoietic tissue and trapped in the vasculature in zebrafish embryos. Human neutrophil-like cells deficient with MFN2 fail to be arrested by activated endothelium under sheer stress or perform chemotaxis on substrates. Deletion of Mfn2 results in a significant reduction of neutrophil infiltration to the inflamed peritoneal cavity in mice. Mfn2-deficient neutrophil-like cells and mouse embryonic fibroblasts display heightened Rac activation. Mechanistically, MFN2 maintains mitochondria-ER interaction and prevents excessive elevation of cytosolic calcium and subsequent phosphorylation of CaMKII upon stimulation. Inhibiting CaMKII or the Rac GEF Tiam rescues the chemotaxis defect that results from Mfn2 depletion. Altogether, we identified an Mfn2-CaMKII-Tiam-Rac axis in regulating neutrophil migration and discovered a role of MFN2 in regulating the actin cytoskeleton.