PUBLICATION
Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton
- Authors
- Zhou, W., Hsu, A.Y., Wang, Y., Syahirah, R., Wang, T., Jeffries, J., Wang, X., Mohammad, H., Seleem, M.N., Umulis, D., Deng, Q.
- ID
- ZDB-PUB-200814-10
- Date
- 2020
- Source
- Journal of Cell Science 133(17): (Journal)
- Registered Authors
- Deng, Qing, Jeffries, Jacob, Syahirah Mohd Sabri, Ramizah
- Keywords
- Actin, Chemotaxis, Leukocyte, Mitochondria, Rac, Zebrafish
- MeSH Terms
-
- Actin Cytoskeleton
- Adhesives
- Animals
- Cell Movement
- Mice
- Neutrophils*
- Zebrafish*
- PubMed
- 32788232 Full text @ J. Cell Sci.
Citation
Zhou, W., Hsu, A.Y., Wang, Y., Syahirah, R., Wang, T., Jeffries, J., Wang, X., Mohammad, H., Seleem, M.N., Umulis, D., Deng, Q. (2020) Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton. Journal of Cell Science. 133(17):.
Abstract
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. Consistently, human neutrophil-like cells deficient with 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 calcium levels, and elevated Rac activation after chemokine stimulation. Restoring mitochondria-ER tether rescues the abnormal calcium levels, Rac hyperactivation, and chemotaxis defect resulted from MFN2 depletion. Finally, inhibition of Rac activation restores chemotaxis in MFN2-deficient neutrophils. Altogether, we identified that MFN2 regulates neutrophil migration via maintaining mitochondria-ER interaction to suppress Rac activation and uncovered a previously unrecognized role of MFN2 in regulating cell migration and the actin cytoskeleton.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping