Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton

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dc.contributor.authorZhou, Wenqingen
dc.contributor.authorHsu, Alan Y.en
dc.contributor.authorWang, Yueyangen
dc.contributor.authorSyahirah, Ramizahen
dc.contributor.authorWang, Tianqien
dc.contributor.authorJeffries, Jacoben
dc.contributor.authorWang, Xuen
dc.contributor.authorMohammad, Haroonen
dc.contributor.authorSeleem, Mohamed N.en
dc.contributor.authorUmulis, Daviden
dc.contributor.authorDeng, Qingen
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.date.accessioned2020-12-10T14:36:38Zen
dc.date.available2020-12-10T14:36:38Zen
dc.date.issued2020-09en
dc.description.abstractNeutrophils 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 neutrophilhomeostasis andchemotaxis in vivo. Mfn2-deficientneutrophils 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.en
dc.description.notesThe work was supported by National Institutes of Health (R35GM119787 to Q.D.; R01HD073156 to D.U.; and P30CA023168 to Purdue Center for Cancer Research for shared resources). W.Z. and A.Y.H. are supported by Cagiantas Fellowships, Purdue University. Deposited in PMC for immediate release.en
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R35GM119787, R01HD073156, P30CA023168]; Cagiantas Fellowships, Purdue Universityen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1242/jcs.248880en
dc.identifier.eissn1477-9137en
dc.identifier.issn0021-9533en
dc.identifier.issue17en
dc.identifier.otherjcs248880en
dc.identifier.pmid32788232en
dc.identifier.urihttp://hdl.handle.net/10919/101062en
dc.identifier.volume133en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectMitochondriaen
dc.subjectChemotaxisen
dc.subjectRacen
dc.subjectZebrafishen
dc.subjectActinen
dc.subjectLeukocyteen
dc.titleMitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeletonen
dc.title.serialJournal of Cell Scienceen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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