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Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton.

Authors
  • Zhou, Wenqing1
  • Hsu, Alan Y1
  • Wang, Yueyang1
  • Syahirah, Ramizah1
  • Wang, Tianqi1
  • Jeffries, Jacob1
  • Wang, Xu2, 3
  • Mohammad, Haroon4
  • Seleem, Mohamed N4, 5
  • Umulis, David2, 3
  • Deng, Qing6, 5, 7
  • 1 Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
  • 2 Department of Agricultural & Biological Engineering, Purdue University, West Lafayette, IN 47907, USA.
  • 3 Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
  • 4 Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA.
  • 5 Purdue Institute for Inflammation, Immunology & Infectious Disease, Purdue University, West Lafayette, IN 47907, USA.
  • 6 Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA [email protected]
  • 7 Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Sep 04, 2020
Volume
133
Issue
17
Identifiers
DOI: 10.1242/jcs.248880
PMID: 32788232
Source
Medline
Keywords
Language
English
License
Unknown

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. 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. © 2020. Published by The Company of Biologists Ltd.

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