Mitofusin-2 stabilizes adherens junctions and suppresses endothelial inflammation via modulation of β-catenin signaling

Young-Mee Kim (), Sarah Krantz, Ankit Jambusaria, Peter T. Toth, Hyung-Geun Moon, Isuru Gunarathna, Gye Young Park and Jalees Rehman ()
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Young-Mee Kim: University of Illinois at Chicago
Sarah Krantz: University of Illinois at Chicago
Ankit Jambusaria: University of Illinois at Chicago
Peter T. Toth: University of Illinois at Chicago
Hyung-Geun Moon: Department of Medicine, University of Illinois at Chicago
Isuru Gunarathna: University of Illinois at Chicago
Gye Young Park: Department of Medicine, University of Illinois at Chicago
Jalees Rehman: University of Illinois at Chicago

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Endothelial barrier integrity is ensured by the stability of the adherens junction (AJ) complexes comprised of vascular endothelial (VE)-cadherin as well as accessory proteins such as β-catenin and p120-catenin. Disruption of the endothelial barrier due to disassembly of AJs results in tissue edema and the influx of inflammatory cells. Using three-dimensional structured illumination microscopy, we observe that the mitochondrial protein Mitofusin-2 (Mfn2) co-localizes at the plasma membrane with VE-cadherin and β-catenin in endothelial cells during homeostasis. Upon inflammatory stimulation, Mfn2 is sulfenylated, the Mfn2/β-catenin complex disassociates from the AJs and Mfn2 accumulates in the nucleus where Mfn2 negatively regulates the transcriptional activity of β-catenin. Endothelial-specific deletion of Mfn2 results in inflammatory activation, indicating an anti-inflammatory role of Mfn2 in vivo. Our results suggest that Mfn2 acts in a non-canonical manner to suppress the inflammatory response by stabilizing cell–cell adherens junctions and by binding to the transcriptional activator β-catenin.

Date: 2021
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DOI: 10.1038/s41467-021-23047-6

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