Mitofusin-2 Stabilizes Adherens Junctions and Suppresses Endothelial Inflammation Via Modulation of β-catenin Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 13

PMID 33980844

Citations 10

Authors

Young-Mee Kim

Sarah Krantz

Ankit Jambusaria

Peter T Toth

Hyung-Geun Moon

Isuru Gunarathna

Gye Young Park

Jalees Rehman

Affiliations

Soon will be listed here.

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.

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References

Eisenberg-Bord M, Shai N, Schuldiner M, Bohnert M . A Tether Is a Tether Is a Tether: Tethering at Membrane Contact Sites. Dev Cell. 2016; 39(4):395-409. DOI: 10.1016/j.devcel.2016.10.022. View

Dorn 2nd G . Mitofusins as mitochondrial anchors and tethers. J Mol Cell Cardiol. 2020; 142:146-153. PMC: 7275906. DOI: 10.1016/j.yjmcc.2020.04.016. View

Winterbourn C, Hampton M . Redox biology: signaling via a peroxiredoxin sensor. Nat Chem Biol. 2014; 11(1):5-6. DOI: 10.1038/nchembio.1722. View

Cantelmo A, Conradi L, Brajic A, Goveia J, Kalucka J, Pircher A . Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. Cancer Cell. 2016; 30(6):968-985. PMC: 5675554. DOI: 10.1016/j.ccell.2016.10.006. View

Hayer A, Shao L, Chung M, Joubert L, Yang H, Tsai F . Engulfed cadherin fingers are polarized junctional structures between collectively migrating endothelial cells. Nat Cell Biol. 2016; 18(12):1311-1323. PMC: 6159904. DOI: 10.1038/ncb3438. View

Kraft L, Lackner L . Mitochondria-driven assembly of a cortical anchor for mitochondria and dynein. J Cell Biol. 2017; 216(10):3061-3071. PMC: 5626545. DOI: 10.1083/jcb.201702022. View

Kaufmann U, Kahlfuss S, Yang J, Ivanova E, Koralov S, Feske S . Calcium Signaling Controls Pathogenic Th17 Cell-Mediated Inflammation by Regulating Mitochondrial Function. Cell Metab. 2019; 29(5):1104-1118.e6. PMC: 6506368. DOI: 10.1016/j.cmet.2019.01.019. View

Escobar-Henriques M, Joaquim M . Mitofusins: Disease Gatekeepers and Hubs in Mitochondrial Quality Control by E3 Ligases. Front Physiol. 2019; 10:517. PMC: 6533591. DOI: 10.3389/fphys.2019.00517. View

Kim J, Kim Y, Kim J, Park D, Bae H, Lee D . YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. J Clin Invest. 2017; 127(9):3441-3461. PMC: 5669570. DOI: 10.1172/JCI93825. View

10.

Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin X . New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018; 560(7717):198-203. PMC: 6329306. DOI: 10.1038/s41586-018-0372-z. View

11.

Ghasemi A, Zahediasl S . Normality tests for statistical analysis: a guide for non-statisticians. Int J Endocrinol Metab. 2013; 10(2):486-9. PMC: 3693611. DOI: 10.5812/ijem.3505. View

12.

Ohmura T, Tian Y, Sarich N, Ke Y, Meliton A, Shah A . Regulation of lung endothelial permeability and inflammatory responses by prostaglandin A2: role of EP4 receptor. Mol Biol Cell. 2017; 28(12):1622-1635. PMC: 5469606. DOI: 10.1091/mbc.E16-09-0639. View

13.

Czerkies M, Korwek Z, Prus W, Kochanczyk M, Jaruszewicz-Blonska J, Tudelska K . Cell fate in antiviral response arises in the crosstalk of IRF, NF-κB and JAK/STAT pathways. Nat Commun. 2018; 9(1):493. PMC: 5799375. DOI: 10.1038/s41467-017-02640-8. View

14.

Filadi R, Pendin D, Pizzo P . Mitofusin 2: from functions to disease. Cell Death Dis. 2018; 9(3):330. PMC: 5832425. DOI: 10.1038/s41419-017-0023-6. View

15.

Yoshioka K, Yoshida K, Cui H, Wakayama T, Takuwa N, Okamoto Y . Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function. Nat Med. 2012; 18(10):1560-9. DOI: 10.1038/nm.2928. View

16.

Tersteeg C, Roodt J, Van Rensburg W, Dekimpe C, Vandeputte N, Pareyn I . -acetylcysteine in preclinical mouse and baboon models of thrombotic thrombocytopenic purpura. Blood. 2016; 129(8):1030-1038. DOI: 10.1182/blood-2016-09-738856. View

17.

Xu W, Kimelman D . Mechanistic insights from structural studies of beta-catenin and its binding partners. J Cell Sci. 2007; 120(Pt 19):3337-44. DOI: 10.1242/jcs.013771. View

18.

Lackner L . The Expanding and Unexpected Functions of Mitochondria Contact Sites. Trends Cell Biol. 2019; 29(7):580-590. PMC: 6590070. DOI: 10.1016/j.tcb.2019.02.009. View

19.

Cardamone M, Tanasa B, Cederquist C, Huang J, Mahdaviani K, Li W . Mitochondrial Retrograde Signaling in Mammals Is Mediated by the Transcriptional Cofactor GPS2 via Direct Mitochondria-to-Nucleus Translocation. Mol Cell. 2018; 69(5):757-772.e7. PMC: 6022402. DOI: 10.1016/j.molcel.2018.01.037. View

20.

Dasgupta S, Rajapakshe K, Zhu B, Nikolai B, Yi P, Putluri N . Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature. 2018; 556(7700):249-254. PMC: 5895503. DOI: 10.1038/s41586-018-0018-1. View