IRUS Total

Neuropilin-1 controls endothelial homeostasis by regulating mitochondrial function and iron-dependent oxidative stress via ABCB8

File Description SizeFormat 
1-s2.0-S2589004218302347-main.pdfPublished version9.99 MBAdobe PDFView/Open
Title: Neuropilin-1 controls endothelial homeostasis by regulating mitochondrial function and iron-dependent oxidative stress via ABCB8
Authors: Issitt, T
Bosseboeuf, E
De Winter, N
Dufton, N
Gestri, G
Senatore, V
Chikh, A
Randi, AM
Raimondi, C
Item Type: Journal Article
Abstract: The transmembrane protein Neuropilin-1 (NRP1) promotes vascular endothelial growth factor (VEGF) and extracellular matrix signalling in endothelial cells (ECs). Although it is established that NRP1 is essential for angiogenesis, little is known about its role in EC homeostasis. Here, we report that NRP1 promotes mitochondrial function in ECs by preventing iron accumulation and iron-induced oxidative stress through a VEGF-independent mechanism in non-angiogenic ECs. Furthermore, NRP1-deficient ECs have reduced growth and show the hallmarks of cellular senescence. We show that a subcellular pool of NRP1 localises in mitochondria and interacts with the mitochondrial transporter ATP-binding-cassette-B8 (ABCB8). NRP1 loss reduces ABCB8 levels, resulting in iron accumulation, iron-induced mitochondrial superoxide production and iron-dependent EC senescence. Treatment of NRP1-deficient ECs with the mitochondria-targeted antioxidant compound mitoTEMPO or with the iron chelator deferoxamine restores mitochondrial activity, inhibits superoxide production and protects from cellular senescence. This finding identifies an unexpected role of NRP1 in EC homeostasis.
Issue Date: 25-Jan-2019
Date of Acceptance: 4-Dec-2018
URI: http://hdl.handle.net/10044/1/65066
DOI: https://dx.doi.org/10.1016/j.isci.2018.12.005
ISSN: 2589-0042
Publisher: Elsevier BV
Start Page: 205
End Page: 223
Journal / Book Title: iScience
Volume: 11
Copyright Statement: © 2018 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International licence (CC BY 4.0 - https://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: FS/16/22/32045
Keywords: Cell Biology
Functional Aspects of Cell Biology
Molecular Biology
Publication Status: Published
Open Access location: https://www.cell.com/action/showPdf?pii=S2589-0042(18)30234-7
Online Publication Date: 2018-12-11
Appears in Collections:National Heart and Lung Institute