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Neuropilin-1 Controls Endothelial Homeostasis by Regulating Mitochondrial Function and Iron-Dependent Oxidative Stress.

Issitt, T; Bosseboeuf, E; De Winter, N; Dufton, N; Gestri, G; Senatore, V; Chikh, A; Randi, AM; Raimondi, C (2019) Neuropilin-1 Controls Endothelial Homeostasis by Regulating Mitochondrial Function and Iron-Dependent Oxidative Stress. iScience, 11. pp. 205-223. ISSN 2589-0042 https://doi.org/10.1016/j.isci.2018.12.005
SGUL Authors: Chikh, Anissa

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Abstract

The transmembrane protein neuropilin-1 (NRP1) promotes vascular endothelial growth factor (VEGF) and extracellular matrix signaling 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 localizes 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.

Item Type: Article
Additional Information: © 2018 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Cell Biology, Functional Aspects of Cell Biology, Molecular Biology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: iScience
ISSN: 2589-0042
Language: eng
Dates:
DateEvent
25 January 2019Published
11 December 2018Published Online
4 December 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
104931/Z/14/Z)Wellcome Trusthttp://dx.doi.org/10.13039/100004440
FS/16/22/32045British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
MR/L003775/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BB/L015129/1Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
FS/13/35/30148British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
PubMed ID: 30623799
Web of Science ID: WOS:000456942200015
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111988
Publisher's version: https://doi.org/10.1016/j.isci.2018.12.005

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