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

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

  • iScience. 2019 Jan 25;11:205-223. doi: 10.1016/j.isci.2018.12.005.
Theo Issitt 1,  Emy Bosseboeuf 1,  Natasha De Winter 1,  Neil Dufton 1,  Gaia Gestri 2,  Valentina Senatore 3,  Anissa Chikh 4,  Anna M Randi 1,  Claudio Raimondi 5
Affiliations

Affiliations

  • 1 Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
  • 2 Division of Biosciences, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
  • 3 UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
  • 4 Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • 5 Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK. Electronic address: c.raimondi@imperial.ac.uk.
PMID: 30623799 DOI: 10.1016/j.isci.2018.12.005
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.

Keywords

Cell Biology; Functional Aspects of Cell Biology; Molecular Biology.

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