Issitt Theo, Bosseboeuf Emy, De Winter Natasha, Dufton Neil, Gestri Gaia, Senatore Valentina, Chikh Anissa, Randi Anna M, Raimondi Claudio
Vascular Sciences, Imperial Centre for Translational and Experimental Medicine, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
Division of Biosciences, Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
iScience. 2019 Jan 25;11:205-223. doi: 10.1016/j.isci.2018.12.005. Epub 2018 Dec 11.
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.
跨膜蛋白神经纤毛蛋白-1（NRP1）在内皮细胞（ECs）中促进血管内皮生长因子（VEGF）和细胞外基质信号传导。尽管已知NRP1对血管生成至关重要，但其在内皮细胞稳态中的作用却知之甚少。在此，我们报告NRP1通过在非血管生成性内皮细胞中通过一种不依赖VEGF的机制防止铁积累和铁诱导的氧化应激，从而促进内皮细胞的线粒体功能。此外，缺乏NRP1的内皮细胞生长减少，并表现出细胞衰老的特征。我们发现NRP1的一个亚细胞池定位于线粒体，并与线粒体转运蛋白ATP结合盒B8（ABCB8）相互作用。NRP1的缺失会降低ABCB8水平，导致铁积累、铁诱导的线粒体超氧化物产生以及铁依赖性内皮细胞衰老。用线粒体靶向抗氧化化合物mitoTEMPO或铁螯合剂去铁胺处理缺乏NRP1的内皮细胞可恢复线粒体活性，抑制超氧化物产生，并防止细胞衰老。这一发现确定了NRP1在内皮细胞稳态中的一个意想不到的作用。
