内质网-线粒体连接增加促进轴突再生。
Increased ER-mitochondria tethering promotes axon regeneration.
机构信息
Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, 44919 Ulsan, South Korea.
National Creative Research Initiative Center for Proteostasis, Ulsan National Institute of Science and Technology, 44919 Ulsan, South Korea.
出版信息
Proc Natl Acad Sci U S A. 2019 Aug 6;116(32):16074-16079. doi: 10.1073/pnas.1818830116. Epub 2019 Jul 22.
Translocation of the endoplasmic reticulum (ER) and mitochondria to the site of axon injury has been shown to facilitate axonal regeneration; however, the existence and physiological importance of ER-mitochondria tethering in the injured axons are unknown. Here, we show that a protein linking ER to mitochondria, the glucose regulated protein 75 (Grp75), is locally translated at axon injury site following axotomy, and that overexpression of Grp75 in primary neurons increases ER-mitochondria tethering to promote regrowth of injured axons. We find that increased ER-mitochondria tethering elevates mitochondrial Ca and enhances ATP generation, thereby promoting regrowth of injured axons. Furthermore, intrathecal delivery of lentiviral vector encoding to an animal with sciatic nerve crush injury enhances axonal regeneration and functional recovery. Together, our findings suggest that increased ER-mitochondria tethering at axonal injury sites may provide a therapeutic strategy for axon regeneration.
内质网（ER）和线粒体向轴突损伤部位的易位已被证明有助于轴突再生；然而，在损伤的轴突中内质网-线粒体连接的存在和生理重要性尚不清楚。在这里，我们表明，一种将 ER 与线粒体连接的蛋白质，葡萄糖调节蛋白 75（Grp75），在轴突切断后在轴突损伤部位局部翻译，并且在原代神经元中过表达 Grp75 会增加 ER-线粒体的连接，以促进损伤轴突的再生。我们发现，增加 ER-线粒体的连接会增加线粒体 Ca2+并增强 ATP 的产生，从而促进损伤轴突的再生。此外，鞘内递送编码 的慢病毒载体到坐骨神经挤压伤的动物中，可增强轴突再生和功能恢复。总之，我们的研究结果表明，在轴突损伤部位增加 ER-线粒体的连接可能为轴突再生提供一种治疗策略。
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