WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering.
WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering.
复制标题
DOI：
10.1016/j.cub.2012.02.043
复制
发表时间：
2012-04-10
期刊：
影响因子：
9.2
通讯作者：
Freeman, Marc R
中科院分区：
文献类型：
--
作者：
Avery, Michelle A;Rooney, Timothy M;Pandya, Jignesh D;Wishart, Thomas M;Gillingwater, Thomas H;Geddes, James W;Sullivan, Patrick G;Freeman, Marc R
WldS（slow Wallerian degeneration）是一种显著的蛋白质，可以抑制轴突和突触的Wallerian变性，但它如何发挥这种作用尚不清楚。在这里，使用果蝇和小鼠模型，我们确定线粒体作为WldS神经保护功能的关键作用部位。将NAD+生物合成酶Nmnat靶向线粒体足以完全表型化WldS，并且WldS特异性定位于来自小鼠脑的突触制备物中的线粒体。活的野生型轴突的轴突切断术诱导轴浆Ca 2+和线粒体运动的终止的戏剧性的尖峰-WldS有力地抑制了这两个事件。令人惊讶的是，WldS还促进了损伤前轴突中基础线粒体运动性的增加，并且体内遗传抑制线粒体运动性显著降低了WldS的保护作用。有趣的是，从WldS小鼠纯化的线粒体表现出增强的Ca 2+缓冲能力。我们提出，增强的WldS+线粒体的Ca 2+缓冲能力，导致线粒体运动性增加，轴突切断诱导的轴突中的Ca 2+升高的抑制，从而抑制沃勒变性。
WldS (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses but how it exerts this effect remains unclear. Here, using Drosophila and mouse models, we identify mitochondria as a key site of action for WldS neuroprotective function. Targeting the NAD+ biosynthetic enzyme Nmnat to mitochondria was sufficient to fully phenocopy WldS, and WldS was specifically localized to mitochondria in synaptic preparations from mouse brain. Axotomy of live wild type axons induced a dramatic spike in axoplasmic Ca2+ and termination of mitochondrial movement—WldS potently suppressed both of these events. Surprisingly, WldS also promoted increased basal mitochondrial motility in axons before injury, and genetically suppressing mitochondrial motility in vivo dramatically reduced the protective effect of WldS. Intriguingly, purified mitochondria from WldS mice exhibited enhanced Ca2+ buffering capacity. We propose that the enhanced Ca2+ buffering capacity of WldS+ mitochondria leads to increased mitochondrial motility, suppression of axotomy-induced Ca2+ elevation in axons, and thereby suppression of Wallerian degeneration.