Faculty of Medicine and Dentistry, Department of Cell Biology, University of Alberta , Edmonton, Alberta, Canada, T6R0K8.
Small GTPases. 2020 Jul;11(4):289-292. doi: 10.1080/21541248.2017.1411312. Epub 2018 Jan 7.
We have shown that multiple sclerosis (MS) and endoplasmic reticulum (ER) stress induce Rab32, an ER/mitochondria-localized small GTPase. High levels of both dominant-active (Q85L) or dominant-inactive (T39N) Rab32 are toxic to neurons. While Rab32Q85L interacts with its effector Drp1 to promote mitochondria fission, it is unclear how Rab32T39N could result as toxic to neurons. Given the perinuclear clustering of mitochondria observed upon transfection of inactive Rab32, we hypothesized Rab32T39N could stall mitochondria within neurites. The movement of mitochondria depends on kinesin-binding Miro proteins. High cytosolic [Ca] is bound by an EF hand motif within Miro proteins, resulting in mitochondrial arrest. Consistent with increased cytosolic [Ca], expression of Rab32T39N arrests mitochondria movement within neurites.
我们已经表明，多发性硬化症（MS）和内质网（ER）应激会诱导 Rab32，一种定位于 ER/线粒体的小 GTPase。高水平的显性激活（Q85L）或显性失活（T39N）Rab32 对神经元有毒性。虽然 Rab32Q85L 与效应蛋白 Drp1 相互作用以促进线粒体裂变，但 Rab32T39N 如何导致神经元毒性尚不清楚。鉴于转染失活 Rab32 时观察到线粒体在核周聚集，我们假设 Rab32T39N 可能会使神经元内的线粒体停滞。线粒体的运动依赖于与驱动蛋白结合的 Miro 蛋白。高细胞浆 [Ca] 通过 Miro 蛋白内的 EF 手模体结合，导致线粒体停滞。与细胞浆 [Ca] 增加一致，Rab32T39N 的表达会使神经元内的线粒体运动停滞。
