MacAskill Andrew F, Brickley Kieran, Stephenson F Anne, Kittler Josef T
Department of Neuroscience, Physiology and Pharmacology, University College London, UK.
Mol Cell Neurosci. 2009 Mar;40(3):301-12. doi: 10.1016/j.mcn.2008.10.016. Epub 2008 Dec 3.
The transport of mitochondria to specific neuronal locations is critical to meet local cellular energy demands and for buffering intracellular calcium. A critical role for kinesin motor proteins in mitochondrial transport in neurons has been demonstrated. Currently however the molecular mechanisms that underlie the recruitment of motor proteins to mitochondria, and how this recruitment is regulated remain unclear. Here we show that a protein trafficking complex comprising the adaptor protein Grif-1 and the atypical GTPase Miro1 can be detected in mammalian brain where it is localised to neuronal mitochondria. Increasing Miro1 expression levels recruits Grif-1 to mitochondria. This results in an enhanced transport of mitochondria towards the distal ends of neuronal processes. Uncoupling Grif-1 recruitment to mitochondria by expressing a Grif-1/Miro1 binding fragment dramatically reduces mitochondrial transport into neuronal processes. Altering Miro1 function by mutating its first GTPase domain affects Miro's ability to recruit Grif-1 to mitochondria and in addition alters mitochondrial distribution and shape along neuronal processes. These data suggest that Miro1 and the kinesin adaptor Grif-1 play an important role in regulating mitochondrial transport in neurons.
线粒体向特定神经元位置的运输对于满足局部细胞能量需求以及缓冲细胞内钙至关重要。已证明驱动蛋白在神经元线粒体运输中起关键作用。然而，目前尚不清楚驱动蛋白募集到线粒体的分子机制以及这种募集是如何被调控的。在这里，我们表明在哺乳动物大脑中可以检测到一种由衔接蛋白Grif-1和非典型GTP酶Miro1组成的蛋白质运输复合体，其定位于神经元线粒体。增加Miro1的表达水平会将Grif-1募集到线粒体。这导致线粒体向神经元突起远端的运输增强。通过表达Grif-1/Miro1结合片段将Grif-1与线粒体的募集解偶联，会显著减少线粒体向神经元突起的运输。通过突变其第一个GTP酶结构域来改变Miro1的功能，会影响Miro1将Grif-1募集到线粒体的能力，此外还会改变线粒体沿神经元突起的分布和形态。这些数据表明，Miro1和驱动蛋白衔接蛋白Grif-1在调节神经元线粒体运输中起重要作用。
