Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
PLoS Genet. 2021 Feb 11;17(2):e1009360. doi: 10.1371/journal.pgen.1009360. eCollection 2021 Feb.
Neurons are highly specialized cells with polarized cellular processes and subcellular domains. As vital organelles for neuronal functions, mitochondria are distributed by microtubule-based transport systems. Although the essential components of mitochondrial transport including motors and cargo adaptors are identified, it is less clear how mitochondrial distribution among somato-dendritic and axonal compartment is regulated. Here, we systematically study mitochondrial motors, including four kinesins, KIF5, KIF17, KIF1, KLP-6, and dynein, and transport regulators in C. elegans PVD neurons. Among all these motors, we found that mitochondrial export from soma to neurites is mainly mediated by KIF5/UNC-116. Interestingly, UNC-116 is especially important for axonal mitochondria, while dynein removes mitochondria from all plus-end dendrites and the axon. We surprisingly found one mitochondrial transport regulator for minus-end dendritic compartment, TRAK-1, and two mitochondrial transport regulators for axonal compartment, CRMP/UNC-33 and JIP3/UNC-16. While JIP3/UNC-16 suppresses axonal mitochondria, CRMP/UNC-33 is critical for axonal mitochondria; nearly no axonal mitochondria present in unc-33 mutants. We showed that UNC-33 is essential for organizing the population of UNC-116-associated microtubule bundles, which are tracks for mitochondrial trafficking. Disarrangement of these tracks impedes mitochondrial transport to the axon. In summary, we identified a compartment-specific transport regulation of mitochondria by UNC-33 through organizing microtubule tracks for different kinesin motors other than microtubule polarity.
神经元是具有极化细胞过程和亚细胞结构域的高度特化细胞。作为神经元功能的重要细胞器,线粒体通过微管为基础的运输系统进行分布。尽管线粒体运输的基本组成部分,包括马达和货物衔接蛋白,已经被鉴定出来,但线粒体在体树突和轴突隔室之间的分布是如何被调节的,这一点还不太清楚。在这里,我们系统地研究了包括四个驱动蛋白(KIF5、KIF17、KIF1 和 KLP-6)和动力蛋白在内的线粒体马达,以及线虫 PVD 神经元中的运输调节剂。在所有这些马达中,我们发现线粒体从体部到神经突的输出主要由 KIF5/UNC-116 介导。有趣的是,UNC-116 对轴突线粒体尤为重要,而动力蛋白则从所有正端树突和轴突中去除线粒体。我们惊讶地发现一个线粒体运输调节剂(TRAK-1)用于负端树突隔室,两个线粒体运输调节剂(CRMP/UNC-33 和 JIP3/UNC-16)用于轴突隔室。虽然 JIP3/UNC-16 抑制轴突线粒体,但 CRMP/UNC-33 对轴突线粒体至关重要;unc-33 突变体中几乎没有轴突线粒体。我们表明,UNC-33 对于组织 UNC-116 相关微管束的群体是至关重要的,这些微管束是线粒体运输的轨道。这些轨道的混乱会阻碍线粒体向轴突的运输。总之,我们通过组织除微管极性之外的不同驱动蛋白的微管轨道,鉴定了 UNC-33 对线粒体的特定隔室运输调节。