Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways.
Differential submitochondrial localization of PINK1 as a molecular switch for mediating distinct mitochondrial signaling pathways.
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DOI：
10.1016/j.cellsig.2015.09.020
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发表时间：
2015-12
影响因子：
4.8
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Fallaize D;Chin LS;Li L
线粒体激酶PINK1突变导致帕金森病（PD），但PINK1作用的亚线粒体位点(s)仍不清楚。在这里，我们报告了三维结构照明显微镜（3D-SIM）实现了蛋白质亚线粒体定位的超分辨率成像。双色3D-SIM成像分析显示，PINK1存在于健康线粒体的嵴膜和嵴内间隙，而不在线粒体外膜（OMM）上。在正常生理条件下，PINK1与其底物TRAP1在嵴膜和嵴内空间共定位。响应线粒体去极化，PINK1而不是TRAP1易位到OMM。PINK1易位到去极化线粒体的OMM不依赖于新蛋白的合成，需要PINK1跨膜结构域和c端区共同作用。我们发现，线粒体去极化诱导的PINK1 OMM易位是将parkin募集到受损线粒体OMM所必需的。我们的研究结果表明，PINK1的不同亚线粒体定位作为一种分子开关，介导两种不同的线粒体信号通路，维持线粒体稳态。此外，我们的研究为PINK1亚线粒体定位失调参与PD发病提供了证据。
Mutations in mitochondrial kinase PINK1 cause Parkinson disease (PD), but the submitochondrial site(s) of PINK1 action remains unclear. Here, we report that three-dimensional structured illumination microscopy (3D-SIM) enables super-resolution imaging of protein submitochondrial localization. Dual-color 3D-SIM imaging analysis revealed that PINK1 resides in the cristae membrane and intracristae space but not on the outer mitochondrial membrane (OMM) of healthy mitochondria. Under normal physiological conditions, PINK1 colocalizes with its substrate TRAP1 in the cristae membrane and intracristae space. In response to mitochondrial depolarization, PINK1, but not TRAP1, translocates to the OMM. The PINK1 translocation to the OMM of depolarized mitochondria is independent of new protein synthesis and requires combined action of PINK1 transmembrane domain and C-terminal region. We found that mitochondrial depolarization-induced PINK1 OMM translocation is required for recruitment of parkin to the OMM of damaged mitochondria. Our findings suggest that differential submitochondrial localization of PINK1 serves as a molecular switch for mediating two distinct mitochondrial signalling pathways in maintenance of mitochondrial homeostasis. Furthermore, our study provides evidence for the involvement of deregulated PINK1 submitochondrial localization in PD pathogenesis.