Intramembrane protease PARL defines a negative regulator of PINK1-and PARK2/Parkin-dependent mitophagy
Intramembrane protease PARL defines a negative regulator of PINK1-and PARK2/Parkin-dependent mitophagy
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DOI：
10.1080/15548627.2015.1063763
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发表时间：
2015-09-01
期刊：
影响因子：
13.3
通讯作者：
Lemberg, Marius K.
中科院分区：
文献类型：
--
作者：
Meissner, Cathrin;Lorenz, Holger;Lemberg, Marius K.
PINK 1和PARK 2/Parkin突变是家族性帕金森病的主要危险因素。虽然其激活的生理机制尚不清楚，但这些蛋白质已在组织培养细胞中显示为去极化线粒体自噬的关键触发剂。在这里，我们表明，消融的线粒体菱形蛋白酶PARL导致逆行易位的膜间空间桥接PINK 1进口中间。随后，它被重新路由到外膜，以招募PARK 2，PARK 2模仿解偶联剂诱导的线粒体自噬。与这种逆行易位机制在神经退行性疾病中的作用一致，我们表明，不被PARL切割的致病性PINK 1突变体影响PINK 1激酶活性和诱导PARK 2介导的线粒体自噬的能力。总之，我们认为PARL是线粒体质量控制的重要内在参与者，帕金森病患者受损线粒体的清除减少表明该系统严重受损。
Mutations in PINK1 and PARK2/Parkin are a main risk factor for familial Parkinson disease. While the physiological mechanism of their activation is unclear, these proteins have been shown in tissue culture cells to serve as a key trigger for autophagy of depolarized mitochondria. Here we show that ablation of the mitochondrial rhomboid protease PARL leads to retrograde translocation of an intermembrane space-bridging PINK1 import intermediate. Subsequently, it is rerouted to the outer membrane in order to recruit PARK2, which phenocopies mitophagy induction by uncoupling agents. Consistent with a role of this retrograde translocation mechanism in neurodegenerative disease, we show that pathogenic PINK1 mutants which are not cleaved by PARL affect PINK1 kinase activity and the ability to induce PARK2-mediated mitophagy. Altogether we suggest that PARL is an important intrinsic player in mitochondrial quality control, a system substantially impaired in Parkinson disease as indicated by reduced removal of damaged mitochondria in affected patients.