Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1
Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1
复制标题
DOI：
10.1016/j.molcel.2019.01.002
复制
发表时间：
2019-03-07
期刊：
影响因子：
16
通讯作者：
Youle, Richard J.
中科院分区：
文献类型：
--
作者：
Sekine, Shiori;Wang, Chunxin;Youle, Richard J.
PTEN诱导的激酶1（PINK 1）突变可导致隐性早发性帕金森病（PD）。输入阻滞导致PINK 1激酶特异性激活受损的线粒体，触发帕金森介导的线粒体自噬。在这里，我们表明，PINK 1的进口是依赖于Tim 23比线粒体膜电位（Δ Psim）。我们确定了一个带负电荷的氨基酸簇基序，它在进化上保守在PINK 1跨膜的C-末端。PINK 1不能积累在线粒体外膜，无论是通过诱变这个带负电荷的基序或通过删除Tom 7，被输入到去极化的线粒体和切割的OMA 1蛋白酶。一些PD患者突变在输入阻滞中也是有缺陷的，并且通过抑制OMA 1而被拯救，这为PD提供了新的潜在药物靶点。这些结果表明，Delta Psi m丢失依赖的PINK 1输入停滞不仅是由Tim 23失活引起的，而且还通过Tom 7和OMA 1之间的主动调节的“拔河”引起。
Mutations in PTEN-induced kinase 1 (PINK1) can cause recessive early-onset Parkinson's disease (PD). Import arrest results in PINK1 kinase activation specifically on damaged mitochondria, triggering Parkin-mediated mitophagy. Here, we show that PINK1 import is less dependent on Tim23 than on mitochondrial membrane potential (Delta Psi m). We identified a negatively charged amino acid cluster motif that is evolutionarily conserved just C-terminal to the PINK1 transmembrane. PINK1 that fails to accumulate at the outer mitochondrial membrane, either by mutagenesis of this negatively charged motif or by deletion of Tom7, is imported into depolarized mitochondria and cleaved by the OMA1 protease. Some PD patient mutations also are defective in import arrest and are rescued by the suppression of OMA1, providing a new potential druggable target for PD. These results suggest that Delta Psi m loss-dependent PINK1 import arrest does not result solely from Tim23 inactivation but also through an actively regulated "tug of war'' between Tom7 and OMA1.