The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria
The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria
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DOI：
10.4161/auto.26122
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发表时间：
2013-11-01
期刊：
影响因子：
13.3
通讯作者：
Youle, Richard J.
中科院分区：
文献类型：
--
作者：
Jin, Seok Min;Youle, Richard J.
有缺陷的线粒体对宿主细胞产生有害影响。为了管理这种风险，线粒体显示出几种质量控制机制：线粒体特异性伴侣和蛋白酶在分子水平上防止错误折叠的蛋白质，分裂/融合和线粒体自噬在细胞器水平上分离和消除损伤。线粒体中未折叠蛋白的增加激活线粒体未折叠蛋白反应（UPRmt）以增加伴侣蛋白的产生，而线粒体激酶PINK 1和E3泛素连接酶PARK 2/Parkin（其突变导致家族性帕金森病）通过线粒体自噬去除去极化的线粒体。然而，目前尚不清楚这些不同水平的质量控制（QC）之间是否存在联系。在这里，我们表明，未折叠蛋白在基质中的表达导致PINK 1在能量健康的线粒体上的积累，导致PARK 2的线粒体易位，线粒体自噬和随后的未折叠蛋白负载的减少。此外，通过LONP 1蛋白酶的敲低，PINK 1积累大大增强。我们认为，未折叠蛋白在线粒体中的积累是线粒体自噬的生理触发。
Defective mitochondria exert deleterious effects on host cells. To manage this risk, mitochondria display several lines of quality control mechanisms: mitochondria-specific chaperones and proteases protect against misfolded proteins at the molecular level, and fission/fusion and mitophagy segregate and eliminate damage at the organelle level. An increase in unfolded proteins in mitochondria activates a mitochondrial unfolded protein response (UPRmt) to increase chaperone production, while the mitochondrial kinase PINK1 and the E3 ubiquitin ligase PARK2/Parkin, whose mutations cause familial Parkinson disease, remove depolarized mitochondria through mitophagy. It is unclear, however, if there is a connection between those different levels of quality control (QC). Here, we show that the expression of unfolded proteins in the matrix causes the accumulation of PINK1 on energetically healthy mitochondria, resulting in mitochondrial translocation of PARK2, mitophagy and subsequent reduction of unfolded protein load. Also, PINK1 accumulation is greatly enhanced by the knockdown of the LONP1 protease. We suggest that the accumulation of unfolded proteins in mitochondria is a physiological trigger of mitophagy.