PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix.
PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix.
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DOI：
10.1371/journal.pgen.1004279
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发表时间：
2014
期刊：
影响因子：
4.5
通讯作者：
Pallanck LJ
中科院分区：
文献类型：
--
作者：
Thomas RE;Andrews LA;Burman JL;Lin WY;Pallanck LJ
PINK1编码一种线粒体靶向的丝氨酸/苏氨酸激酶，它的功能丧失突变导致了一种早发性可遗传的帕金森氏病。以前的工作表明，PINK1在健康细胞中被结构性降解，但选择性地聚集在去极化的线粒体表面，从而启动它们的自噬降解。尽管已知PINK1是几种线粒体蛋白水解酶的切割靶点，但这些酶是否导致健康线粒体中PINK1的结构性降解仍不清楚。为了探索PINK1被降解的机制，我们在果蝇黑腹果蝇中进行了影响PINK1丰度的线粒体蛋白酶的筛选。我们发现，针对基质定位的蛋白酶Lon的遗传扰动导致加工的PINK1物种在几个线粒体隔间中戏剧性地积累，包括基质。Lon基因敲除并没有降低线粒体膜电位，也没有触发线粒体未折叠蛋白应激反应(UPRmt)的激活，这表明Lon缺陷动物体内PINK1的积累不是线粒体去极化或UPRmt的次要结果。此外，Lon对PINK1丰度的影响具有高度的特异性，因为Lon失活对其他线粒体蛋白的丰度几乎没有影响。进一步的研究表明，Lon失活后积累的PINK1的加工形式能够在体内激活PINK1-Parkin通路。因此，我们的研究结果表明，Lon通过促进健康线粒体基质中PINK1的降解，在调节PINK1-Parkin通路中发挥重要作用。线粒体是重要的细胞器，提供细胞的大部分能量，并执行许多其他关键功能。有缺陷的线粒体的逐渐积累被认为在衰老和包括帕金森氏症在内的神经系统疾病中发挥作用。因此，选择性地消除有缺陷的线粒体对细胞来说是一项至关重要的任务，而PINK1蛋白最近被发现在这一过程中发挥了关键作用。PINK1在线粒体受损后积聚在线粒体表面，启动了一个最终导致缺陷线粒体消除的过程。以前的工作表明，PINK1不会在健康的线粒体上积累，因为它会迅速降解。然而，目前还不清楚这种退化是如何以及在哪里发生的。我们的工作表明，Lon蛋白水解酶能促进线粒体基质中PINK1的降解。这一发现为线粒体质量控制的机制提供了新的见解，并揭示了治疗与缺陷线粒体积累相关的许多疾病的潜在策略。
Loss-of-function mutations in PINK1, which encodes a mitochondrially targeted serine/threonine kinase, result in an early-onset heritable form of Parkinson's disease. Previous work has shown that PINK1 is constitutively degraded in healthy cells, but selectively accumulates on the surface of depolarized mitochondria, thereby initiating their autophagic degradation. Although PINK1 is known to be a cleavage target of several mitochondrial proteases, whether these proteases account for the constitutive degradation of PINK1 in healthy mitochondria remains unclear. To explore the mechanism by which PINK1 is degraded, we performed a screen for mitochondrial proteases that influence PINK1 abundance in the fruit fly Drosophila melanogaster. We found that genetic perturbations targeting the matrix-localized protease Lon caused dramatic accumulation of processed PINK1 species in several mitochondrial compartments, including the matrix. Knockdown of Lon did not decrease mitochondrial membrane potential or trigger activation of the mitochondrial unfolded protein stress response (UPRmt), indicating that PINK1 accumulation in Lon-deficient animals is not a secondary consequence of mitochondrial depolarization or the UPRmt. Moreover, the influence of Lon on PINK1 abundance was highly specific, as Lon inactivation had little or no effect on the abundance of other mitochondrial proteins. Further studies indicated that the processed forms of PINK1 that accumulate upon Lon inactivation are capable of activating the PINK1-Parkin pathway in vivo. Our findings thus suggest that Lon plays an essential role in regulating the PINK1-Parkin pathway by promoting the degradation of PINK1 in the matrix of healthy mitochondria. Mitochondria are essential organelles that provide most of the cell's energy and perform many other critical functions. The gradual accumulation of defective mitochondria is thought to play a role in aging and in diseases of the nervous system, including Parkinson's disease. The selective elimination of defective mitochondria is therefore a vital task for the cell, and the protein PINK1 was recently identified as a critical player in this process. PINK1 accumulates on the surface of mitochondria after they are damaged, starting a process that leads ultimately to the elimination of defective mitochondria. Previous work indicated that PINK1 does not accumulate on healthy mitochondria because it is rapidly degraded. However, it was unclear exactly how and where this degradation occurred. Our work shows that Lon protease promotes the degradation of PINK1 in the mitochondrial matrix. This finding provides new insight into the mechanisms of mitochondrial quality control, and reveals a potential strategy for treating the many diseases associated with the accumulation of defective mitochondria.
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DOI：
10.1083/jcb.201008084
发表时间：
2010-11-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jin SM;Lazarou M;Wang C;Kane LA;Narendra DP;Youle RJ
通讯作者：
Youle RJ
影响因子：
4.8
作者：
Becker, Dorothea;Richter, Judith;Voos, Wolfgang
通讯作者：
Voos, Wolfgang
影响因子：
13.3
作者：
Jin, Seok Min;Youle, Richard J.
通讯作者：
Youle, Richard J.
影响因子：
4.7
作者：
Lin W;Kang UJ
通讯作者：
Kang UJ
DOI：
10.1083/jcb.200809125
发表时间：
2008-12-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Narendra D;Tanaka A;Suen DF;Youle RJ
通讯作者：
Youle RJ