Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin
Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin
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DOI：
10.1073/pnas.0913485107
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发表时间：
2010-03-16
影响因子：
11.1
通讯作者：
Whitworth, Alexander J.
中科院分区：
文献类型：
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作者：
Ziviani, Elena;Tao, Ran N.;Whitworth, Alexander J.
E3泛素连接酶Parkin的缺失会导致早发性帕金森氏症，这是一种病因不明的神经退行性疾病。Parkin与多种细胞过程有关，包括蛋白质降解、线粒体动态平衡和自噬；然而，其在发病机制中的确切作用尚不清楚。最近的证据表明，Parkin被招募到受损的线粒体，可能影响线粒体的分裂和/或融合，以调节它们的自噬周转。招募的确切机制和泛素化目标尚不清楚。在这里，我们展示了在果蝇细胞中，PINK1需要招募Parkin到功能失调的线粒体，并促进它们的降解。此外，PINK1和Parkin还介导了线粒体外表面丰富因子MFN的泛素化。果蝇PINK1或Parkin的缺失会导致体内MFN丰度的增加，并伴随着线粒体的延长。这些发现提供了PINK1/Parkin通路影响线粒体分裂/融合的分子机制，正如先前的遗传相互作用研究所表明的那样。我们推测，MFN泛素化可能提供了一种机制，通过这种机制，最终受损的线粒体被标记和隔离，以便通过自噬进行降解。
Loss of the E3 ubiquitin ligase Parkin causes early onset Parkinson's disease, a neurodegenerative disorder of unknown etiology. Parkin has been linked to multiple cellular processes including protein degradation, mitochondrial homeostasis, and autophagy; however, its precise role in pathogenesis is unclear. Recent evidence suggests that Parkin is recruited to damaged mitochondria, possibly affecting mitochondrial fission and/or fusion, to mediate their autophagic turnover. The precise mechanism of recruitment and the ubiquitination target are unclear. Here we show in Drosophila cells that PINK1 is required to recruit Parkin to dysfunctional mitochondria and promote their degradation. Furthermore, PINK1 and Parkin mediate the ubiquitination of the profusion factor Mfn on the outer surface of mitochondria. Loss of Drosophila PINK1 or parkin causes an increase in Mfn abundance in vivo and concomitant elongation of mitochondria. These findings provide a molecular mechanism by which the PINK1/Parkin pathway affects mitochondrial fission/fusion as suggested by previous genetic interaction studies. We hypothesize that Mfn ubiquitination may provide a mechanism by which terminally damaged mitochondria are labeled and sequestered for degradation by autophagy.