Regulation of ER-mitochondria contacts by Parkin via Mfn2
Regulation of ER-mitochondria contacts by Parkin via Mfn2
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DOI：
10.1016/j.phrs.2018.09.006
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发表时间：
2018-12-01
影响因子：
9.3
通讯作者：
Ziviani, Elena
中科院分区：
文献类型：
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作者：
Basso, Valentina;Marchesan, Elena;Ziviani, Elena
Parkin是一种E3泛素连接酶和帕金森病（PD）相关基因，它易位到受损的线粒体，并通过自噬（一种称为线粒体自噬的过程）驱动它们的消除。线粒体前融合蛋白Mitofusins （Mfn1和Mfn2）被发现是Parkin介导的泛素化的靶标。Mfns是嵌入线粒体外膜的跨膜GTPase，是邻近线粒体介导融合所必需的。在哺乳动物中，Mfn2还形成能够将线粒体束缚在内质网（ER）上的复合物，这是线粒体能量代谢、钙（Ca2+）在细胞器之间转移和Ca2+依赖性细胞死亡所必需的结构特征。尽管其具有基本的生理作用，但控制er -线粒体串扰的分子机制尚不清楚。近年来，泛素化已成为调节蛋白质功能的有力工具，通过调节蛋白质亚细胞定位和蛋白质与其他蛋白质相互作用的能力。泛素化也是一种可逆机制，它可以通过相反的泛素化-去泛素化事件来主动控制。在这项工作中，我们发现在Parkin缺陷细胞和Parkin突变的人成纤维细胞中，内质网和线粒体之间的系链减少。我们确定了Parkin依赖泛素化的位点，并表明非泛素化的Mfn2突变体无法恢复er -线粒体的物理和功能相互作用。最后，我们利用已建立的帕金森病体内模型证明，通过表达er -线粒体合成连接子来操纵er -线粒体系结足以挽救与体内帕金森病果蝇模型相关的运动缺陷。
Parkin, an E3 ubiquitin ligase and a Parkinson's disease (PD) related gene, translocates to impaired mitochondria and drives their elimination via autophagy, a process known as mitophagy. Mitochondrial pro-fusion protein Mitofusins (Mfn1 and Mfn2) were found to be a target for Parkin mediated ubiquitination. Mfns are trans membrane GTPase embedded in the outer membrane of mitochondria, which are required on adjacent mitochondria to mediate fusion. In mammals, Mfn2 also forms complexes that are capable of tethering mitochondria to endoplasmic reticulum (ER), a structural feature essential for mitochondrial energy metabolism, calcium (Ca2+) transfer between the organelles and Ca2+ dependent cell death. Despite its fundamental physiological role, the molecular mechanisms that control ER-mitochondria cross talk are obscure. Ubiquitination has recently emerged as a powerful tool to modulate protein function, via regulation of protein subcellular localization and protein ability to interact with other proteins. Ubiquitination is also a reversible mechanism, which can be actively controlled by opposing ubiquitination-deubiquitination events. In this work we found that in Parkin deficient cells and parkin mutant human fibroblasts, the tether between ER and mitochondria is decreased. We identified the site of Parkin dependent ubiquitination and showed that the non-ubiquitinatable Mfn2 mutant fails to restore ER-mitochondria physical and functional interaction. Finally, we took advantage of an established in vivo model of PD to demonstrate that manipulation of ER-mitochondria tethering by expressing an ER-mitochondria synthetic linker is sufficient to rescue the locomotor deficit associated to an in vivo Drosophila model of PD.