Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin.
Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin.
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DOI：
10.1083/jcb.201007013
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发表时间：
2010-12-27
期刊：
影响因子：
--
通讯作者：
Youle RJ
中科院分区：
文献类型：
--
作者：
Tanaka A;Cleland MM;Xu S;Narendra DP;Suen DF;Karbowski M;Youle RJ
帕金泛素连接酶标记丝裂融合蛋白Mfn1和Mfn2的蛋白酶体依赖性降解，通过阻止它们与健康细胞器融合来促进受损线粒体的处理。线粒体的损伤可导致线粒体内膜的去极化，从而使受损的线粒体对通过自噬的选择性消除敏感。然而，解偶联的线粒体与极化的线粒体的融合可以补偿损伤，逆转膜去极化和线粒体自噬。Parkin是一种E3泛素连接酶，在帕金森病的单基因形式中突变，最近发现其诱导受损线粒体的选择性自噬。在这里，我们表明，泛素化的线粒体融合蛋白Mfn1和Mfn2，大GTP酶介导的线粒体融合，是由帕金诱导膜去极化后，导致其降解的蛋白酶体和p97依赖的方式。p97是一种AAA+ ATP酶，在表达Parkin的细胞解偶联后在线粒体上积累，并且p97和蛋白酶体活性都是Parkin介导的线粒体自噬所需的。在去极化后线粒体分裂后，帕金可能通过消除丝裂融合蛋白来阻止或延迟线粒体的再融合。抑制Drp1介导的线粒体分裂、蛋白酶体或p97可防止帕金森病诱导的线粒体自噬。
The Parkin ubiquitin ligase marks the mitofusins Mfn1 and Mfn2 for proteasome-dependent degradation, promoting disposal of damaged mitochondria by preventing their fusion with healthy organelles. Damage to mitochondria can lead to the depolarization of the inner mitochondrial membrane, thereby sensitizing impaired mitochondria for selective elimination by autophagy. However, fusion of uncoupled mitochondria with polarized mitochondria can compensate for damage, reverse membrane depolarization, and obviate mitophagy. Parkin, an E3 ubiquitin ligase that is mutated in monogenic forms of Parkinson’s disease, was recently found to induce selective autophagy of damaged mitochondria. Here we show that ubiquitination of mitofusins Mfn1 and Mfn2, large GTPases that mediate mitochondrial fusion, is induced by Parkin upon membrane depolarization and leads to their degradation in a proteasome- and p97-dependent manner. p97, a AAA+ ATPase, accumulates on mitochondria upon uncoupling of Parkin-expressing cells, and both p97 and proteasome activity are required for Parkin-mediated mitophagy. After mitochondrial fission upon depolarization, Parkin prevents or delays refusion of mitochondria, likely by the elimination of mitofusins. Inhibition of Drp1-mediated mitochondrial fission, the proteasome, or p97 prevents Parkin-induced mitophagy.
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