p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both
p62/SQSTM1 is required for Parkin-induced mitochondrial clustering but not mitophagy; VDAC1 is dispensable for both
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DOI：
10.4161/auto.6.8.13426
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发表时间：
2010-11-16
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：
Narendra, Derek P.;Kane, Lesley A.;Youle, Richard J.
线粒体随着年龄的增长而受损，由此导致的线粒体功能障碍与包括帕金森病在内的许多疾病有关。我们最近证明，与隐性形式的帕金森病有关的E3泛素连接酶Parkin，在从胞浆移位到线粒体后，导致有丝分裂增加和线粒体分布的改变。研究Parkin是如何导致这些变化的，可能会提供对导致隔离和消除受损线粒体的机制的洞察。我们报道，在Parkin从胞浆转位到线粒体之后，Parkin(但不是致病突变体)促进线粒体底物K63连接的多泛素化(S)，并将泛素和Lc3结合蛋白p62/SQSTM1招募到线粒体。P62/SQSTM1在募集后，通过其PB1结构域，以类似于其多泛素化蛋白聚集的方式，介导功能障碍的线粒体的聚集。令人惊讶的是，与最近报道的泛素诱导的吞噬和异种吞噬形成对比的是，p62似乎对有丝分裂吞噬是可有可无的。同样，线粒体锚定的泛素足以招募p62并促进线粒体聚集，但不促进有丝分裂。虽然VDAC1(而不是VDAC2)在线粒体去极化后被泛素化，但我们发现VDAC1不能完全解释去极化后观察到的线粒体K63连接的泛素免疫反应，因为它也在VDAC1/3(-/-)小鼠胚胎成纤维细胞中观察到。此外，我们发现VDAC1和VDAC3对于p62的募集、线粒体聚集和有丝分裂都是必不可少的。这些结果表明，线粒体在被Parkin以不依赖于VDAC1的方式招募后，由p62聚集。他们还表明，P62以外的蛋白质可能是VDAC1以外的Parkin底物下游吞噬有丝分裂所必需的。
Mitochondria sustain damage with aging, and the resulting mitochondrial dysfunction has been implicated in a number of diseases including Parkinson disease. We recently demonstrated that the E3 ubiquitin ligase Parkin, which is linked to recessive forms of parkinsonism, causes a dramatic increase in mitophagy and a change in mitochondrial distribution, following its translocation from the cytosol to mitochondria. Investigating how Parkin induces these changes may offer insight into the mechanisms that lead to the sequestration and elimination of damaged mitochondria. We report that following Parkin's translocation from the cytosol to mitochondria, Parkin (but not a pathogenic mutant) promotes the K63-linked polyubiquitination of mitochondrial substrate(s) and recruits the ubiquitin-and LC3-binding protein, p62/SQSTM1, to mitochondria. After its recruitment, p62/SQSTM1 mediates the aggregation of dysfunctional mitochondria through polymerization via its PB1 domain, in a manner analogous to its aggregation of polyubiquitinated proteins. Surprisingly and in contrast to what has been recently reported for ubiquitin-induced pexophagy and xenophagy, p62 appears to be dispensable for mitophagy. Similarly, mitochondrial-anchored ubiquitin is sufficient to recruit p62 and promote mitochondrial clustering, but does not promote mitophagy. Although VDAC1 (but not VDAC2) is ubiquitinated following mitochondrial depolarization, we find VDAC1 cannot fully account for the mitochondrial K63-linked ubiquitin immunoreactivity observed following depolarization, as it is also observed in VDAC1/3(-/-) mouse embryonic fibroblasts. Additionally, we find VDAC1 and VDAC3 are dispensable for the recruitment of p62, mitochondrial clustering and mitophagy. These results demonstrate that mitochondria are aggregated by p62, following its recruitment by Parkin in a VDAC1-independent manner. They also suggest that proteins other than p62 are likely required for mitophagy downstream of Parkin substrates other than VDAC1.