Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
J Cell Biol. 2010 Dec 27;191(7):1367-80. doi: 10.1083/jcb.201007013. Epub 2010 Dec 20.
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.
线粒体损伤可导致线粒体内膜去极化，从而使受损的线粒体对自噬的选择性消除变得敏感。然而，未偶联的线粒体与极化的线粒体融合可以补偿损伤，逆转膜去极化，并避免自噬。Parkin 是一种 E3 泛素连接酶，在单基因形式的帕金森病中发生突变，最近发现它可诱导受损线粒体的选择性自噬。本文作者表示，Parkin 在膜去极化时诱导大 GTP 酶线粒体融合蛋白 Mfn1 和 Mfn2 的泛素化，导致它们以依赖蛋白酶体和 p97 的方式降解。p97 是一种 AAA+ATP 酶，在 Parkin 表达细胞解偶联时会在线粒体上积累，并且 p97 和蛋白酶体活性都是 Parkin 介导的线粒体自噬所必需的。在去极化后的线粒体分裂之后，Parkin 阻止或延迟线粒体的融合，这可能是通过消除线粒体融合蛋白来实现的。抑制 Drp1 介导的线粒体分裂、蛋白酶体或 p97 可防止 Parkin 诱导的线粒体自噬。
