Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA.
Department of Pediatrics, Division of Neonatology, Vanderbilt University, Nashville, TN, 37232, USA.
Sci Rep. 2020 Mar 19;10(1):5028. doi: 10.1038/s41598-020-61796-4.
Loss-of-function mutations in the E3 ubiquitin ligase parkin have been implicated in the death of dopaminergic neurons in the substantia nigra, which is the root cause of dopamine deficit in the striatum in Parkinson's disease. Parkin ubiquitinates proteins on mitochondria that lost membrane potential, promoting the elimination of damaged mitochondria. Neuroprotective activity of parkin has been linked to its critical role in the mitochondria maintenance. Here we report a novel regulatory mechanism: another E3 ubiquitin ligase Mdm2 directly binds parkin and enhances its enzymatic activity in vitro and in intact cells. Mdm2 translocates to damaged mitochondria independently of parkin, enhances parkin-dependent ubiquitination of the outer mitochondria membrane protein mitofusin1. Mdm2 facilitates and its knockdown reduces parkin-dependent mitophagy. Thus, ubiquitously expressed Mdm2 might enhance cytoprotective parkin activity. The data suggest that parkin activation by Mdm2 could be targeted to increase its neuroprotective functions, which has implications for anti-parkinsonian therapy.
E3 泛素连接酶 parkin 的功能丧失突变与黑质多巴胺能神经元的死亡有关，这是帕金森病纹状体中多巴胺缺乏的根本原因。Parkin 泛素化失去膜电位的线粒体蛋白，促进受损线粒体的清除。Parkin 的神经保护活性与其在维持线粒体中的关键作用有关。在这里，我们报告了一种新的调节机制：另一种 E3 泛素连接酶 Mdm2 直接与 parkin 结合，并在体外和完整细胞中增强其酶活性。Mdm2 独立于 parkin 易位到受损的线粒体，增强 parkin 依赖性对线粒体膜蛋白融合素 1 的泛素化。Mdm2 促进并敲低会减少 parkin 依赖性的线粒体自噬。因此，广泛表达的 Mdm2 可能增强细胞保护 parkin 活性。这些数据表明，Mdm2 对 parkin 的激活可以作为增加其神经保护功能的靶点，这对帕金森病的治疗具有重要意义。
