Laboratory of Functional Neurogenetics, Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Centre for Neurodegenerative Diseases, Tübingen, Germany.
Autophagy. 2010 Oct;6(7):871-8. doi: 10.4161/auto.6.7.13286. Epub 2010 Oct 3.
Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps. Here we show that whole mitochondria are turned over via macroautophagy. Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. This may be due to the decreased physical binding activity of PD-linked PINK1 mutations to Parkin. Thus, PINK1 mutations abrogate autophagy of impaired mitochondria upstream of Parkin. In addition to compromised PINK1 kinase activity, reduced binding of PINK1 to Parkin leads to failure in Parkin mitochondrial translocation, resulting in the accumulation of damaged mitochondria, which may contribute to disease pathogenesis.
线粒体功能障碍是许多神经退行性疾病的早期征兆。最近，两种帕金森病（PD）相关基因 PINK1 和 Parkin 被证明通过选择性自噬（mitophagy）介导受损线粒体的降解。PINK1 激酶活性对于 Parkin 迅速有效地募集到受损线粒体是必需的。与 PD 相关的 Parkin 突变在不同的步骤干扰 mitophagy 过程。在这里，我们表明整个线粒体通过巨自噬进行周转。此外，与疾病相关的 PINK1 突变也会损害去极化线粒体的选择性降解。这可能是由于 PD 相关 PINK1 突变与 Parkin 的物理结合活性降低。因此，PINK1 突变在上游 Parkin 之前废除了受损线粒体的自噬。除了 PINK1 激酶活性受损外，PINK1 与 Parkin 的结合减少导致 Parkin 在线粒体易位中失败，导致受损线粒体的积累，这可能有助于疾病的发病机制。
