Nature2014-06-23 4:45 PM

线粒体自噬对帕金森氏症的影响 The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy

论文摘要 

影响在受损线粒体的清除(线粒体自噬)中所涉及的两种酶(泛素连接酶parkin和蛋白激酶PINK1)的“功能丧失突变”与家族性帕金森氏症有关。这项研究表明,USP30 (一种局限于线粒体的去泛素酶)通过去除由parkin放置的泛素标签来对抗线粒体自噬。 降低USP30的活性会增强神经元中的线粒体降解,USP30 的抑制会挽救由parkin中的致病性突变引起的有缺陷的线粒体自噬作用。在一个果蝇模型中,USP30 的抑制在同时缺失parkin和PINK1的果蝇中都能提高线粒体完整性和存活率。因此,USP30 的抑制可以促进线粒体清除和质量控制,对帕金森氏症有潜在好处。

Abstract 

Cells maintain healthy mitochondria by degrading damaged mitochondria through mitophagy; defective mitophagy is linked to Parkinson’s disease. Here we report that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (also known as PARK2) and protein kinase PINK1, which are encoded by two genes associated with Parkinson’s disease. Parkin ubiquitinates and tags damaged mitochondria for clearance. Overexpression of USP30 removes ubiquitin attached by parkin onto damaged mitochondria and blocks parkin’s ability to drive mitophagy, whereas reducing USP30 activity enhances mitochondrial degradation in neurons. Global ubiquitination site profiling identified multiple mitochondrial substrates oppositely regulated by parkin and USP30. Knockdown of USP30 rescues the defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin- or PINK1-deficient flies. Knockdown of USP30 in dopaminergic neurons protects flies against paraquat toxicity in vivo, ameliorating defects in dopamine levels, motor function and organismal survival. Thus USP30 inhibition is potentially beneficial for Parkinson’s disease by promoting mitochondrial clearance and quality control.

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