Gehrke Stephan, Wu Zhihao, Klinkenberg Michael, Sun Yaping, Auburger Georg, Guo Su, Lu Bingwei
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Experimental Neurology, Goethe University Medical School, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
Cell Metab. 2015 Jan 6;21(1):95-108. doi: 10.1016/j.cmet.2014.12.007.
Mitochondria play essential roles in many aspects of biology, and their dysfunction has been linked to diverse diseases. Central to mitochondrial function is oxidative phosphorylation (OXPHOS), accomplished by respiratory chain complexes (RCCs) encoded by nuclear and mitochondrial genomes. How RCC biogenesis is regulated in metazoans is poorly understood. Here we show that Parkinson's disease (PD)-associated genes PINK1 and Parkin direct localized translation of certain nuclear-encoded RCC (nRCC) mRNAs. Translationally repressed nRCC mRNAs are localized in a PINK1/Tom20-dependent manner to mitochondrial outer membrane, where they are derepressed and activated by PINK1/Parkin through displacement of translation repressors, including Pumilio and Glorund/hnRNP-F, a Parkin substrate, and enhanced binding of activators such as eIF4G. Inhibiting the translation repressors rescued nRCC mRNA translation and neuromuscular-degeneration phenotypes of PINK1 mutant, whereas inhibiting eIF4G had opposite effects. Our results reveal previously unknown functions of PINK1/Parkin in RNA metabolism and suggest new approaches to mitochondrial restoration and disease intervention.
线粒体在生物学的许多方面发挥着至关重要的作用，其功能障碍与多种疾病相关。线粒体功能的核心是氧化磷酸化（OXPHOS），这是由核基因组和线粒体基因组编码的呼吸链复合物（RCCs）完成的。后生动物中RCC生物发生是如何被调控的，目前还知之甚少。在这里，我们表明帕金森病（PD）相关基因PINK1和Parkin指导某些核编码的RCC（nRCC）mRNA的局部翻译。翻译受抑制的nRCC mRNA以PINK1/Tom20依赖的方式定位于线粒体外膜，在那里它们被PINK1/Parkin通过取代包括Pumilio和Glorund/hnRNP-F（一种Parkin底物）在内的翻译抑制因子以及增强诸如eIF4G等激活因子的结合而解除抑制并被激活。抑制翻译抑制因子可挽救nRCC mRNA翻译以及PINK1突变体的神经肌肉变性表型，而抑制eIF4G则产生相反的效果。我们的结果揭示了PINK1/Parkin在RNA代谢中以前未知的功能，并提出了线粒体修复和疾病干预的新方法。
