Key Laboratory of Brain Functional Genomics of Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, and Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China.
Cell Death Differ. 2018 May;25(5):904-917. doi: 10.1038/s41418-017-0027-x. Epub 2017 Dec 12.
PINK1 mutations that disrupt its kinase activity cause autosomal recessive early onset Parkinson's disease (PD). Although research in recent years has elucidated a PINK1-Parkin pathway of mitophagy activation that requires PINK1 kinase activity, mitophagy-independent functions of PINK1 and their possible roles in PD pathogenesis have been proposed. Using an unbiased quantitative mass spectrometry approach to analyze the phosphoproteome in primary neurons from wild type and Pink1 knockout mice after mitochondrial depolarization, we uncovered PINK1-regulated phosphorylation sites, which involve coordinated activation of multiple signaling pathways that control cellular response to stress. We further identified the pro-apoptotic protein BAD as a potential mitochondrial substrate of PINK1 both in vitro and in vivo, and found that cells more susceptible to a12poptosis induced by mitochondrial damage can be rescued by phosphorylation mimic BAD. Our results thus suggest that PINK1 kinase activity is important for pro-apoptotic protein function in regulation of cell death.
PINK1 突变会破坏其激酶活性，导致常染色体隐性早发性帕金森病（PD）。尽管近年来的研究已经阐明了需要 PINK1 激酶活性的 PINK1-Parkin 途径的线粒体自噬激活，但 PINK1 的非依赖性功能及其在 PD 发病机制中的可能作用已被提出。我们使用一种无偏的定量质谱分析方法来分析线粒体去极化后来自野生型和 Pink1 敲除小鼠的原代神经元的磷酸蛋白质组，揭示了 PINK1 调节的磷酸化位点，这些位点涉及控制细胞对应激反应的多个信号通路的协调激活。我们进一步鉴定了促凋亡蛋白 BAD 作为 PINK1 的潜在线粒体底物，无论是在体外还是在体内，并且发现对线粒体损伤诱导的 a12poptosis 更敏感的细胞可以通过磷酸化模拟 BAD 来挽救。因此，我们的结果表明，PINK1 激酶活性对于调节细胞死亡的促凋亡蛋白功能很重要。
