Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558, Japan.
J Biol Chem. 2011 Mar 4;286(9):7182-9. doi: 10.1074/jbc.M110.179390. Epub 2010 Dec 21.
Accumulating evidence indicates that dysfunction of mitochondria is a common feature of Parkinson disease. Functional loss of a familial Parkinson disease-linked gene, BRPK/PINK1 (PINK1), results in deterioration of mitochondrial functions and eventual neuronal cell death. A mitochondrial chaperone protein has been shown to be a substrate of PINK1 kinase activity. In this study, we demonstrated that PINK1 has another action point in the cytoplasm. Phosphorylation of Akt at Ser-473 was enhanced by overexpression of PINK1, and the Akt activation was crucial for protection of SH-SY5Y cells from various cytotoxic agents, including oxidative stress. Enhanced Akt phosphorylation was not due to activation of phosphatidylinositol 3-kinase but due to activation of mammalian target of rapamycin complex 2 (mTORC2) by PINK1. Rictor, a specific component of mTORC2, was phosphorylated by overexpression of PINK1. Furthermore, overexpression of PINK1 enhanced cell motility. These results indicate that PINK1 exerts its cytoprotective function not only in mitochondria but also in the cytoplasm through activation of mTORC2.
越来越多的证据表明，线粒体功能障碍是帕金森病的一个共同特征。家族性帕金森病相关基因 BRPK/PINK1(PINK1) 的功能丧失导致线粒体功能恶化，最终导致神经元细胞死亡。已经证明一种线粒体伴侣蛋白是 PINK1 激酶活性的底物。在这项研究中，我们证明 PINK1 在细胞质中有另一个作用点。过表达 PINK1 增强了 Akt 在 Ser-473 处的磷酸化，Akt 的激活对于保护 SH-SY5Y 细胞免受各种细胞毒性剂，包括氧化应激的损伤至关重要。增强的 Akt 磷酸化不是由于磷脂酰肌醇 3-激酶的激活，而是由于 PINK1 激活了雷帕霉素靶蛋白复合物 2(mTORC2)。Rictor 是 mTORC2 的特定组成部分，过表达 PINK1 可使其磷酸化。此外，过表达 PINK1 可增强细胞迁移能力。这些结果表明，PINK1 通过激活 mTORC2，不仅在线粒体中，而且在细胞质中发挥其细胞保护功能。
