Cho Bongki, Cho Hyo Min, Kim Hyun Jung, Jeong Jaehoon, Park Sang Ki, Hwang Eun Mi, Park Jae-Yong, Kim Woon Ryoung, Kim Hyun, Sun Woong
Department of Anatomy, College of Medicine, Korea University, Seoul, Republic of Korea.
Department of Life Science, Pohang University of Science and Technology, Pohang, Gyungbuk, Republic of Korea.
Exp Mol Med. 2014 Jul 11;46(7):e105. doi: 10.1038/emm.2014.36.
Mitochondrial functions are essential for the survival and function of neurons. Recently, it has been demonstrated that mitochondrial functions are highly associated with mitochondrial morphology, which is dynamically changed by the balance between fusion and fission. Mitochondrial morphology is primarily controlled by the activation of dynamin-related proteins including dynamin-related protein 1 (Drp1), which promotes mitochondrial fission. Drp1 activity is regulated by several post-translational modifications, thereby modifying mitochondrial morphology. Here, we found that phosphorylation of Drp1 at serine 616 (S616) is mediated by cyclin-dependent kinase 5 (CDK5) in post-mitotic rat neurons. Perturbation of CDK5 activity modified the level of Drp1S616 phosphorylation and mitochondrial morphology in neurons. In addition, phosphorylated Drp1S616 preferentially localized as a cytosolic monomer compared with total Drp1. Furthermore, roscovitine, a chemical inhibitor of CDKs, increased oligomerization and mitochondrial translocation of Drp1, suggesting that CDK5-dependent phosphorylation of Drp1 serves to reduce Drp1's fission-promoting activity. Taken together, we propose that CDK5 has a significant role in the regulation of mitochondrial morphology via inhibitory phosphorylation of Drp1S616 in post-mitotic neurons.
线粒体功能对于神经元的存活和功能至关重要。最近，有研究表明线粒体功能与线粒体形态高度相关，而线粒体形态会因融合与裂变之间的平衡而动态变化。线粒体形态主要受包括动力相关蛋白1（Drp1）在内的动力相关蛋白的激活控制，Drp1可促进线粒体裂变。Drp1的活性受多种翻译后修饰的调节，从而改变线粒体形态。在此，我们发现丝氨酸616（S616）位点的Drp1磷酸化是由有丝分裂后大鼠神经元中的细胞周期蛋白依赖性激酶5（CDK5）介导的。CDK5活性的扰动改变了神经元中Drp1S616的磷酸化水平和线粒体形态。此外，与总Drp1相比，磷酸化的Drp1S616优先定位于胞质单体。此外，细胞周期蛋白依赖性激酶的化学抑制剂roscovitine增加了Drp1的寡聚化和线粒体转位，这表明CDK5依赖性的Drp1磷酸化作用是降低Drp1的促裂变活性。综上所述，我们认为CDK5在有丝分裂后神经元中通过对Drp1S616的抑制性磷酸化在调节线粒体形态方面发挥着重要作用。
