PKA 在线粒体裂变中对 Drp1-Ser637 的磷酸化状态通过 PINK1/Parkin 调节线粒体自噬,从而在有丝分裂过程中发挥多极纺锤体组装

The phosphorylation status of Drp1-Ser637 by PKA in mitochondrial fission modulates

mitophagy via PINK1/Parkin to exert multipolar spindles assembly during mitosis




Keywords:mitochondria; Drp1; PKA; phosphorylation; mitophagy; centrosomes; multipolar spindles
关键词:线粒体; Drp1; PKA;磷酸化;线粒体自噬;中心体;多极主轴

作者:Young MP, Schug ZT, Booth DM, Yule DI, Mikoshiba K, Hajnóczky G, Joseph SK
出版期刊:《Biomolecules》 2021/3/13


Mitochondrial fission and fusion cycles are integrated with cell cycle progression. Here we first re-visited how mitochondrial ETC inhibition disturbed mitosis progression, resulting in multipolar spindles formation in HeLa cells. Inhibitors of ETC complex I (rotenone, ROT) and complex III (antimycin A, AA) decreased the phosphorylation of Plk1 T210 and Aurora A T288 in the mitotic phase (M-phase), especially ROT, affecting the dynamic phosphorylation status of fission protein dynamin-related protein 1 (Drp1) and the Ser637/Ser616 ratio. We then tested whether specific Drp1 inhibitors, Mdivi-1 or Dynasore, affected the dynamic phosphorylation status of Drp1.Similar to the effects of ROT and AA, our results showed that Mdivi-1 but not Dynasore influenced the dynamic phosphorylation status of Ser637 and Ser616 in Drp1, which converged with mitotic kinases (Cdk1, Plk1, Aurora A) and centrosome-associated proteins to significantly accelerate mitotic defects. Moreover, our data also indicated that evoking mito-Drp1-Ser637 by protein kinase A (PKA) rather than Drp1-Ser616 by Cdk1/Cyclin B resulted in mitochondrial fission via the PINK1/Parkin pathway to promote more efficient mitophagy and simultaneously caused multipolar spindles.Collectively, this study is the first to uncover that mito-Drp1-Ser637 by PKA, but not Drp1-Ser616,drives mitophagy to exert multipolar spindles formation during M-phase.


线粒体裂变和融合周期与细胞周期进程相结合。在这里,我们首先重新审视了线粒体 ETC 抑制如何干扰有丝分裂进程,导致 HeLa 细胞中形成多极纺锤体。ETC 复合物 I(鱼藤酮,ROT)和复合物 III 的抑制剂( antimycin A, AA) 降低 Plk1 T210 和 Aurora A T288 在有丝分裂期 (M 期) 尤其是 ROT 的磷酸化, 影响裂变蛋白动力相关蛋白 1 (Drp1) 的动态磷酸化状态和 Ser637/Ser616 比值. 然后我们测试了特定的 Drp1 抑制剂 Mdivi-1 或 Dynasore 是否会影响 Drp1 的动态磷酸化状态。类似于 ROT 和 AA 的影响,我们的结果表明 Mdivi-1 而不是 Dynasore 影响 Ser637 的动态磷酸化状态和Drp1 中的 Ser616,与有丝分裂激酶(Cdk1、Plk1、Aurora A)和中心体相关蛋白融合以显着加速有丝分裂缺陷。此外,我们的数据还表明,蛋白激酶 A (PKA) 而非 Drp1-Ser616 Cdk1/Cyclin B 引起 mito-Drp1-Ser637 通过 PINK1/Parkin 途径导致线粒体裂变,以促进更有效的线粒体自噬,同时引起多极纺锤体。总的来说,这项研究是第一个发现 PKA 的 mito-Drp1-Ser637,但不是 Drp1-Ser616,在 M 期驱动 mitophagy 发挥多极纺锤体的形成。