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DRP1-Ser637 的磷酸化状态由 PKA 在分裂调节中的线粒体调控通过 PINK1/Parkin 介导的线粒体自噬，在有丝分裂过程中发挥多极纺锤体组装的作用。

The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis.

机构信息

Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan.

Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan.

出版信息

Biomolecules. 2021 Mar 13;11(3):424. doi: 10.3390/biom11030424.

DOI:10.3390/biom11030424
PMID:33805672
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7998912/
Abstract

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.

摘要

线粒体的分裂和融合循环与细胞周期的进展相整合。在这里，我们首先重新探讨了线粒体 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 III 抑制剂（抗霉素 A，AA）抑制有丝分裂期（M 期）Plk1 T210 和 Aurora A T288 的磷酸化，特别是 ROT，影响分裂蛋白 dynamin-related protein 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。与 ROT 和 AA 的作用相似，我们的结果表明 Mdivi-1 而不是 Dynasore 影响 Drp1 的 Ser637 和 Ser616 的动态磷酸化状态，这与有丝分裂激酶（Cdk1、Plk1、Aurora A）和中心体相关蛋白的作用一致，可显著加速有丝分裂缺陷。此外，我们的数据还表明，蛋白激酶 A（PKA）引发的 mito-Drp1-Ser637 而不是 Cdk1/Cyclin B 引发的 Drp1-Ser616 可通过 PINK1/Parkin 途径引发线粒体分裂，以促进更有效的线粒体自噬，并同时导致多极纺锤体。总之，这项研究首次揭示了 PKA 引发的 mito-Drp1-Ser637 而不是 Drp1-Ser616 驱动线粒体自噬，在 M 期发挥作用导致多极纺锤体形成。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/4d1a804f13f9/biomolecules-11-00424-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/1cabb94c1283/biomolecules-11-00424-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/2535d8a11f91/biomolecules-11-00424-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/b72d8b0e9574/biomolecules-11-00424-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/17d857101d85/biomolecules-11-00424-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/33b0587bda51/biomolecules-11-00424-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/292d741179f4/biomolecules-11-00424-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/29a3d3fe3f16/biomolecules-11-00424-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/4d1a804f13f9/biomolecules-11-00424-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/1cabb94c1283/biomolecules-11-00424-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/2535d8a11f91/biomolecules-11-00424-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/b72d8b0e9574/biomolecules-11-00424-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/17d857101d85/biomolecules-11-00424-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/33b0587bda51/biomolecules-11-00424-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/292d741179f4/biomolecules-11-00424-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/29a3d3fe3f16/biomolecules-11-00424-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2e69/7998912/4d1a804f13f9/biomolecules-11-00424-g008.jpg

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