The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis
Huey-Jiun Ko,
Cheng-Yu Tsai,
Shean-Jaw Chiou,
Yun-Ling Lai,
Chi-Huei Wang,
Jiin-Tsuey Cheng,
Tsung-Hsien Chuang,
Chi-Ying F. Huang,
Aij-Lie Kwan,
Joon-Khim Loh,
Yi-Ren Hong
Affiliations
Huey-Jiun Ko
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
Cheng-Yu Tsai
Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University and National Health Research Institutes, Kaohsiung 80708, Taiwan
Shean-Jaw Chiou
Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
Yun-Ling Lai
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
Chi-Huei Wang
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
Jiin-Tsuey Cheng
Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
Tsung-Hsien Chuang
Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University and National Health Research Institutes, Kaohsiung 80708, Taiwan
Chi-Ying F. Huang
Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
Aij-Lie Kwan
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
Joon-Khim Loh
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
Yi-Ren Hong
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
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.
