Calmodulin-dependent protein kinase II (CaMKII) mediates radiation-induced mitochondrial fission by regulating the phosphorylation of dynamin-related protein 1 (Drp1) at serine 616 |
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Authors: | Tomoki Bo Tohru Yamamori Motofumi Suzuki Yuri Sakai Kumiko Yamamoto Osamu Inanami |
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Institution: | 1. Laboratory of Radiation Biology, Department of Applied Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan;2. Radiation and Cancer Biology Team, National Institutes for Quantum and Radiobiological Science and Technology, Chiba, Japan |
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Abstract: | Mitochondrial dynamics are suggested to be indispensable for the maintenance of cellular quality and function in response to various stresses. While ionizing radiation (IR) stimulates mitochondrial fission, which is mediated by the mitochondrial fission protein, dynamin-related protein 1 (Drp1), it remains unclear how IR promotes Drp1 activation and subsequent mitochondrial fission. Therefore, we conducted this study to investigate these concerns. First, we found that X-irradiation triggered Drp1 phosphorylation at serine 616 (S616) but not at serine 637 (S637). Reconstitution analysis revealed that introduction of wild-type (WT) Drp1 recovered radiation-induced mitochondrial fission, which was absent in Drp1-deficient cells. Compared with cells transfected with WT or S637A Drp1, the change in mitochondrial shape following irradiation was mitigated in S616A Drp1-transfected cells. Furthermore, inhibition of CaMKII significantly suppressed Drp1 S616 phosphorylation and mitochondrial fission induced by IR. These results suggest that Drp1 phosphorylation at S616, but not at S637, is prerequisite for radiation-induced mitochondrial fission and that CaMKII regulates Drp1 phosphorylation at S616 following irradiation. |
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Keywords: | CaMKII Drp1 Ionizing radiation Mitochondrial dynamics Phosphorylation CaMKII calmodulin-dependent protein kinase II cPKC conventional protein kinase C CDK1 cyclin-dependent kinase 1 Drp1 dynamin-related protein 1 GFX GF109203X Gö Gö6976 IR ionizing radiation Fis1 mitochondrial fission protein 1 Mff mitochondrial fission factor Mfn1/2 mitofusin 1/2 Opa1 optic atrophy 1 PMA phorbol 12-myristate 13-acetate PTMs posttranslational modifications PKCδ protein kinase C δ S616 serine 616 S637 serine 637 S693 serine 693 WT wild-type |
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