Department of Pharmacology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, 04763 Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, 04763 Seoul, Republic of Korea.
Department of Pharmacology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, 04763 Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, 04763 Seoul, Republic of Korea; Hanyang Biomedical Research Institute, 222 Wangsimni-ro, Seongdong-gu, 04763 Seoul, Republic of Korea.
Toxicol Lett. 2023 Jun 1;382:1-12. doi: 10.1016/j.toxlet.2023.05.002. Epub 2023 May 6.
CK2 regulates receptor-mediated mitophagy that removes damaged mitochondria. The PINK1/Parkin pathways also involve mitochondrial clearance through mitophagy. However, it is not clear whether CK2 regulates PINK1/Parkin-dependent mitophagy in response to stress. Rotenone treatment showed a decrease of FUNDC1 expression in the mitochondrial fraction of SH-SY5Y and HeLa cells, but an increase of PINK1/Parkin expression only in SH-SY5Y cells. Interestingly, CK2 inhibition increased mitochondrial LC3II expression in rotenone-treated HeLa cells, whereas it decreased in SH-SY5Y cells, indicating that CK2 mediates rotenone-induced mitophagy in dopaminergic neurons. Furthermore, FUNDC1 expression increased in rotenone-treated SH-SY5Y cells by CK2 inhibition, whereas it decreased in HeLa cells. CK2 inhibition also blocked the increase of Drp1, PINK1 and Parkin translocation into mitochondria and decrease of PGAM5 expression in rotenone-treated SH-SY5Y cells. As expected, rotenone treatment in PGAM5-knockdown cells reduced the expression of PINK1 and Parkin and decrease of LC3II expression. Interestingly, we observed that knockdown of CK2α or PGAM5 induced a further increase in caspase-3 expression. These results suggest that PINK1/Parkin-dependent mitophagy was dominant over FUNDC1 receptor-mediated mitophagy. Collectively, our findings suggest that CK2 can positively induce PINK1/Parkin-dependent mitophagy, and that mitophagy regulates cytoprotective effects by CK2 signaling in dopaminergic neurons. DATA AVAILABILITY STATEMENT: All data generated or analyzed during this study are available upon request.
CK2 调节受体介导线粒体自噬，去除受损的线粒体。PINK1/Parkin 途径也通过线粒体自噬参与线粒体清除。然而，CK2 是否调节 PINK1/Parkin 依赖性线粒体自噬以应对应激尚不清楚。鱼藤酮处理显示 SH-SY5Y 和 HeLa 细胞线粒体部分 FUNDC1 表达减少，但仅在 SH-SY5Y 细胞中 PINK1/Parkin 表达增加。有趣的是，CK2 抑制增加了鱼藤酮处理的 HeLa 细胞中线粒体 LC3II 的表达，而在 SH-SY5Y 细胞中则减少，表明 CK2 介导多巴胺能神经元中的鱼藤酮诱导的线粒体自噬。此外，CK2 抑制增加了鱼藤酮处理的 SH-SY5Y 细胞中 FUNDC1 的表达，而在 HeLa 细胞中则减少。CK2 抑制还阻断了鱼藤酮处理的 SH-SY5Y 细胞中 Drp1、PINK1 和 Parkin 易位到线粒体以及 PGAM5 表达减少。正如预期的那样，PGAM5 敲低细胞中的鱼藤酮处理降低了 PINK1 和 Parkin 的表达和 LC3II 的表达减少。有趣的是，我们观察到 CK2α 或 PGAM5 的敲低诱导了 caspase-3 表达的进一步增加。这些结果表明，PINK1/Parkin 依赖性线粒体自噬占主导地位，而 FUNDC1 受体介导的线粒体自噬。总之，我们的研究结果表明，CK2 可以正向诱导 PINK1/Parkin 依赖性线粒体自噬，而线粒体自噬通过 CK2 信号调节多巴胺能神经元的细胞保护作用。数据可用性声明：本研究中生成或分析的所有数据均可应要求提供。
