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<p>Mitophagy refers to selective mitochondrial autophagy to remove damaged mitochondria and plays a critical role in maintaining mitochondria homeostasis. Casein kinase 2α (CK2α) is involved in mitophagy regulation in dopaminergic neurons. Endoplasmic reticulum (ER) stress releases calcium into mitochondria, leading to mitochondrial dysfunction and contributing to various diseases. However, it is not clear whether CK2α regulates ER-mediated mitochondrial dysfunction and mitophagy in response to ER stress. Therefore, we investigated the effects of ER stress on mitophagy during rotenone-induced ER stress and mitochondrial damage in SH-SY5Y cells and elucidated the role of CK2α in this process. Rotenone increased the expression of P-PERK and P-IRE1α, thereby activating ER stress sensors. CK2α inhibition suppressed PERK and IRE1α activation and their downstream signaling components (eIF2α, ATF4, CHOP and XBP1s). Furthermore, CK2α inhibition enhanced PINK1/Parkin-mediated mitophagy by increasing PINK1 and Parkin translocation to mitochondria in addition to inducing LC3II expression. These results suggest that CK2α regulates PINK/Parkin-dependent mitophagy in rotenone-treated cells. Interestingly, treatment of cells with the PERK inhibitor GSK2606414 also resulted in increased PINK1/Parkin-mediated mitophagy. Moreover, CK2α inhibition reduced rotenone-induced apoptosis by modulating PERK signaling. These findings suggest that CK2α plays a key role in regulating the ER stress response and PERK-dependent PINK1/Parkin-mediated mitophagy in our rotenone-induced apoptosis model. This study highlights the therapeutic potential of CK2α signal regulation for treating diseases driven by ER stress and mitochondrial dysfunction, offering a promising avenue for future research.</p>

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CK2α Regulates Endoplasmic Reticulum Stress-Mediated Mitophagy via the PERK/ATF4/CHOP Pathway in Rotenone-Treated SH-SY5Y Cells

  • 期刊论文

  • 发表日期：

    2025年11月19日

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  • Kyung Mi Lim,
  • Jungwook Hwang,
  • Hyun Chul Koh

摘要

Mitophagy refers to selective mitochondrial autophagy to remove damaged mitochondria and plays a critical role in maintaining mitochondria homeostasis. Casein kinase 2α (CK2α) is involved in mitophagy regulation in dopaminergic neurons. Endoplasmic reticulum (ER) stress releases calcium into mitochondria, leading to mitochondrial dysfunction and contributing to various diseases. However, it is not clear whether CK2α regulates ER-mediated mitochondrial dysfunction and mitophagy in response to ER stress. Therefore, we investigated the effects of ER stress on mitophagy during rotenone-induced ER stress and mitochondrial damage in SH-SY5Y cells and elucidated the role of CK2α in this process. Rotenone increased the expression of P-PERK and P-IRE1α, thereby activating ER stress sensors. CK2α inhibition suppressed PERK and IRE1α activation and their downstream signaling components (eIF2α, ATF4, CHOP and XBP1s). Furthermore, CK2α inhibition enhanced PINK1/Parkin-mediated mitophagy by increasing PINK1 and Parkin translocation to mitochondria in addition to inducing LC3II expression. These results suggest that CK2α regulates PINK/Parkin-dependent mitophagy in rotenone-treated cells. Interestingly, treatment of cells with the PERK inhibitor GSK2606414 also resulted in increased PINK1/Parkin-mediated mitophagy. Moreover, CK2α inhibition reduced rotenone-induced apoptosis by modulating PERK signaling. These findings suggest that CK2α plays a key role in regulating the ER stress response and PERK-dependent PINK1/Parkin-mediated mitophagy in our rotenone-induced apoptosis model. This study highlights the therapeutic potential of CK2α signal regulation for treating diseases driven by ER stress and mitochondrial dysfunction, offering a promising avenue for future research.