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

Abstract

Mitophagy refers to selective mitochondrial autophagy to remove damaged mitochondria and plays a critical role in maintaining mitochondria homeostasis. Casein kinase 2 alpha (CK2 alpha) 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 CK2 alpha 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 CK2 alpha in this process. Rotenone increased the expression of P-PERK and P-IRE1 alpha, thereby activating ER stress sensors. CK2 alpha inhibition suppressed PERK and IRE1 alpha activation and their downstream signaling components (eIF2 alpha, ATF4, CHOP and XBP1s). Furthermore, CK2 alpha inhibition enhanced PINK1/Parkin-mediated mitophagy by increasing PINK1 and Parkin translocation to mitochondria in addition to inducing LC3II expression. These results suggest that CK2 alpha 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, CK2 alpha inhibition reduced rotenone-induced apoptosis by modulating PERK signaling. These findings suggest that CK2 alpha 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 CK2 alpha signal regulation for treating diseases driven by ER stress and mitochondrial dysfunction, offering a promising avenue for future research.