Selenium-SelK-GPX4 axis protects nucleus pulposus cells against mechanical overloading-induced ferroptosis and attenuates senescence of intervertebral disc

作者：Chunwang Jia, Ziqian Xiang, Pengfei Zhang, Long Liu, Xuetao Zhu, Ruixuan Yu, Zhicheng Liu, Shaoyi Wang, Kaiwen Liu, Zihao Wang, Krasimir Vasilev, Shuanhu Zhou, Ziwen Geng, Xinyu Liu, Yunpeng Zhao, Yuan Gao, Lei Cheng, Yuhua Li · 发表于：Cellular and Molecular Life Sciences · 年份：2024 · DOI：10.1007/s00018-023-05067-1 · 被引用次数：62 · 研究领域：Spine and Intervertebral Disc Pathology、Pregnancy-related medical research、Selenium in Biological Systems

Abstract Intervertebral disc degeneration (IVDD) is one of the most prevalent spinal degenerative disorders and imposes places heavy medical and economic burdens on individuals and society. Mechanical overloading applied to the intervertebral disc (IVD) has been widely recognized as an important cause of IVDD. Mechanical overloading-induced chondrocyte ferroptosis was reported, but the potential association between ferroptosis and mechanical overloading remains to be illustrated in nucleus pulposus (NP) cells. In this study, we discovered that excessive mechanical loading induced ferroptosis and endoplasmic reticulum (ER) stress, which were detected by mitochondria and associated markers, by increasing the intracellular free Ca 2+ level through the Piezo1 ion channel localized on the plasma membrane and ER membrane in NP cells. Besides, we proposed that intracellular free Ca 2+ level elevation and the activation of ER stress are positive feedback processes that promote each other, consistent with the results that the level of ER stress in coccygeal discs of aged Piezo1-CKO mice were significantly lower than that of aged WT mice. Then, we confirmed that selenium supplementation decreased intracellular free Ca 2+ level by mitigating ER stress through upregulating Selenoprotein K (SelK) expression. Besides, ferroptosis caused by the impaired production and function of Glutathione peroxidase 4 (GPX4) due to mechanical overloading-induced calcium overload could be improved by sele...