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

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

  • Cell Mol Life Sci. 2024 Jan 22;81(1):49. doi: 10.1007/s00018-023-05067-1.
Chunwang Jia # 1,  Ziqian Xiang # 1,  Pengfei Zhang # 1,  Long Liu 2,  Xuetao Zhu 1,  Ruixuan Yu 1,  Zhicheng Liu 1,  Shaoyi Wang 1,  Kaiwen Liu 1,  Zihao Wang 1,  Krasimir Vasilev 3 4,  Shuanhu Zhou 5,  Ziwen Geng 6,  Xinyu Liu 1,  Yunpeng Zhao 7,  Yuan Gao 8,  Lei Cheng 9,  Yuhua Li 10
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China.
  • 2 Department of Pathology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, People's Republic of China.
  • 3 Academic Unit of STEM, University of South Australia, Mawson Lakes, Adelaide, SA, 5095, Australia.
  • 4 College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia.
  • 5 Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 6 Qilu Institute of Technology, Jinan, 250200, Shandong, People's Republic of China.
  • 7 Department of Orthopaedics, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China. lwwzyp@email.sdu.edu.cn.
  • 8 Department of Orthopaedics, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China. ygao@email.sdu.edu.cn.
  • 9 Department of Orthopaedics, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China. chenglei@email.sdu.edu.cn.
  • 10 Department of Orthopaedics, Cheeloo College of Medicine, Qilu Hospital, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China. liyuhua@qiluhospital.com.
  • # Contributed equally.
PMID: 38252317 DOI: 10.1007/s00018-023-05067-1
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 CA2+ level through the Piezo1 ion channel localized on the plasma membrane and ER membrane in NP cells. Besides, we proposed that intracellular free CA2+ 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 CA2+ 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 selenium supplementation through Se-GPX4 axis and Se-SelK axis in vivo and in vitro, eventually presenting the stabilization of the extracellular matrix (ECM). Our findings reveal the important role of Ferroptosis in mechanical overloading-induced IVDD, and selenium supplementation promotes significance to attenuate Ferroptosis and thus alleviates IVDD, which might provide insights into potential therapeutic interventions for IVDD.

Keywords

Endoplasmic reticulum stress; Ferroptosis; GPX4; Mechanical stress; SelK; Selenium.

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