Zhang Yang, Gao Yucheng, Liu Shuanggong, Yang Guowei, Rong Yijun, Wu Dongjin, Gao Zengxin
Department of Spinal Surgery, Zhongda Hospital, College of Medicine, Southeast University, NO.87 Ding Jia Qiao, Nanjing, Jiangsu, 210009, People's Republic of China.
Department of Orthopaedics, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan, Shandong, 250033, People's Republic of China.
J Orthop Surg Res. 2025 Jul 8;20(1):630. doi: 10.1186/s13018-025-06033-2.
BACKGROUND: Intervertebral disc degeneration (IVDD) is a multifactorial disorder and a leading contributor to chronic low back pain (LBP), highlighting the need for novel therapeutic strategies. Recent studies indicate that ferroptosis, driven by oxidative stress, plays a key role in the loss of nucleus pulposus cells (NPCs) during IVDD. Vacuole membrane protein 1 (VMP1), a membrane-associated regulator of autophagy, is known to influence various cellular processes. However, its role in IVDD remains unclear. This study investigates the function of VMP1 in IVDD and the mechanisms involved. METHODS: We established a rat model of IVDD to investigate the correlation between VMP1 expression and ferroptosis during IVDD progression. In vitro, a ferroptosis model of NPCs was induced using tert-butyl hydroperoxide (TBHP) to examine the effects of VMP1 knockdown on NPC apoptosis, extracellular matrix (ECM) degradation, ferroptosis, PINK1/Parkin-dependent mitophagy, and mitochondrial function. Furthermore, cyclosporin A (CsA), a mitophagy inhibitor, was employed to explore the role and potential mechanisms of VMP1 overexpression in regulating PINK1/Parkin-mediated mitophagy, mitochondrial function, and ferroptosis. RESULTS: In this study, we observed a significant downregulation of VMP1 expression in a rat model of IVDD, which was accompanied by the occurrence of ferroptosis. Subsequent experiments revealed that VMP1 knockdown aggravated apoptosis and ECM degradation in NPCs. Furthermore, we demonstrated that VMP1 silencing promoted ferroptosis, inhibited PINK1/Parkin-dependent mitophagy, and impaired mitochondrial function in NPCs. In contrast, VMP1 overexpression enhanced PINK1/Parkin-mediated mitophagy, mitigated mitochondrial dysfunction, and suppressed ferroptosis. Notably, these protective effects were abolished by treatment with CsA. CONCLUSIONS: This study demonstrates that VMP1 alleviates IVDD by inhibiting ferroptosis and mitochondrial dysfunction in NPCs, a protective effect mediated through the promotion of PINK1/Parkin-dependent mitophagy. Our study underscores the pivotal role of VMP1 in coordinating mitophagy and ferroptosis during IVDD pathogenesis, identifying VMP1 as a potential therapeutic target for IVDD treatment.
背景：椎间盘退变（IVDD）是一种多因素疾病，是慢性下腰痛（LBP）的主要原因，这凸显了对新型治疗策略的需求。最近的研究表明，由氧化应激驱动的铁死亡在IVDD期间髓核细胞（NPC）的丢失中起关键作用。液泡膜蛋白1（VMP1）是一种与自噬相关的膜调节因子，已知其会影响各种细胞过程。然而，其在IVDD中的作用仍不清楚。本研究调查了VMP1在IVDD中的功能及其相关机制。 方法：我们建立了IVDD大鼠模型，以研究IVDD进展过程中VMP1表达与铁死亡之间的相关性。在体外，使用叔丁基过氧化氢（TBHP）诱导NPC的铁死亡模型，以检查VMP1敲低对NPC凋亡、细胞外基质（ECM）降解、铁死亡、PINK1/Parkin依赖性线粒体自噬和线粒体功能的影响。此外，使用线粒体自噬抑制剂环孢素A（CsA）来探索VMP1过表达在调节PINK1/Parkin介导的线粒体自噬、线粒体功能和铁死亡中的作用及潜在机制。 结果：在本研究中，我们观察到IVDD大鼠模型中VMP1表达显著下调，同时伴有铁死亡的发生。随后的实验表明，VMP1敲低加剧了NPC的凋亡和ECM降解。此外，我们证明VMP1沉默促进了NPC中的铁死亡，抑制了PINK1/Parkin依赖性线粒体自噬，并损害了线粒体功能。相反，VMP1过表达增强了PINK1/Parkin介导的线粒体自噬，减轻了线粒体功能障碍，并抑制了铁死亡。值得注意的是，CsA处理消除了这些保护作用。 结论：本研究表明，VMP1通过抑制NPC中的铁死亡和线粒体功能障碍来减轻IVDD，这种保护作用是通过促进PINK1/Parkin依赖性线粒体自噬介导的。我们的研究强调了VMP1在IVDD发病机制中协调线粒体自噬和铁死亡的关键作用，确定VMP1为IVDD治疗的潜在靶点。
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