VMP1 attenuates ferroptosis and mitochondrial dysfunction in nucleus pulposus cells through the PINK1/Parkin-mediated...

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.

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.

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.

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.