The main pathological mechanism of intervertebral disc degeneration (IVDD) is the programmed apoptosis of nucleus pulposus (NP) cells. Oxidative stress is a significant cause of IVDD. Whether mitophagy is induced by strong oxidative stress in IVDD remains to be determined. This study aimed to investigate the relationship between oxidative stress and mitophagy and to better understand the mechanism of IVDD in vivo and in vitro. To this end, we obtained primary NP cells from the human NP and subsequently exposed them to TBHP. We observed that oxidative stress induced mitophagy to cause apoptosis in NP cells, and we suppressed mitophagy and found that NP cells were protected against apoptosis. Interestingly, TBHP resulted in mitophagy through the inhibition of the HIF-1α/NDUFA4L2 pathway. Therefore, the upregulation of mitochondrial NDUFA4L2 restricted mitophagy induced by oxidative stress. Furthermore, the expression levels of HIF-1α and NDUFA4L2 were decreased in human IVDD. In conclusion, these results demonstrated that the upregulation of NDUFA4L2 ameliorated the apoptosis of NP cells by repressing excessive mitophagy, which ultimately alleviated IVDD. These findings show for the first time that NDUFA4L2 and mitophagy may be potential therapeutic targets for IVDD.

椎间盘退变（IVDD）的主要病理机制是髓核（NP）细胞程序性凋亡。氧化应激是 IVDD 的重要原因。线粒体自噬是否由 IVDD 中的强氧化应激诱导仍有待确定。本研究旨在探讨氧化应激与线粒体自噬之间的关系，并更好地了解 IVDD 在体内和体外的作用机制。为此，我们从人类 NP 中获得了原代 NP 细胞，随后将它们暴露于 TBHP。我们观察到氧化应激诱导线粒体自噬导致 NP 细胞凋亡，我们抑制线粒体自噬并发现 NP 细胞受到保护而不会凋亡。有趣的是，TBHP 通过抑制 HIF-1α/NDUFA4L2 通路导致线粒体自噬。所以，线粒体 NDUFA4L2 的上调限制了氧化应激诱导的线粒体自噬。此外，人类 IVDD 中 HIF-1α 和 NDUFA4L2 的表达水平降低。总之，这些结果表明，NDUFA4L2的上调通过抑制过度线粒体自噬改善了NP细胞的凋亡，最终缓解了IVDD。这些发现首次表明 NDUFA4L2 和线粒体自噬可能是 IVDD 的潜在治疗靶点。