Abstract：
The pathogenesis of intervertebral disc degeneration (IVDD) involves complex signaling networks and various effector molecules, and our understanding of the pathogenesis of IVDD is limited. Hypoxia inducible factor-1α (HIF-1α) is closely related to IVDD, and there is excessive oxidative stress concurrent with IVDD. In this study, we found that HIF-1α could protect nucleus pulposus cells from excessive oxidative stress by reversing the imbalance between oxidants and antioxidants and thus mitigating the oxidative stress-induced mitochondrial impairment. With further exploration, we found that pyruvate dehydrogenase kinase 1 (PDK-1) was involved in the protective effect of HIF-1α on nucleus pulposus cells under oxidative stress. We suggested that HIF-1α could preserve the mitochondrial integrity and activate glycolysis in nucleus pulposus cells via PDK-1, and the addition of DCA, a PDK-1 inhibitor, could blunt the protective effect of HIF-1α. In addition, the HIF-1α/PDK-1 regulatory axis was also confirmed in vivo through HIF-1α knockout mice model. Therefore, we propose that HIF-1α protects nucleus pulposus cells from excessive oxidative stress by maintaining the mitochondrial integrity and glycolysis via PDK-1, thus enriching the insight into the protective mechanism of HIF-1α against IVDD, and providing a novel therapeutic target for the treatment of IVDD.
摘要：
椎间盘退变(IVDD)的发病机制涉及复杂的信号网络和多种效应分子,我们对IVDD发病机制的认识有限。缺氧诱导因子-1α(HIF-1α)与IVDD密切相关,与IVDD同时存在过度的氧化应激。在这项研究中,我们发现HIF-1α可以通过逆转氧化剂和抗氧化剂之间的失衡，从而减轻氧化应激诱导的线粒体损伤，从而保护髓核细胞免受过度的氧化应激。随着进一步的探索,我们发现丙酮酸脱氢酶激酶1（PDK-1）参与了HIF-1α对髓核细胞在氧化应激下的保护作用。我们认为HIF-1α可以通过PDK-1和DCA的加入保持线粒体完整性并激活髓核细胞的糖酵解，PDK-1抑制剂，可以削弱HIF-1α的保护作用。此外,HIF-1α/PDK-1调节轴也通过HIF-1α敲除小鼠模型在体内得到证实。因此,我们认为HIF-1α通过PDK-1维持线粒体完整性和糖酵解来保护髓核细胞免受过度的氧化应激，从而丰富了HIF-1α对IVDD的保护机制，为IVDD的治疗提供了新的治疗靶点。
