HIF-1α α protects nucleus pulposus cells from oxidative stress-induced mitochondrial impairment through PDK-1

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-1 alpha (HIF-1 alpha) is closely related to IVDD, and there is excessive oxidative stress concurrent with IVDD. In this study, we found that HIF-1 alpha 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-1 alpha on nucleus pulposus cells under oxidative stress. We suggested that HIF-1 alpha 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-1 alpha. In addition, the HIF-1 alpha/PDK-1 regulatory axis was also confirmed in vivo through HIF-1 alpha knockout mice model. Therefore, we propose that HIF-1 alpha protects nucleus pulposus cells from excessive oxidative stress by maintaining the mitochondrial integrity and glycolysis via PDK1, thus enriching the insight into the protective mechanism of HIF-1 alpha against IVDD, and providing a novel therapeutic target for the treatment of IVDD.