Abstract
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.
Highlights
intervertebral disc degeneration (IVDD) is one of the most common diseases that leads to a decline in quality of life and a high socioeconomic burden
nucleus pulposus (NP) cell apoptotic death induced by oxidative stress is a main factor of IVDD23,24
Flow cytometry analysis of Annexin V-FITC/PI staining and Hoechst 33258 staining revealed that the percentage of apoptotic NP cells with surface-associated annexin-V staining and nuclear condensation gradually increased with increasing concentrations of TBHP treatment (50, 100, 200, 400, and 800 μM) for 6 h (Fig. S1a-c)
Summary
IVDD is one of the most common diseases that leads to a decline in quality of life and a high socioeconomic burden. IVDD is an important cause of low back pain, sciatica, and spinal stenosis. 80% of adult humans suffer from neck or back pain at some point in their lives[1]. The pathogenesis of IVDD has not been clearly illuminated. Cellular redox status is involved in regulating metabolic signaling pathways in cells. This parameter is regulated by the rates of production and breakdown of reactive oxygen species (ROS)[2].
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