The mitochondrial UPR induced by ATF5 attenuates intervertebral disc degeneration via cooperating with mitophagy

Abstract

Abstract Intervertebral disc degeneration (IVDD) is an aging disease that results in a low quality of life and heavy socioeconomic burden. The mitochondrial unfolded protein response (UPRmt) is involved in various aging-related diseases. Our study aims to investigate the role and underlying mechanism of UPRmt in IVDD. Nucleus pulposus (NP) cells were treated by IL-1β and nicotinamide riboside (NR) served as UPRmt inducer to treat NP cells. TUNEL assay, Western blot and Flow cytometry were used to determine the apoptosis of NP cells. Detection of ATP, NAD + and NADH were used to determine the function of mitochondria. MRI, Safranin O-fast green staining and Immunohistochemical examination were used to determine the degree of IVDD in vivo. In the present study, we discovered that the level of UPRmt was significantly lower in the human tissue of patients with IVDD than in healthy controls. In vitro, UPRmt and mitophagy levels were promoted in NP cells after IL-1β treatment. Upregulation of UPRmt by NR and Atf5 overexpression inhibited the apoptosis of NP cells induced by IL-1β treatment and further improved mitophagy. Silencing of Pink1 reversed the protective effects of NR and inhibited mitophagy induced by the UPRmt. In vivo, NR might attenuate the degree of IDD by activating the UPRmt in rats. In summary, the UPRmt was involved in IVDD by regulating Pink1-induced mitophagy. Mitophagy induced by the UPRmt might be a potential therapeutic target for IVDD.