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

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 (UPR mt ) take part in various aging-related diseases. Our research intents to explore the role and underlying mechanism of UPR mt in IVDD. Nucleus pulposus (NP) cells were exposed to IL-1β and nicotinamide riboside (NR) served as UPR mt inducer to treat NP cells. Detection of ATP, NAD + and NADH were used to determine the function of mitochondria. MRI, Safranin O-fast green and Immunohistochemical examination were used to determine the degree of IVDD in vivo. In this study, we discovered that UPR mt was increased markedly in the NP cells of human IVDD tissues than in healthy controls. In vitro, UPR mt and mitophagy levels were promoted in NP cells treated with IL-1β. Upregulation of UPR mt by NR and Atf5 overexpression inhibited NP cell apoptosis and further improved mitophagy. Silencing of Pink1 reversed the protective effects of NR and inhibited mitophagy induced by the UPR mt . In vivo, NR might attenuate the degree of IDD by activating the UPR mt in rats. In summary, the UPR mt was involved in IVDD by regulating Pink1-induced mitophagy. Mitophagy induced by the UPR mt might be a latent treated target for IVDD. Graphical Abstract • UPR mt was upregulated in the NP cells of degenerative intervertebral disc. • UPR mt regulated by Atf5 could activate mitophagy to protect NP cells from apoptosis. • Nicotinamide riboside as UPR mt inducer reduced NP cells apoptosis, thereby delaying the process of IVDD.