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

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.

• 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.