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.

中文翻译：

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ATF5诱导的线粒体UPR通过与线粒体自噬协同减轻椎间盘退变

椎间盘退变（IVDD）是一种导致生活质量低下和沉重社会经济负担的衰老疾病。线粒体未折叠蛋白反应（UPR ^mt）参与多种与衰老相关的疾病。^{我们的研究旨在探讨UPR mt}在IVDD中的作用和潜在机制。将髓核（NP）细胞暴露于IL-1β和烟酰胺核苷（NR）作为UPR ^mt诱导剂来处理NP细胞。ATP、NAD+和NADH的检测用于确定线粒体的功能。采用MRI、Safranin O-fast green和免疫组织化学检查来确定体内IVDD的程度。在这项研究中，我们发现人类 IVDD 组织的 NP 细胞中的UPR ^{mt比健康对照显着增加。}在体外，用 IL-1β 处理的 NP 细胞中 UPR ^mt和线粒体自噬水平得到提升。NR 和 Atf5 过表达上调 UPR ^{mt可抑制 NP 细胞凋亡并进一步改善线粒体自噬。}Pink1 的沉默逆转了 NR 的保护作用并抑制了 UPR ^mt诱导的线粒体自噬。在体内，NR 可能通过激活大鼠的UPR ^mt来减轻 IDD 的程度。总之，UPR ^mt通过调节 Pink1 诱导的线粒体自噬参与 IVDD。UPR ^mt诱导的线粒体自噬可能是 IVDD 的潜在治疗靶点。

图形概要

• UPR ^mt在退变椎间盘的 NP 细胞中上调。

• Atf5 调控的 UPR ^mt可以激活线粒体自噬，保护 NP 细胞免于凋亡。

• 烟酰胺核苷作为UPR ^mt诱导剂可减少NP 细胞凋亡，从而延缓IVDD 过程。