Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration
Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration
复制标题
自噬通量的恢复可挽救氧化损伤和线粒体功能障碍，防止椎间盘退变
DOI：
10.1155/2019/7810320
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发表时间：
2019-12-30
影响因子：
--
通讯作者：
Zhang, Yukun
中科院分区：
文献类型：
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作者：
Kang, Liang;Xiang, Qian;Zhang, Yukun
氧化应激诱导的线粒体功能障碍和髓核细胞凋亡在椎间盘退变（IDD）的发生发展中起着至关重要的作用。越来越多的研究表明，针对受损的自噬流的干预措施可以通过减轻氧化损伤来维持细胞的稳态。在这里，我们研究了姜黄素（CUR），一种已知的自噬激活剂，在体外和体内对IDD的影响。CUR抑制叔丁基过氧化氢-（TBHP-）诱导的氧化应激和线粒体功能障碍，从而抑制人NP细胞凋亡，衰老和ECM降解。CUR处理以AMPK/mTOR/ULK 1依赖性方式诱导自噬并增强自噬通量。值得注意的是，CUR减轻TBHP诱导的自噬体-溶酶体融合的中断和溶酶体功能的损害，从而有助于恢复阻断的自噬清除。CUR在TBHP刺激的人NP细胞中的这些保护作用类似于由自噬诱导剂雷帕霉素产生的作用，但该作用被3-甲基腺嘌呤和化合物C介导的自噬起始抑制或氯喹介导的自噬通量阻塞部分消除。最后，CUR还对体内穿刺诱导的IDD进展具有保护作用。我们的研究结果表明，通过增强自噬加上自噬通量的恢复来抑制过量的ROS产生和线粒体功能障碍，改善了TBHP诱导的人NP细胞凋亡、衰老和ECM降解。因此，维持自噬的正常功能是IDD的一种有希望的治疗策略，CUR可能是IDD的有效治疗剂。
Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.