SIRT1 alleviates high-magnitude compression-induced senescence in nucleus pulposus cells via PINK1-dependent mitophagy
SIRT1 alleviates high-magnitude compression-induced senescence in nucleus pulposus cells via PINK1-dependent mitophagy
复制标题
SIRT1 通过 PINK1 依赖性线粒体自噬减轻高强度压缩诱导的髓核细胞衰老
DOI：
10.18632/aging.103587
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发表时间：
2020-08-31
期刊：
影响因子：
5.2
通讯作者：
Li, Pei
中科院分区：
文献类型：
--
作者：
Wang, Yiyang;Wang, Haoming;Li, Pei
机械过载引起的髓核（NP）细胞衰老在椎间盘退变（IVDD）的发病机制中起着重要作用。沉默交配型信息调节器 2 同源物 2 (SIRT1) 介导的途径在多种应激下保持正常的 NP 细胞表型和线粒体稳态。我们旨在通过评估 SIRT1 过表达对高强度压缩诱导的 NP 细胞衰老的影响来研究 SIRT1 在 IVDD 中的作用。高强度压缩会导致人类 NP 细胞的细胞衰老和线粒体功能障碍。此外，SIRT1过表达往往会减轻压力下NP细胞的衰老和线粒体功能障碍。鉴于 SIRT1 的线粒体自噬诱导特性，我们对 NP 细胞中的线粒体自噬活性进行了评估，以进一步证明其潜在机制。结果表明，SIRT1 过表达可减轻遭受高强度压缩的 NP 细胞的衰老和线粒体损伤。然而，PINK1（一种关键的线粒体自噬调节因子）的缺失会损害线粒体自噬，并阻断 SIRT1 对 NP 细胞中压缩诱导衰老的保护作用。综上所述，这些结果表明SIRT1在减轻高强度压缩下NP细胞衰老和线粒体功能障碍方面发挥保护作用，其机制与PINK1依赖性线粒体自噬的调节有关。我们的研究结果可能为 IVDD 治疗提供潜在的治疗方法。
Mechanical overloading-induced nucleus pulposus (NP) cells senescence plays an important role in the pathogenesis of intervertebral disc degeneration (IVDD). The silent mating type information regulator 2 homolog-1 (SIRT1)-mediated pathway preserves the normal NP cell phenotype and mitochondrial homeostasis under multiple stresses. We aimed to investigate the role of SIRT1 in IVDD by assessing the effects of SIRT1 overexpression on high-magnitude compression-induced senescence in NP cells. High-magnitude compression induced cellular senescence and mitochondrial dysfunction in human NP cells. Moreover, SIRT1 overexpression tended to alleviate NP cell senescence and mitochondrial dysfunction under compressive stress. Given the mitophagy-inducing property of SIRT1, activity of mitophagy was evaluated in NP cells to further demonstrate the underlying mechanism. The results showed that SIRT1-overexpression attenuated senescence and mitochondrial injury in NP cells subjected to high-magnitude compression. However, depletion of PINK1, a key mitophagic regulator, impaired mitophagy and blocked the protective role of SIRT1 against compression induced senescence in NP cells. In summary, these results suggest that SIRT1 plays a protective role in alleviating NP cell senescence and mitochondrial dysfunction under high-magnitude compression, the mechanism of which is associated with the regulation of PINK1-dependent mitophagy. Our findings may provide a potential therapeutic approach for IVDD treatment.