Resveratrol reduces DRP1-mediated mitochondrial dysfunction via the SIRT1-PGC1α signaling pathway in manganese-induced nerve damage in mice
Resveratrol reduces DRP1-mediated mitochondrial dysfunction via the SIRT1-PGC1α signaling pathway in manganese-induced nerve damage in mice
复制标题
白藜芦醇通过 SIRT1-PGC1α 信号通路减少锰诱导的小鼠神经损伤中 DRP1 介导的线粒体功能障碍。
DOI：
10.1002/tox.23397
复制
发表时间：
2021-11-05
影响因子：
4.5
通讯作者：
Xu, Bin
中科院分区：
文献类型：
--
作者：
Lei, Meng-Yu;Cong, Lin;Xu, Bin
过量的锰（Mn）暴露可引起神经损伤和线粒体功能障碍，这可能涉及线粒体动力学缺陷。白藜芦醇（RSV）通过激活sirtuin 1 （SIRT1）发挥广泛的有益作用，因此可能通过SIRT1调节过氧化物酶体增殖体激活受体- γ辅助激活因子1- α (PGC-1 α)积极影响mn诱导的线粒体损伤。在本研究中，我们研究了RSV减轻Mn引起的C57 BL/6小鼠神经损伤和线粒体断裂的分子机制。我们的研究结果表明，RSV激活了SIRT1的去乙酰化酶活性，并保护线粒体活性氧的激增，线粒体膜电位的丧失以及Mn引起的ATP的衰减。因此，RSV抑制线粒体分裂并保护神经细胞。去乙酰化酶活性增加导致PGC-1 α乙酰化降低，PGC-1 α通过结合DRP1启动子直接调节DRP1的表达。通过添加SIRT1抑制剂EX527， rsv预处理小鼠中drp1介导的线粒体断裂的衰减被消除。综上所述，这些发现表明RSV通过调节SIRT1/PGC-1 α信号通路减轻DRP1介导的mn诱导的线粒体功能障碍。
Excessive manganese (Mn) exposure can cause nerve damage and mitochondrial dysfunction, which may involve defects in mitochondrial dynamics. Resveratrol (RSV) exerts a wide range of beneficial effects via activation of sirtuin 1 (SIRT1) and thus may positively impact Mn-induced mitochondrial damage through the regulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1 alpha) by SIRT1. In this study, we investigated the molecular mechanisms by which RSV alleviates the nerve injury and mitochondrial fragmentation caused by Mn in C57 BL/6 mice. Our results demonstrated that RSV activated the deacetylase activity of SIRT1 and protected against the surge of mitochondrial reactive oxygen species, the loss of mitochondrial membrane potential, and the attenuation of ATP caused by Mn. RSV, therefore, inhibits mitochondrial fragmentation and safeguards neural cells. Increased deacetylase activity led to a reduction in the acetylation of PGC-1 alpha, which directly regulates DRP1 expression by binding to the DRP1 promoter. The resultant attenuation of DRP1-mediated mitochondrial fragmentation in RSV-pretreated mice was abolished by the addition of the SIRT1 inhibitor EX527. Taken together, these findings indicate that RSV alleviates Mn-induced mitochondrial dysfunction mediated by DRP1 by modulating the SIRT1/PGC-1 alpha signaling pathway.