Chronic manganese (Mn) exposure can disturb mitochondrial homeostasis leading to mitochondrial dysfunction, which is involved in Mn‐induced neurodegenerative diseases. Resveratrol (RSV), as a promoter of mitochondrial biogenesis, plays a significant role against mitochondrial dysfunction. However, whether RSV can relieve Mn‐induced neuronal injury and mitochondrial dysfunction remains unknown. Sirtuin 3 (SIRT3), a main mitochondrial sirtuin, is an important regulator of mitochondria to maintain mitochondrial homeostasis. Therefore, this study investigated whether SIRT3 was required for RSV alleviating Mn‐induced mitochondrial dysfunction in primary cultured neurons from C57BL/6 mice. Here, we showed that Mn (100 and 200 μM) exposure for 24 hr caused significant neuronal damage and mitochondrial dysfunction through increasing mitochondrial ROS, reducing mitochondrial membrane potential and adenosine triphosphate level, and leading to mitochondrial network fragmentation, which could be ameliorated by RSV pretreatment in primary cultured neurons. Additionally, our results also indicated that RSV could activate the SIRT1/PGC‐1α signaling pathway and alleviate Mn‐induced disruption of mitochondrial biogenesis by increasing SIRT1 expression and activity, enhancing deacetylation of PGC‐1α. Furthermore, SIRT3 over‐expression increased deacetylation of mitochondrial transcription factor A and mitochondrial DNA (mtDNA) copy number. Oppositely, silencing SIRT3 increased acetylation of mitochondrial transcription factor A and decreased mtDNA copy number. Our results showed SIRT3 was required for the protective effect of RSV in mitochondrial biogenesis. In conclusion, our findings demonstrated that RSV could ameliorate Mn‐induced neuronal injury and mitochondrial dysfunction in primary cultured neurons through activating the SIRT1/ PGC‐1α signaling pathway, and that SIRT3 is required for promoting mitochondrial biogenesis and attenuating Mn‐induced mitochondrial dysfunction.

中文翻译：

---

Sirtuin 3是白藜芦醇对锰诱导的原代培养神经元线粒体生物发生破坏的保护作用所必需的。

慢性锰（Mn）暴露会干扰线粒体稳态，导致线粒体功能障碍，这与Mn引起的神经退行性疾病有关。白藜芦醇（RSV），作为线粒体生物发生的促进剂，在对抗线粒体功能障碍中起着重要的作用。然而，RSV是否能缓解Mn引起的神经元损伤和线粒体功能障碍尚不清楚。Sirtuin 3（SIRT3）是线粒体的主要沉默信号蛋白，是维持线粒体体内稳态的重要线粒体调节剂。因此，本研究调查了SIRT3是否需要RSV来缓解C57BL / 6小鼠原代培养的神经元中Mn诱导的线粒体功能障碍。在这里，我们发现Mn（100和200μM）暴露24小时会通过增加线粒体ROS引起严重的神经元损伤和线粒体功能障碍，降低线粒体膜电位和三磷酸腺苷水平，并导致线粒体网络断裂，这可以通过RSV预处理在原代培养的神经元中得到改善。此外，我们的研究结果还表明，RSV可以通过提高SIRT1的表达和活性，增强PGC-1α的脱乙酰作用来激活SIRT1 /PGC-1α信号通路并减轻Mn诱导的线粒体生物发生破坏。此外，SIRT3的过表达增加了线粒体转录因子A和线粒体DNA（mtDNA）拷贝数的脱乙酰作用。相反，沉默SIRT3会增加线粒体转录因子A的乙酰化程度，并降低mtDNA拷贝数。我们的结果表明，SIRT3是RSV在线粒体生物发生中的保护作用所必需的。结论，