Sirtuin 3 is required for the protective effect of Resveratrol on Manganese‐induced disruption of mitochondrial biogenesis in primary cultured neurons

• Published in: Journal of neurochemistry 2021-01, Vol.156 (1), p.121-135
• Main Authors: Sun, Qian, Kang, Run‐Run, Chen, Kai‐Ge, Liu, Kuan, Ma, Zhuo, Liu, Chang, Deng, Yu, Liu, Wei, Xu, Bin
• Format: Article
• Language: English
• Subjects: Acetylation; Adenosine triphosphate; Animals; ATP; Biosynthesis; Cells, Cultured; Copy number; Deacetylation; Disruption; Exposure; Homeostasis; Manganese; Manganese - toxicity; Membrane potential; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - drug effects; mitochondrial biogenesis; Mitochondrial DNA; Neurodegenerative diseases; Neurons; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - pharmacology; neurotoxicity; Organelle Biogenesis; Resveratrol; Resveratrol - pharmacology; Signal transduction; Signaling; SIRT1 protein; Sirtuin 3 - metabolism; Transcription factors
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15095

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. Resveratrol (RSV) can relieve Mn‐induced neuronal injury and promote mitochondrial biogenesis through activating sirtuin 3 (SIRT3). Neurons were extracted from newborn mice born within 24 hr for primary neuron culture. Mn treatment induced mitochondrial damage, including increased mitochondrial ROS, and decreased ATP and MMP levels, which could be alleviated by pretreatment with RSV. Moreover, we used SIRT3 silencing or overexpression to confirm that SIRT3 was required for the promotion of mitochon