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

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 ameliorates disorders of mitochondrial biogenesis and mitophagy in rats continuously exposed to benzo(a)pyrene from embryonic development through adolescence.

Exposure to benzo(a)pyrene (BaP) is associated with poor neurodevelopment in children and memory impairment in adults. Previous research has demonstrated that mitochondrial damage plays an important role in BaP-induced neurotoxicity. Of interest, increasing evidence has suggested that resveratrol (RSV) can alleviate nerve cell damage, however the exact mechanisms of biological activity in mitochondria are not fully understood. In the current study, Wistar rats were exposed to BaP (1, 2, 4 mg/kg) and/or RSV (15, 30 mg/kg) during embryonic development and adolescence, and learning and memory ability, mitochondrial damage, and the expression of proteins associated with mitochondrial biogenesis and mitophagy were evaluated. These studies indicated that 2 and 4 mg/kg BaP could induce disorders of mitochondrial biogenesis and mitophagy, which leads to abnormal nerve cell development. However, pretreatment with 30 mg/kg RSV alleviated cell damage and the disorder of mitochondrial biogenesis by activating the AMPK/PGC-1α signaling pathway and promoting mitophagy. These findings suggested that RSV had utility in promoting mitochondrial homeostasis against BaP-induced nerve cell damage in the hippocampus of rats.

Resveratrol prevents benzo(a)pyrene-induced disruption of mitochondrial homeostasis via the AMPK signaling pathway in primary cultured neurons.

Exposure to benzo(a)pyrene (BaP) has been shown to cause mitochondrial dysfunction and injury to neural cells. Resveratrol (RSV) has been studied as an antioxidant, anti-inflammatory, anti-apoptotic, and anticancer agent and can modulate mitochondrial function in vitro and in vivo. However, the molecular mechanisms underlying RSV's protection against mitochondrial dysfunction have not been fully elucidated. To investigate whether RSV can effectively prevent BaP-induced mitochondrial dysfunction, we tested the effects of RSV in primary neuronal models. Our results confirmed that neurons exhibited mitochondrial dysfunction and apoptosis in the mitochondrial pathway after BaP-treatment, and that pretreatment with RSV could reduce that dysfunction. Further, our results indicated that RSV pretreatment enhanced mitochondrial biogenesis via the AMPK/PGC-1α pathway and activated mitophagy via the PINK1-Parkin and AMPK/ULK1 pathways, thereby coordinating mitochondrial homeostasis. We also found that RSV could alleviate mitochondrial network fragmentation caused by BaP. This work provided insights into the role of RSV in preventing BaP-induced primary neuronal apoptosis in the mitochondrial pathway, mainly via regulation of mitochondrial biogenesis and mitophagy through AMPK pathway, thus maintaining the integrity of the mitochondrial network.