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

Abstract

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.

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update

“…Specifically, it has been demonstrated that down-regulation of SIRT1 under Mn exposure (0–1000 μM Mn for 24 h) is associated with proapoptotic signaling and FOXO3a activation [ 103 ]. In Mn-exposed primary cultured neurons (100, 200 μM Mn for 24 h) up-regulation of SIRT3 expression was shown to be involved in protective effects of resveratrol against Mn-induced mitochondrial dysfunction [ 104 ] which may be at least partially mediated by the role of SIRT3 in regulation of Mn-SOD activity [ 105 ].…”

The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

“…Resveratrol was also shown to protect against neurodegeneration by activating sirt1 which activates PGC1a that accelerates mitochondrial biogenesis (which replaces mPTP-damaged mitochondria with newly minted mitochondria) [ 270 , 271 ]. Resveratrol activation of sirt3 (which inhibits mPTP) was also demonstrated in several studies [ 271 , 272 , 273 ].…”

Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

“…The molecule of RV was shown to be an activator of SIRT1 [ 79 , 139 , 142 , 167 ]. It has been reported that RV ameliorates ROS under oxidative stress [ 142 , 143 ] and inflammatory conditions [ 139 ].…”

“…The molecule of RV was shown to be an activator of SIRT1 [ 79 , 139 , 142 , 167 ]. It has been reported that RV ameliorates ROS under oxidative stress [ 142 , 143 ] and inflammatory conditions [ 139 ]. It was reported that RV also increases the expression of SIRT3; hence, it activates SIRT1, which in turn deacetylates PGC1a.…”

“…It was reported that RV also increases the expression of SIRT3; hence, it activates SIRT1, which in turn deacetylates PGC1a. This transcription factor is influenced by RV to bind to SIRT3 promoter in neurons exposed to high concentrations of manganese [ 142 ]. The data suggest that RV rescues cell integrity by not only enhancing mitochondrial biogenesis due to SIRT1-mediated deacetylation of PGC1a and SIRT3-mediated deacetylation of TFAM [ 142 ] but also by inducing mitophagy, as is confirmed by the increase of proteins such as PINK1 and parkin in cardiac injury [ 106 ].…”