SIRT3 expression alleviates microglia activation‑induced dopaminergic neuron injury through the mitochondrial pathway

Abstract

The mitochondrial protein sirtuin 3 (SIRT3) can counteract cell damage caused by oxidative stress and inflammation, and contribute to cell survival primarily by improving mitochondrial function. However, the effects of SIRT3 in dopaminergic neuronal cells (DACs) remain unclear. In our previous studies, microglia activation-associated cytotoxicity was observed to promote the apoptosis of DACs, along with the decrease of SIRT3 expression. The aim of the present study was to explore the potential neuroprotective effect of SIRT3 expression against dopaminergic neuron injury caused by microglia activation, and clarify its possible mechanisms. SIRT3 overexpression in DACs reduced the production of intracellular reactive oxygen species (ROS), cell apoptosis rate, mitochondrial membrane potential (ΔΨm) depolarization, opening of mitochondrial permeability transition pore (mPTP) and cyclophilin D (CypD) protein level, and promoted cell cycle progression. However, SIRT3 siRNA-mediated knockdown further aggravated microglia activation-mediated cytotoxicity, including ROS accumulation, increased cell apoptosis and mPTP opening, elevated the CypD level, enhanced mitochondrial ΔΨm depolarization, concomitant to cell cycle arrest at G 0 /G 1 phase. The mechanisms of SIRT3 mitigated microglia activation-induced DAC dysfunction, which included decreased mPTP opening and Bax/Bcl-2 ratio, inhibition of mitochondrial cytochrome c release to the cytoplasm, reduced caspase-3/9 activity, increased LC3II/LC3I and beclin-1 protein expression levels, and decreased nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing protein 3 (NLRP3), caspase-1, IL-1β and IL-18 protein expression. In conclusion, these results indicated that SIRT3 expression attenuated cell damage caused by microglia activation through the mitochondrial apoptosis pathway in DACs. The mitophagy-NLRP3 inflammasome pathway may also be associated with this neuroprotection. These findings may provide new intervention targets for the survival of dopaminergic neurons and the prevention and treatment of Parkinson's disease.

Sirt3 Protects Retinal Pigment Epithelial Cells From High Glucose-Induced Injury by Promoting Mitophagy Through the AMPK/mTOR/ULK1 Pathway

“…37 Moreover, knockdown of Sirt3 using siRNA in microglia further exacerbates the cytotoxicity mediated by microglial activation, including increased accumulation of ROS and enhanced apoptosis. 38 Based on these studies, we overexpressed Sirt3 by lentiviral transfection and we found that apoptosis was inhibited in the high glucose group. This is consistent with the results of other studies.…”

Iron homeostasis imbalance and ferroptosis in brain diseases

“…In addition, it is also suggested that the accumulation of α‐syn in PD inhibits mitochondrial function by affecting the level of mitochondrial sirtuin 3 protein, an NAD + ‐dependent deacetylase that regulates the acetylation/deacetylation level of complex I 201 . The sirtuin 3 in mitochondria has been proven to prevent dopaminergic neuron loss in a rodent model of PD 202 . This indicates that dysfunction of complex I plays an important role in mediating PD pathology.…”

“… 201 The sirtuin 3 in mitochondria has been proven to prevent dopaminergic neuron loss in a rodent model of PD. 202 This indicates that dysfunction of complex I plays an important role in mediating PD pathology. In addition, complex II–IV are also inhibited to varying degrees in PD, suggesting impaired mitochondrial oxidative respiration in PD.…”

A Promising Strategy to Treat Neurodegenerative Diseases by SIRT3 Activation

“…Microglial activation-induced oxidative stress injury on NSCs has been shown to be prevented by SIRT3 in a coculture system [ 113 ]. Microglial activation-induced cytotoxicity in dopaminergic neuronal cells is alleviated by Sirt3 overexpression while Sirt3 gene aggravates neurotoxicity [ 114 ]. HIV TAT protein induces senescence in mouse primary microglial cells with downregulation of SIRT3 while overexpression of Sirt3 in these cells reverses this senescence-like phenotype [ 115 ].…”

“…Another study reported that SIRT3 overexpression protects rotenone-treated SH-SY5Y cells by decreasing apoptosis and ROS and by preventing α-synuclein accumulation whereas Sirt3 silencing results in increased cell apoptosis, reduced SOD and GSH, and increased accumulation of α-synuclein [ 135 ]. The activated BV2 cells, a mouse microglial cell line, have been shown to promote apoptosis and decrease Sirt3 expression in MN9D cells, mouse midbrain dopaminergic cell line [ 136 ] whereas Sirt3 expression in MN9D cells shows a neuroprotective effect against microglia activation-induced neuronal injury, by modulating mitophagy-NLRP3 inflammasome pathway [ 114 ].…”