Over-expression of the Sirt3 sirtuin Protects neuronally differentiated PC12 Cells from degeneration induced by oxidative stress and trophic withdrawal

Shulyakova, Natalya; Sidorova-Darmos, Elena; Fong, Jamie; Zhang, Guangming; Mills, Linda R.; Eubanks, James H.

doi:10.1016/j.brainres.2014.08.066

Cited by 25 publications

(23 citation statements)

References 74 publications

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“…Oxidative stress has been observed to play a critical role in EBI [26]. A recent in vitro experiment demonstrated that the upregulated protein expression of SIRT3 in PC12 cells secondary to oxygen-glucose deprivation (OGD) was an endogenous feedback response for neuroprotection [27]. Consistently, our results revealed early decrease of the expression of SIRT3 protein as well as its mRNA.…”

Section: Discussionsupporting

confidence: 86%

SIRT3 Expression Decreases with Reactive Oxygen Species Generation in Rat Cortical Neurons during Early Brain Injury Induced by Experimental Subarachnoid Hemorrhage

Huang

et al. 2016

BioMed Research International

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Sirtuin3 (SIRT3) is an important protein deacetylase which predominantly presents in mitochondria and exhibits broad bioactivities including regulating energy metabolism and counteracting inflammatory effect. Since inflammatory cascade was proved to be critical for pathological damage following subarachnoid hemorrhage (SAH), we investigated the overall expression and cell-specific distribution of SIRT3 in the cerebral cortex of Sprague-Dawley rats with experimental SAH induced by internal carotid perforation. Results suggested that SIRT3 was expressed abundantly in neurons and endothelia but rarely in gliocytes in normal cerebral cortex. After experimental SAH, mRNA and protein expressions of SIRT3 decreased significantly as early as 8 hours and dropped to the minimum value at 24 h after SAH. By contrast, SOD2 expression increased slowly as early as 12 hours after experimental SAH, rose up sharply at the following 12 hours, and then was maintained at a higher level. In conclusion, attenuated SIRT3 expression in cortical neurons was associated closely with enhanced reactive oxygen species generation and cellular apoptosis, implying that SIRT3 might play an important neuroprotective role during early brain injury following SAH.

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Section: Discussionsupporting

confidence: 86%

SIRT3 Expression Decreases with Reactive Oxygen Species Generation in Rat Cortical Neurons during Early Brain Injury Induced by Experimental Subarachnoid Hemorrhage

Huang

et al. 2016

BioMed Research International

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“…10, A and B). In light of the oxidative stress-ameliorative effects assigned to SIRT3 function in caloric restriction studies and the protective effect of overexpressed SIRT3 in neural cells (41,42), stimulation of SIRT3 activity has been proposed to reduce mitochondrial deficits associated with cerebral oxidative stress and neurodegeneration (76). However, our studies showing that Sirt3 gene ablation protected mitochondria against cerebral IR-induced damage suggest that small molecule inhibitors of SIRT3 activity could be beneficial in the stroke treatment.…”

Section: Discussioncontrasting

confidence: 46%

“…Thus, SIRT3 has been shown to operate in both stress resistance (anti-apoptosis) (37,38) and tumor suppression (pro-apoptosis) (39,40). In neuronal cells, SIRT3 overexpression protected cultured cortical neurons against excitotoxicity (41) and differentiated PC12 cells from oxidative stress-induced cell death (42).…”

Section: Increases Enzyme Activity Investigation Of the Sirt3 Role Imentioning

confidence: 99%

SIRT3 Deacetylates Ceramide Synthases

Novgorodov

Riley

Keffler

et al. 2016

Journal of Biological Chemistry

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Experimental evidence supports the role of mitochondrial ceramide accumulation as a cause of mitochondrial dysfunction and brain injury after stroke. Herein, we report that SIRT3 regulates mitochondrial ceramide biosynthesis via deacetylation of ceramide synthase (CerS) 1, 2, and 6. Reciprocal immunoprecipitation experiments revealed that CerS1, CerS2, and CerS6, but not CerS4, are associated with SIRT3 in cerebral mitochondria. Furthermore, CerS1, -2, and -6 are hyperacetylated in the mitochondria of SIRT3-null mice, and SIRT3 directly deacetylates the ceramide synthases in a NAD ؉ -dependent manner that increases enzyme activity. Investigation of the SIRT3 role in mitochondrial response to brain ischemia/reperfusion (IR) showed that SIRT3-mediated deacetylation of ceramide synthases increased enzyme activity and ceramide accumulation after IR. Functional studies demonstrated that absence of SIRT3 rescued the IR-induced blockade of the electron transport chain at the level of complex III, attenuated mitochondrial outer membrane permeabilization, and decreased reactive oxygen species generation and protein carbonyls in mitochondria. Importantly, Sirt3 gene ablation reduced the brain injury after IR. These data support the hypothesis that IR triggers SIRT3-dependent deacetylation of ceramide synthases and the elevation of ceramide, which could inhibit complex III, leading to increased reactive oxygen species generation and brain injury. The results of these studies highlight a novel mechanism of SIRT3 involvement in modulating mitochondrial ceramide biosynthesis and suggest an important role of SIRT3 in mitochondrial dysfunction and brain injury after experimental stroke.

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“…Recently, SIRT3 has been also identified as a stress responsive deacetylase and plays an important role in protecting cells under stress conditions. SIRT3 could attenuate the effect of oxidative stress on several different cell lines [ 2 , 7 – 9 ]. In addition, the SIRT3-catalyzed deacetylation of 8-oxoguanine-DNA glycosylase 1 (OGG1) protects mitochondrial DNA from oxidative damage and prevents apoptotic cell death under oxidative stress [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Protective Role of Sirtuin3 (SIRT3) in Oxidative Stress Mediated by Hepatitis B Virus X Protein Expression

et al. 2016

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Background/AimThe hepatitis B virus (HBV) infection is accompanied by the induction of oxidative stress, especially mediated by HBV X protein (HBx). Oxidative stress has been implicated in a series of pathological states, such as DNA damage, cell survival and apoptosis. However, the host factor by which cells protect themselves under this oxidative stress is poorly understood.Methodology/Principal FindingsIn this study, we first confirmed that HBV infection significantly induced oxidative stress. Moreover, viral protein HBx plays a major role in the oxidative stress induced by HBV. Importantly, we found that mitochondrial protein SIRT3 overexpression could decrease reactive oxygen species (ROS) induced by HBx while SIRT3 knockdown increased HBx-induced ROS. Importantly, SIRT3 overexpression abolished oxidative damage of HBx-expressing cells as evidenced by γH2AX and AP sites measurements. In contrast, SIRT3 knockdown promoted HBx-induced oxidative damage. In addition, we also observed that oxidant H2O2 markedly promoted HBV replication while the antioxidant N-acetyl-L-cysteine (NAC) inhibited HBV replication. Significantly, SIRT3 overexpression inhibited HBV replication by reducing cellular ROS level.Conclusions/SignificanceCollectively, these data suggest HBx expression induces oxidative stress, which promotes cellular oxidative damage and viral replication during HBV pathogenesis. Mitochondrial protein SIRT3 protected HBx expressing-cells from oxidative damage and inhibited HBV replication possibly by decreased cellular ROS level. These studies shed new light on the physiological significance of SIRT3 on HBx-induced oxidative stress, which can contribute to the liver pathogenesis.

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Over-expression of the Sirt3 sirtuin Protects neuronally differentiated PC12 Cells from degeneration induced by oxidative stress and trophic withdrawal

Cited by 25 publications

References 74 publications

SIRT3 Expression Decreases with Reactive Oxygen Species Generation in Rat Cortical Neurons during Early Brain Injury Induced by Experimental Subarachnoid Hemorrhage

SIRT3 Expression Decreases with Reactive Oxygen Species Generation in Rat Cortical Neurons during Early Brain Injury Induced by Experimental Subarachnoid Hemorrhage

SIRT3 Deacetylates Ceramide Synthases

Protective Role of Sirtuin3 (SIRT3) in Oxidative Stress Mediated by Hepatitis B Virus X Protein Expression

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