Novel mechanisms for superoxide-scavenging activity of human manganese superoxide dismutase determined by the K68 key acetylation site

Lü, Jiaqi; Cheng, Kuoyuan; Zhang, Bo; Xu, Hui‐Xiong; Cao, Yunyun; Guo, Fei; Feng, Xudong; Xia, Qing

doi:10.1016/j.freeradbiomed.2015.04.011

Cited by 46 publications

(52 citation statements)

References 52 publications

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“…One main target of SIRT3 that has been widely investigated in oxidative stress is SOD2, the major enzymatic superoxide scavenger localized in the mitochondria . SIRT3 primarily regulates ROS clearance by altering the acetylation of SOD2, which increases SOD2 activity and thus regulates ROS homeostasis . Previous studies showed that upregulating SIRT3 expression or activity represents a promising way to ameliorate oxidative stress‐induced tissue damage.…”

Section: Discussionmentioning

confidence: 99%

Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3‐dependent regulation of oxidative stress and apoptosis

Zhai

Duan

et al. 2017

Journal of Pineal Research

291

208

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Sirtuins are a family of highly evolutionarily conserved nicotinamide adenine nucleotide-dependent histone deacetylases. Sirtuin-3 (SIRT3) is a member of the sirtuin family that is localized primarily to the mitochondria and protects against oxidative stress-related diseases, including myocardial ischemia/reperfusion (MI/R) injury. Melatonin has a favorable effect in ameliorating MI/R injury. We hypothesized that melatonin protects against MI/R injury by activating the SIRT3 signaling pathway. In this study, mice were pretreated with or without a selective SIRT3 inhibitor and then subjected to MI/R operation. Melatonin was administered intraperitoneally (20 mg/kg) 10 minutes before reperfusion. Melatonin treatment improved postischemic cardiac contractile function, decreased infarct size, diminished lactate dehydrogenase release, reduced the apoptotic index, and ameliorated oxidative damage. Notably, MI/R induced a significant decrease in myocardial SIRT3 expression and activity, whereas the melatonin treatment upregulated SIRT3 expression and activity, and thus decreased the acetylation of superoxide dismutase 2 (SOD2). In addition, melatonin increased Bcl-2 expression and decreased Bax, Caspase-3, and cleaved Caspase-3 levels in response to MI/R. However, the cardioprotective effects of melatonin were largely abolished by the selective SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP), suggesting that SIRT3 plays an essential role in mediating the cardioprotective effects of melatonin. In vitro studies confirmed that melatonin also protected H9c2 cells against simulated ischemia/reperfusion injury (SIR) by attenuating oxidative stress and apoptosis, while SIRT3-targeted siRNA diminished these effects. Taken together, our results demonstrate for the first time that melatonin treatment ameliorates MI/R injury by reducing oxidative stress and apoptosis via activating the SIRT3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3‐dependent regulation of oxidative stress and apoptosis

Zhai

Duan

et al. 2017

Journal of Pineal Research

291

208

View full text Add to dashboard Cite

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“…Importantly, SOD2 can be regulated by numerous transcriptional, translational, and posttranslational mechanisms, including protein acetylation (Miao and St Clair, 2009, Huang et al, 1997, Chen et al, 2011, Gao et al, 2016, Qiu et al, 2010). Specifically, acetylation of K68 and K122, among other sites, can decrease SOD2 activity and remains an interesting target for numerous disease pathologies (Ozden et al, 2011, Zhu et al, 2012, Zou et al, 2016, Lu et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

“…This localized positive charge is hypothesized to attract and guide the superoxide anion towards the active site of SOD2. Acetylation of K68 and other lysine residues eliminates this localized positive charge, leading to a reduced affinity of the superoxide anion at the active site (Zhu et al, 2012, Lu et al, 2015). Importantly, our data demonstrate that chronic ethanol metabolism significantly alters the isoelectric point of hepatic SOD2; however, further studies are needed in order to explore the impact of lysine acetylation, succinylation, and other PTMs on SOD2 charge-state dynamics and quaternary structure.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, Zhu et al demonstrated that acetylation of SOD2 K122 decreased the enzymatic activity via masking the positively charged amino acids of the active site (Zhu et al, 2012). Lu et al also showed that acetylation of SOD2 K68 reduced its activity via modulating structure and charge state (Lu et al, 2015). SOD is responsible for detoxifying superoxide radicals by catalyzing the conversion of the superoxide anion into hydrogen peroxide and molecular oxygen.…”

Section: Introductionmentioning

confidence: 99%

“…The present study examines the effect of ethanol-induced protein hyperacetylation on SOD2, a protein with 16 lysine residues prone to acetylation. Importantly, it has been reported that SOD2 K68 and K122 are key regulators of enzymatic activity due to alterations in protein charge-state dynamics (Ozden et al, 2011, Zou et al, 2016, Lu et al, 2015, Zhu et al, 2012). Since oxidative stress is a central mechanism of ethanol-induced liver injury, and we previously observed SOD2 hyperacetylation upon ethanol administration, we investigated the hypothesis that chronic ethanol consumption increases SOD2 acetylation, leading to alterations in SOD2 protein structure and activity, potentially contributing to overall mitochondrial dysregulation and the progression of ALD (Fritz et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation

Assiri

Roy

Harris

et al. 2017

Alcohol Clin Exp Res

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Background Chronic ethanol consumption is a major cause of liver disease worldwide. Oxidative stress is a known consequence of ethanol metabolism and is thought to contribute significantly to alcoholic liver disease (ALD). Therefore, elucidating pathways leading to sustained oxidative stress and downstream redox imbalances may reveal how ethanol consumption leads to ALD. Recent studies suggest that ethanol metabolism impacts mitochondrial antioxidant processes through a number of proteomic alterations, including hyperacetylation of key antioxidant proteins. Methods In order to elucidate mechanisms of ethanol-induced hepatic oxidative stress, we investigate a role for protein hyperacetylation in modulating mitochondrial superoxide dismutase (SOD2) structure and function in a 6-week Lieber-DeCarli murine model of ethanol consumption. Our experimental approach includes immunoblotting, immunohistochemistry, activity assays, mass spectrometry, and in silico modeling. Results We found that ethanol metabolism significantly increased the acetylation of SOD2 at two functionally relevant lysine sites, K68 and K122, resulting in a 40% decrease in enzyme activity while overall SOD2 abundance was unchanged. In vitro studies also reveal which lysine residues are more susceptible to acetylation. Immunohistochemical analysis demonstrates that SOD2 hyperacetylation occurs near zone 3 within the liver, which is the main ethanol-metabolizing region of the liver. Conclusion Overall, the findings presented in this study support a role for ethanol-induced lysine acetylation as an adverse post-translational modification within the mitochondria that directly impacts SOD2 charge-state and activity. Lastly, the data presented here indicate that protein hyperacetylation may be a major factor contributing to an imbalance in hepatic redox homeostasis due to chronic ethanol metabolism.

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SOD2 and Sirt3 Control Osteoclastogenesis by Regulating Mitochondrial ROS

Kim

Lee

Kim

et al. 2016

Journal of Bone and Mineral Research

108

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Reactive oxygen species (ROS) are an indispensable element of cellular signal transduction in various cell types, including bone cells. In particular, osteoclasts (OCs), cells specialized for bone resorption, utilize ROS as second messengers during receptor activator of NF-κB ligand (RANKL)-induced differentiation and activation. In addition, because of the high energy demands of bone-resorbing activity, OCs contain large amounts of mitochondria, the source of the majority of total ROS. In this study, we focused on the regulation of ROS generated from mitochondria during osteoclastogenesis. We observed that the level of mitochondrial superoxide dismutase 2 (SOD2), an enzyme responsible for reducing superoxide radicals in mitochondria, was increased by RANKL. siRNA-mediated knockdown (KD) of SOD2 increased ROS levels and enhanced OC differentiation. Conversely, overexpression of SOD2 reduced osteoclastogenesis by decreasing ROS levels. Moreover, we found that NAD-dependent deacetylase sirtuin 3 (Sirt3), an activator of SOD2 in mitochondria, was induced by RANKL. Sirt3-targeted siRNA decreased SOD2 activity by reducing deacetylation of lysine 68 of SOD2, leading to increased osteoclastogenesis. Furthermore, in vivo KD of SOD2 or Sirt3 in ICR mouse calvariae decreased bone volume and increased OC surface, supporting the results of in vitro experiments. Taken together, our findings demonstrate for the first time to our knowledge that the regulation of mitochondrial ROS by SOD2 and Sirt3 plays an important role in fine-tuning the OC differentiation program. © 2016 American Society for Bone and Mineral Research.

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Novel mechanisms for superoxide-scavenging activity of human manganese superoxide dismutase determined by the K68 key acetylation site

Cited by 46 publications

References 52 publications

Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3‐dependent regulation of oxidative stress and apoptosis

Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3‐dependent regulation of oxidative stress and apoptosis

Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation

SOD2 and Sirt3 Control Osteoclastogenesis by Regulating Mitochondrial ROS

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