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SIRT3-dependent mitochondrial oxidative stress in sodium fluoride-induced hepatotoxicity and salvage by melatonin

Chao Song, Jiamin Zhao, Jingcheng Zhang, Tingchao Mao, Beibei Fu, Haibo Wu, Yong Zhang
doi: https://doi.org/10.1101/107813
Chao Song
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest 89 A&F University, Yangling 712100, Shaanxi, China.
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Jiamin Zhao
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest 89 A&F University, Yangling 712100, Shaanxi, China.
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Jingcheng Zhang
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest 89 A&F University, Yangling 712100, Shaanxi, China.
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Tingchao Mao
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest 89 A&F University, Yangling 712100, Shaanxi, China.
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Beibei Fu
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest 89 A&F University, Yangling 712100, Shaanxi, China.
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Haibo Wu
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest 89 A&F University, Yangling 712100, Shaanxi, China.
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  • For correspondence: hbwu029@nwsuaf.edu.cn zhangy1956@sina.com
Yong Zhang
College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China.Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest 89 A&F University, Yangling 712100, Shaanxi, China.
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  • For correspondence: hbwu029@nwsuaf.edu.cn zhangy1956@sina.com
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Abstract

Oxidative stress induced by fluoride (F) is associated with fluorosis formation, but the underlying molecular mechanism remains unclear. In this study, Melatonin pretreatment suppressed F-induced hepatocyte injury in HepG2 cells. Melatonin increases the activity of superoxide dismutase (SOD2) by enhancing sirtuin 3 (SIRT3)-mediated deacetylation and promotes SOD2 gene expression via SIRT3-regulated DNA-binding activity of forkhead box O3 (FoxO3a), indicating that melatonin markedly enhanced mROS scavenging in F-exposed HepG2 cells. Notably, melatonin activated the peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α). PGC-1α interacted with the estrogen-related receptor alpha (ERRα) bound to the SIRT3 promoter, where it functions as a transcription factor to regulate SIRT3 expression. Furthermore, daily injection of melatonin for 30 days inhibited F-induced oxidative stress in mice liver, leading to improvement of liver function. Mechanistic study revealed that the protective effects of melatonin were associated with down-regulation of JNK1/2 phosphorylation in vitro and in vivo. Collectively, our data suggest a novel role of melatonin in preventing F-induced oxidative stress through activation of the SIRT3 pathway.

Footnotes

  • This work was funded by the State Key Program (No. 31530075) of National Natural Science Foundation of China and China Postdoctoral Science Foundation Grant (No. 2016M590978)

  • Abbreviations

    NaF
    Sodium fluoride
    Mel
    Melatonin
    mROS
    Mitochondrial reactive oxygen species
    SOD2
    Mitochondrial manganese superoxide dismutase
    PGC-1α
    Peroxisome proliferator-activated receptor gamma coactivator 1α
    ERRα
    Estrogen-related receptor alpha
    MDA
    Malondialdehyde
    GSH
    Glutathione
    ChIP
    Chromatin immunoprecipitation assay
    EMSA
    Electrophoretic mobility shift assay
    ALT
    Alanine aminotransferase
    AST
    Aspartate aminotransferase
    JNK1/2
    d c-Jun NH2-terminal kinase-1/2
    WT
    wild-type
    MUT
    mutation
    Ab
    antibody
  • Copyright 
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    Posted February 11, 2017.
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    SIRT3-dependent mitochondrial oxidative stress in sodium fluoride-induced hepatotoxicity and salvage by melatonin
    Chao Song, Jiamin Zhao, Jingcheng Zhang, Tingchao Mao, Beibei Fu, Haibo Wu, Yong Zhang
    bioRxiv 107813; doi: https://doi.org/10.1101/107813
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    SIRT3-dependent mitochondrial oxidative stress in sodium fluoride-induced hepatotoxicity and salvage by melatonin
    Chao Song, Jiamin Zhao, Jingcheng Zhang, Tingchao Mao, Beibei Fu, Haibo Wu, Yong Zhang
    bioRxiv 107813; doi: https://doi.org/10.1101/107813

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