TY - JOUR T1 - SIRT3-dependent mitochondrial oxidative stress in sodium fluoride-induced hepatotoxicity and salvage by melatonin JF - bioRxiv DO - 10.1101/107813 SP - 107813 AU - Chao Song AU - Jiamin Zhao AU - Jingcheng Zhang AU - Tingchao Mao AU - Beibei Fu AU - Haibo Wu AU - Yong Zhang Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/02/11/107813.abstract N2 - 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.AbbreviationsNaFSodium fluorideMelMelatoninmROSMitochondrial reactive oxygen speciesSOD2Mitochondrial manganese superoxide dismutasePGC-1αPeroxisome proliferator-activated receptor gamma coactivator 1αERRαEstrogen-related receptor alphaMDAMalondialdehydeGSHGlutathioneChIPChromatin immunoprecipitation assayEMSAElectrophoretic mobility shift assayALTAlanine aminotransferaseASTAspartate aminotransferaseJNK1/2d c-Jun NH2-terminal kinase-1/2WTwild-typeMUTmutationAbantibody ER -