title: Melatonin Improves mitochondrial function by promoting MT1/SIRT1/PGC-1 alpha-dependent mitochondrial biogenesis in cadmium-induced hepatotoxicity in vitro.
abstract: Melatonin is an indolamine synthesized in the pineal gland that has a wide range of physiological functions, and it has been under clinical investigation for expanded applications. Increasing evidence demonstrates that melatonin can ameliorate cadmium-induced hepatotoxicity. However, the potentially protective effects of melatonin against cadmium-induced hepatotoxicity and the underlying mechanisms of this protection remain unclear. This study investigates the protective effects of melatonin pretreatment on cadmium-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10 μM) for 12 h. We found that Cd stimulated cytotoxicity, disrupted the mitochondrial membrane potential, increased reactive oxygen species production, and decreased mitochondrial mass and mitochondrial DNA content. Consistent with this finding, Cd exposure was associated with decreased Sirtuin 1 (SIRT1) protein expression and activity, thus promoted acetylation of PGC-1 alpha, a key enzyme involved in mitochondrial biogenesis and function, although Cd did not disrupt the interaction between SIRT1 and PGC-1 alpha. However, all cadmium-induced mitochondrial oxidative injuries were efficiently attenuated by melatonin pretreatment. Moreover, Sirtinol and SIRT1 siRNA each blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT1/ PGC-1 alpha signaling. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to promote SIRT1/ PGC-1 alpha signaling. In summary, our results indicate that SIRT1 plays an essential role in the ability of moderate melatonin to stimulate PGC-1 alpha and improve mitochondrial biogenesis and function at least partially through melatonin receptors in cadmium-induced hepatotoxicity.
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Pan
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Pi
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Shangcheng
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Hepatobiliary Surgery, XinQiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Zhengwang
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Jia
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Renyan
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Mindi
authors.initials: M
authors.lastname: He
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Weixia
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of occupational health, Third Military Medical University, Chongqing 400038, People's Republic of China lunazhou00@163.com.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D019256:Cadmium Chloride / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D044122:Receptor, Melatonin, MT1 / Q000096:biosynthesis*; D056564:Sirtuin 1 / Q000096:biosynthesis*; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D044122:Receptor, Melatonin, MT1; D014157:Transcription Factors; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D019256:Cadmium Chloride; D008550:Melatonin
keywords: PGC-1 alpha; SIRT1; cadmium; hepatotoxicity; melatonin; melatonin receptor 1