title: Nickel exposure induces oxidative damage to mitochondrial DNA in Neuro2a cells: the neuroprotective roles of melatonin.
abstract: Recent studies suggest that oxidative stress and mitochondrial dysfunction play important roles in the neurotoxicity of nickel. Because mitochondrial DNA (mtDNA) is highly vulnerable to oxidative stress and melatonin can efficiently protect mtDNA against oxidative damage in various pathological conditions, the aims of this study were to determine whether mtDNA oxidative damage was involved in the neurotoxicity of nickel and to assay the neuroprotective effects of melatonin in mtDNA. In this study, we exposed mouse neuroblastoma cell lines (Neuro2a) to different concentrations of nickel chloride (NiCl(2), 0.125, 0.25, and 0.5 mm) for 24 hr. We found that nickel significantly increased reactive oxygen species (ROS) production and mitochondrial superoxide levels. In addition, nickel exposure increased mitochondrial 8-hydroxyguanine (8-OHdG) content and reduced mtDNA content and mtDNA transcript levels. Consistent with this finding, nickel was found to destroy mtDNA nucleoid structure and decrease protein levels of Tfam, a key protein component for nucleoid organization. However, all the oxidative damage to mtDNA induced by nickel was efficiently attenuated by melatonin pretreatment. Our results suggest that oxidative damage to mtDNA may account for the neurotoxicity of nickel. Melatonin has great pharmacological potential in protecting mtDNA against the adverse effects of nickel in the nervous system.
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing, China.
authors.forename: Shang-Cheng
authors.initials: SC
authors.lastname: Xu
authors.forename: Min-Di
authors.initials: MD
authors.lastname: He
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Zhong
authors.forename: Yan-Wen
authors.initials: YW
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Zheng-Ping
authors.initials: ZP
authors.lastname: Yu
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D009532:Nickel / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D013481:Superoxides; D009532:Nickel; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D008550:Melatonin