Department of Occupational Health, Third Military Medical University, Chongqing, China.
J Pineal Res. 2011 Nov;51(4):426-33. doi: 10.1111/j.1600-079X.2011.00906.x. Epub 2011 Jul 29.
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.
最近的研究表明，氧化应激和线粒体功能障碍在镍的神经毒性中发挥重要作用。由于线粒体 DNA（mtDNA）极易受到氧化应激的影响，而褪黑素在各种病理条件下能有效地保护 mtDNA 免受氧化损伤，因此本研究旨在确定 mtDNA 氧化损伤是否参与镍的神经毒性，并检测褪黑素对 mtDNA 的神经保护作用。在这项研究中，我们将不同浓度的氯化镍（NiCl2，0.125、0.25 和 0.5mM）暴露于小鼠神经母细胞瘤细胞系（Neuro2a）24 小时。结果发现镍显著增加了活性氧（ROS）的产生和线粒体超氧物水平。此外，镍暴露增加了线粒体 8-羟基鸟嘌呤（8-OHdG）含量，降低了 mtDNA 含量和 mtDNA 转录水平。与这一发现一致的是，镍被发现破坏了 mtDNA 核小体结构，并降低了 Tfam 的蛋白水平，而 Tfam 是核小体组织的关键蛋白成分。然而，镍诱导的 mtDNA 所有氧化损伤均被褪黑素预处理有效减轻。我们的结果表明，mtDNA 的氧化损伤可能是镍神经毒性的原因。褪黑素在保护 mtDNA 免受镍对神经系统的不良影响方面具有很大的药理学潜力。
