Abstract：
Recent studies are identified the mitochondria as critical targets of 2, 2\', 4, 4\'-tetrabromodiphenyl ether (PBDE-47) induced neurotoxicity. This study aimed at examining the impact of PBDE-47 exposure on mitochondrial translation, and its subsequent effect on PBDE-47 neurotoxicity. The Sprague-Dawley (SD) rat model and neuroendocrine pheochromocytoma (PC12) cells were adopted for the measurements of mitochondrial ATP levels, mitochondrial translation products, and expressions of important mitochondrial regulators, such as required meiotic nuclear division 1 (RMND1), estrogen-related receptor α (ERRα), and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). To delve into the role of PGC-1α/ERRα axis in mitochondrial translation, 2-(4-tert-butylphenyl) benzimidazole (ZLN005) was employed. Both cellular and animal model results shown that PBDE-47 impeded PGC-1α/ERRα axis and mitochondrial translation. PBDE-47 suppressed mitochondrial function in rat hippocampus and PC12 cells by decreasing relative mitochondrial DNA (mtDNA) content, mitochondrial translation products, and mitochondrial ATP levels. Particularly, ZLN005 reversed PBDE-47 neurotoxicity by enhancing mitochondrial translation through activation of PGC-1α/ERRα axis, yet suppressing PGC-1α with siRNA attenuates its neuroprotective effect in vitro. In conclusion, this work highlights the importance of mitochondrial translation in PBDE-47 neurotoxicity by presenting results from cellular and animal models and suggests a potential therapeutic approach through activation of PGC-1α/ERRα axis. ENVIRONMENTAL IMPLICATION: PBDEs have attracted extensive attention because of their high lipophilicity, persistence, and detection levels in various environmental media. Increasing evidence has shown that neurodevelopmental disorders in children are associated with PBDE exposure. Several studies have also found that perinatal PBDE exposure can cause long-lasting neurobehavioral abnormalities in experimental animals. Our recent studies have also demonstrated the impact of PBDE-47 exposure on mitochondrial biogenesis and dynamics, leading to memory and neurobehavioral deficits. Therefore, we explore whether the pathological mechanism of PBDE-47-induced neurotoxicity involves the regulation of mitochondrial translation through the PGC-1α/ERRα axis.
摘要：
最近的研究确定线粒体是2，2'，4，4'-四溴二苯醚（PBDE-47）诱导的神经毒性。本研究旨在研究PBDE-47暴露对线粒体翻译的影响。及其对PBDE-47神经毒性的后续影响。采用Sprague-Dawley(SD)大鼠模型和神经内分泌嗜铬细胞瘤(PC12)细胞检测线粒体ATP水平,线粒体翻译产物，以及重要线粒体调节因子的表达，如必需减数分裂核分裂1（RMND1），雌激素相关受体α（ERRα），和过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1α）。探讨PGC-1α/ERRα轴在线粒体翻译中的作用,使用2-(4-叔丁基苯基)苯并咪唑(ZLN005)。细胞和动物模型结果表明，PBDE-47阻碍了PGC-1α/ERRα轴和线粒体翻译。PBDE-47通过降低线粒体DNA（mtDNA）相对含量抑制大鼠海马和PC12细胞的线粒体功能，线粒体翻译产物，和线粒体ATP水平。特别是,ZLN005通过激活PGC-1α/ERRα轴来增强线粒体翻译，从而逆转PBDE-47的神经毒性，然而，用siRNA抑制PGC-1α会减弱其在体外的神经保护作用。总之,这项工作通过提供细胞和动物模型的结果，突出了线粒体翻译在PBDE-47神经毒性中的重要性，并通过激活PGC-1α/ERRα轴提出了一种潜在的治疗方法。环境意义:多溴二苯醚因其高亲脂性而受到广泛关注,持久性,和各种环境介质中的检测水平。越来越多的证据表明，儿童神经发育障碍与多溴二苯醚暴露有关。几项研究还发现，围产期多溴二苯醚暴露可导致实验动物的长期神经行为异常。我们最近的研究还证明了多溴二苯醚-47暴露对线粒体生物发生和动力学的影响，导致记忆和神经行为缺陷。因此,我们探讨PBDE-47诱导的神经毒性的病理机制是否涉及通过PGC-1α/ERRα轴调节线粒体翻译。
