Methylmercury (MeHg) is a neurotoxin associated with foetal neurodevelopmental and adult cognitive deficits. Neurons are highly dependent on the tricarboxylic acid cycle and oxidative phosphorylation to produce ATP and meet their high energy demands. Therefore, mitochondrial quality control (MQC) is critical for neuronal homeostasis. While existing studies have generated a wealth of data on the toxicity of MeHg, the complex cascades and molecular pathways governing the mitochondrial network remain to be elucidated. Here, 0.6, 1.2 and 2.4 mg/kg body weight of MeHg were administered intragastrically to pregnant Sprague Dawley rats to model maternal MeHg exposure. The results of the study revealed that MeHg-treated rats tended to perform more directionless repetitive strategies in the Morris Water Maze and fewer target-orientation strategies than control offspring. Moreover, pathological injury and synaptic toxicity were observed in the hippocampus. Transmission electron microscopy (TEM) demonstrated that the autophagosomes encapsulated damaged mitochondria, while showing a typical mitochondrial fission phenotype, which was supported by the activation of PINK1-dependent key regulators of mitophagy. Moreover, there was upregulation of DRP1 and FIS1. Additionally, MeHg compensation promoted mitochondrial biogenesis, as evidenced by the activation of the mitochondrial PGC1-α-NRF1-TFAM signalling pathway. Notably, SIRT3/AMPK was activated by MeHg, and the expression and activity of p-AMPK, p-LKB1 and SIRT3 were consistently coordinated. Collectively, these findings provide new insights into the potential molecular mechanisms regulating MeHg-induced cognitive deficits through SIRT3/AMPK MQC network coordination.

中文翻译：

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线粒体质量控制的分子串扰和假定机制：与甲基汞引起的认知障碍的隐藏联系


甲基汞 (MeHg) 是一种与胎儿神经发育和成人认知缺陷相关的神经毒素。神经元高度依赖三羧酸循环和氧化磷酸化来产生 ATP 并满足其高能量需求。因此，线粒体质量控制（MQC）对于神经元稳态至关重要。虽然现有的研究已经产生了大量关于甲基汞毒性的数据，但控制线粒体网络的复杂级联和分子途径仍有待阐明。在此，对怀孕的 Sprague Dawley 大鼠进行胃内注射 0.6、1.2 和 2.4 毫克/千克体重的甲基汞，以模拟母体甲基汞暴露。研究结果显示，与对照后代相比，甲基汞治疗的大鼠倾向于在莫里斯水迷宫中执行更多无方向的重复策略，而目标导向策略更少。此外，在海马中观察到病理损伤和突触毒性。透射电子显微镜 (TEM) 表明自噬体包裹着受损的线粒体，同时显示出典型的线粒体裂变表型，这得到了 PINK1 依赖性线粒体自噬关键调节因子激活的支持。此外，DRP1 和 FIS1 上调。此外，MeHg 补偿促进了线粒体生物发生，线粒体 PGC1-α-NRF1-TFAM 信号通路的激活证明了这一点。值得注意的是，SIRT3/AMPK 被 MeHg 激活，并且 p-AMPK、p-LKB1 和 SIRT3 的表达和活性一致协调。总的来说，这些发现为通过 SIRT3/AMPK MQC 网络协调调节 MeHg 诱导的认知缺陷的潜在分子机制提供了新的见解。