Cai Haiqing, He Junxiu, Zheng Wanting, Cheng Hong, Ge Xiaoting, Bao Yu, Wei Yue, Zhou Yanfeng, Liang Xiaolin, Chen Xing, Liu Chaoqun, Wang Fei, Yang Xiaobo
Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
Department of Nutrition and Food Hygiene, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
Mol Neurobiol. 2025 May;62(5):5961-5976. doi: 10.1007/s12035-024-04648-w. Epub 2024 Dec 14.
Environmental metal mixtures can cause combined neurotoxicity, but the underlying mechanism remains unclear. Mitochondria are crucial for energy metabolism in the nervous system, and their dysfunction leads to neurodegeneration. Zinc (Zn) is a coenzyme of many mitochondrial enzymes that controls mitochondrial function. This study investigated the role of Zn in the neurotoxicity induced by Mn + Pb and Pb + As mixtures. Zn supplementation improved the survival rate and learning ability of Caenorhabditis elegans following their exposure to mixtures of Mn + Pb and Pb + As by enhancing their mitochondrial morphology, membrane potential, and respiratory chain. Similarly, in HT22 cells, Zn mitigated the decrease in cellular activity and increase in apoptosis induced by the Mn + Pb and Pb + As mixtures by improving mitochondrial morphology and function. Mechanistically, Zn activated the PINK1 and MFN-2/OPA-1 pathways, promoting mitophagy and mitochondrial fusion. However, inhibition of mitophagy reversed the protective effect of Zn, indicating its reliance on mitophagy for neuroprotection. Our study demonstrated that Zn alleviates the combined neurotoxicity of Mn + Pb and Pb + As mixtures by enhancing mitophagy and mitochondrial fusion, suggesting that Zn supplementation is a potential treatment for metal-induced neurotoxicity.
环境金属混合物可导致联合神经毒性，但其潜在机制仍不清楚。线粒体对神经系统的能量代谢至关重要，其功能障碍会导致神经退行性变。锌（Zn）是许多控制线粒体功能的线粒体酶的辅酶。本研究调查了锌在锰+铅和铅+砷混合物诱导的神经毒性中的作用。补充锌可通过增强秀丽隐杆线虫的线粒体形态、膜电位和呼吸链，提高其在暴露于锰+铅和铅+砷混合物后的存活率和学习能力。同样，在HT22细胞中，锌通过改善线粒体形态和功能，减轻了锰+铅和铅+砷混合物诱导的细胞活性降低和细胞凋亡增加。机制上，锌激活了PINK1和MFN-2/OPA-1通路，促进了线粒体自噬和线粒体融合。然而，抑制线粒体自噬可逆转锌的保护作用，表明其神经保护作用依赖于线粒体自噬。我们的研究表明，锌通过增强线粒体自噬和线粒体融合来减轻锰+铅和铅+砷混合物的联合神经毒性，提示补充锌可能是治疗金属诱导神经毒性的一种潜在方法。
