Basic School of Medicine, Hebei Key Laboratory for Chronic Diseases, North China University of Science and Technology, Tangshan, China.
School of Public Health, North China University of Science and Technology, Tangshan, China.
Cardiovasc Toxicol. 2023 Dec;23(11-12):388-405. doi: 10.1007/s12012-023-09811-8. Epub 2023 Oct 16.
Zinc homeostasis is essential for maintaining redox balance, cell proliferation, and apoptosis. However, excessive zinc exposure is toxic and leads to mitochondrial dysfunction. In this study, we established a zinc overload model by treating rat cardiomyocyte H9c2 cells with Zn at different concentrations. Our results showed that zinc overload increased LDH and reactive oxygen species (ROS) levels, leading to cell death, mitochondrial membrane potential decrease and impaired mitochondrial function and dynamics. Furthermore, zinc overload activated the PINK1/Parkin signaling pathway and induced mitochondrial autophagy via ROS, while NAC inhibited mitophagy and weakened the activation of PINK1/Parkin pathway, thereby preserving mitochondrial biogenesis. In addition, our data also showed that Mfn2 deletion increased ROS production and exacerbated cytotoxicity induced by zinc overload. Our results therefore suggest that Zn-induced ROS generation causes mitochondrial autophagy and mitochondrial dysfunction, damaging H9c2 cardiomyocytes. Additionally, Mfn2 may play a key role in zinc ion-mediated endoplasmic reticulum and mitochondrial interactions. Our results provide a new perspective on zinc-induced toxicology.
锌稳态对于维持氧化还原平衡、细胞增殖和细胞凋亡至关重要。然而，过量的锌暴露是有毒的，并导致线粒体功能障碍。在这项研究中，我们通过用不同浓度的 Zn 处理大鼠心肌细胞 H9c2 细胞来建立锌过载模型。我们的结果表明，锌过载增加了 LDH 和活性氧（ROS）的水平，导致细胞死亡、线粒体膜电位下降以及线粒体功能和动力学受损。此外，锌过载通过 ROS 激活 PINK1/Parkin 信号通路并诱导线粒体自噬，而 NAC 抑制自噬并减弱 PINK1/Parkin 通路的激活，从而维持线粒体生物发生。此外，我们的数据还表明，Mfn2 缺失增加了 ROS 的产生，并加剧了锌过载引起的细胞毒性。因此，我们的结果表明，Zn 诱导的 ROS 生成导致线粒体自噬和线粒体功能障碍，从而损伤 H9c2 心肌细胞。此外，Mfn2 可能在锌离子介导的内质网和线粒体相互作用中发挥关键作用。我们的结果为锌诱导的毒理学提供了新的视角。
