Department of Occupational Health, Third Military Medical University, Chongqing, People's Republic of China.
Cell Death Dis. 2013 Mar 14;4(3):e540. doi: 10.1038/cddis.2013.7.
Mitochondria are critical targets in the hepatotoxicity of cadmium (Cd). Abnormal mitochondrial dynamics have been increasingly implicated in mitochondrial dysfunction in pathophysiological conditions. Therefore, our study aimed to investigate the effects and underlying mechanism of Cd on mitochondrial dynamics during hepatotoxicity. In the L02 liver cell lines, 12 μM cadmium chloride (CdCl₂) exposure induced excessive mitochondrial fragmentation as early as 3 h post-treatment with Cd, which preceded the mitochondrial dysfunction such as reactive oxygen species (ROS) overproduction, mitochondrial membrane potential (ΔΨm) loss and ATP reduction. Concurrent to mitochondrial fragmentation, CdCl₂ treatment increased the protein levels of dynamin-related protein (Drp1) and promoted the recruitment of Drp1 into mitochondria. Strikingly, mitochondrial fragmentation also occurred in the liver tissue of rats exposed to CdCl₂, accompanied by enhanced recruitment of Drp1 into mitochondria. Moreover, in L02 cells, Drp1 silencing could effectively reverse Cd-induced mitochondrial fragmentation and mitochondrial dysfunction. Furthermore, the increased expression and mitochondrial recruitment of Drp1 were tightly related to the disturbance of calcium homeostasis, which could be prevented by both chelating [Ca²⁺]i and inhibiting [Ca²⁺]m uptake. Overall, our study indicated that Cd induced Drp1-dependent mitochondrial fragmentation by disturbing calcium homeostasis to promote hepatotoxicity. Manipulation of Drp1 may be the potential avenue for developing novel strategies to protect against cadmium-induced hepatotoxicity.
线粒体是镉（Cd）肝毒性的关键靶点。异常的线粒体动力学在病理生理条件下的线粒体功能障碍中越来越受到关注。因此，我们的研究旨在探讨 Cd 在肝毒性期间对线粒体动力学的影响及其潜在机制。在 L02 肝细胞系中，12 μM 氯化镉（CdCl₂）暴露在 Cd 处理后 3 小时即可诱导过度的线粒体碎片化，这先于活性氧（ROS）过度产生、线粒体膜电位（ΔΨm）丧失和 ATP 减少等线粒体功能障碍。与线粒体碎片化同时发生的是，CdCl₂处理增加了与线粒体分裂相关的蛋白（Drp1）的蛋白水平，并促进了 Drp1 向线粒体的募集。引人注目的是，在暴露于 CdCl₂的大鼠肝组织中也发生了线粒体碎片化，同时伴随着 Drp1 向线粒体的募集增加。此外，在 L02 细胞中，Drp1 沉默可以有效逆转 Cd 诱导的线粒体碎片化和线粒体功能障碍。此外，Drp1 的表达增加和向线粒体的募集与钙稳态的紊乱密切相关，这可以通过螯合[Ca²⁺]i 和抑制[Ca²⁺]m 摄取来预防。总的来说，我们的研究表明，Cd 通过扰乱钙稳态诱导 Drp1 依赖性线粒体碎片化，从而促进肝毒性。操纵 Drp1 可能是开发针对镉诱导肝毒性的新型保护策略的潜在途径。
