Copper (Cu) is one of the ubiquitous environmental pollutants which have raised wide concerns about the potential toxic effects and public health threat. For deeply investigating the nephrotoxicity induced by Cu, the effects of Cu on mitochondria-mediated apoptosis in kidney were first to analyze by combining metabolomics and molecular biology techniques. In this study, broiler chicks were fed with different contents of Cu (11, 110, 220, and 330 mg/kg Cu) for 49 d. The results of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining and transmission electron microscope showed that Cu could induce apoptosis in kidney, characterized by the increasing of TUNEL-positive cells and mitochondrial vacuolation. Additionally, a total of 62 differential metabolites were detected by liquid chromatography-mass spectrometry (LC-MS), and mainly enriched in the metabolic pathways including riboflavin metabolism, glutathione metabolism, sphingolipid metabolism, and glycerophospholipid metabolism, which were closely to mitochondrial metabolism. Meanwhile, the decreased mitochondrial membrane potential (MMP), increased mitochondrial membrane permeability and the change of mRNA and protein expression levels associated with mitochondria-mediated apoptosis and mitochondrial dynamics confirmed that Cu could induce mitochondria-mediated apoptosis. Therefore, our results demonstrated that Cu induced mitochondria-mediated apoptosis in kidney. Moreover, this study highlighted the metabolic characteristics of Cu to kidney, which suggested that mitochondrial metabolism could be considered as an important factor influencing toxicity.

铜 (Cu) 是一种普遍存在的环境污染物，引起了人们对潜在毒性影响和公共健康威胁的广泛关注。为深入研究铜的肾毒性，首先结合代谢组学和分子生物学技术分析铜对线粒体介导的肾细胞凋亡的影响。在本研究中，肉鸡饲喂不同含量的铜（11、110、220 和 330 毫克/千克铜）49 天。末端脱氧核苷酸转移酶介导的dUTP-生物素缺口末端标记（TUNEL）染色和透射电镜结果显示，Cu可诱导肾细胞凋亡，其特征是TUNEL阳性细胞增多和线粒体空泡化。此外，液相色谱-质谱（LC-MS）共检测到62种差异代谢物，主要富集于与线粒体代谢密切相关的核黄素代谢、谷胱甘肽代谢、鞘脂代谢和甘油磷脂代谢等代谢途径。同时，与线粒体介导的细胞凋亡和线粒体动力学相关的线粒体膜电位 (MMP) 降低、线粒体膜通透性增加以及 mRNA 和蛋白质表达水平的变化证实了铜可以诱导线粒体介导的细胞凋亡。因此，我们的研究结果表明，Cu 在肾脏中诱导线粒体介导的细胞凋亡。此外，本研究强调了铜对肾脏的代谢特征，