Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, People's Republic of China.
College of Life Sciences, Mudanjiang Medical University, Mudanjiang, People's Republic of China.
Environ Toxicol. 2023 Mar;38(3):579-590. doi: 10.1002/tox.23704. Epub 2022 Nov 15.
The accumulation of copper (Cu) in the organisms could lead to kidney damage by causing mitochondrial dysfunction. Given that mitochondria are one of the targets of Cu poisoning, this study aimed to investigate the role of mitophagy in Cu-induced mitochondrial dysfunction in renal tubular epithelial cells to understand the mechanism of Cu nephrotoxicity. Hence, the cells were treated with different concentrations of Cu sulfate (CuSO ) (0, 100, and 200 μM), and mitophagy inhibitor (Cyclosporine A, 0.5 μM) and/or 200 μM CuSO in the combination for 12 h. Results showed that Cu caused mitochondrial swelling, vacuoles, and cristae fracture; increased the number of mitochondrial and lysosome fluorescent aggregation points; upregulated the mRNA levels of mitophagy-associated genes (LC3A, LC3B, P62, BNIP3, NIX, OPTN, NDP52, Cyp D LAMP1, and LAMP2) and protein levels of LC3II/LC3I, BNIP3, and NIX, downregulated the mRNA and protein levels of P62; reduced the mitochondrial membrane potential (MMP), ATP content, mitochondrial respiratory control rate (RCR), mitochondrial respiratory control rate (OPR), and the mRNA and protein levels of PGC-1α, TOMM20, and Mfn2, but increased the mRNA and protein levels of Drp1. Besides, cotreatment with Cu and CsA dramatically decreased the level of mitophagy, but increased mitochondrial division, further reduced MMP, ATP content, RCR, and OPR, mitochondrial fusion and thereby reduced mitochondrial biogenesis. Taken together, these data indicated that Cu exposure induced BNIP3/NIX-dependent mitophagy in duck renal tubular epithelial cells, and inhibition of mitophagy aggravated Cu-induced mitochondrial dysfunction.
铜（Cu）在生物体内的积累可导致线粒体功能障碍，进而引发肾脏损伤。鉴于线粒体是 Cu 中毒的靶标之一，本研究旨在探讨自噬在 Cu 诱导的肾小管上皮细胞线粒体功能障碍中的作用，以了解 Cu 肾毒性的机制。因此，用不同浓度的硫酸铜（CuSO）（0、100 和 200 μM）、自噬抑制剂（环孢素 A，0.5 μM）以及 200 μM CuSO 和自噬抑制剂的组合处理细胞 12 小时。结果表明，Cu 导致线粒体肿胀、空泡和嵴断裂；增加了线粒体和溶酶体荧光聚集点的数量；上调了自噬相关基因（LC3A、LC3B、P62、BNIP3、NIX、OPTN、NDP52、Cyp D LAMP1 和 LAMP2）的 mRNA 水平和 LC3II/LC3I、BNIP3 和 NIX 的蛋白水平，下调了 P62 的 mRNA 和蛋白水平；降低了线粒体膜电位（MMP）、ATP 含量、线粒体呼吸控制率（RCR）、线粒体呼吸控制率（OPR）、PGC-1α、TOMM20 和 Mfn2 的 mRNA 和蛋白水平，但增加了 Drp1 的 mRNA 和蛋白水平。此外，Cu 和 CsA 共同处理显著降低了自噬水平，但增加了线粒体分裂，进一步降低了 MMP、ATP 含量、RCR 和 OPR、线粒体融合，从而减少了线粒体生物发生。总之，这些数据表明，Cu 暴露诱导了鸭肾小管上皮细胞中 BNIP3/NIX 依赖性自噬，而自噬的抑制加重了 Cu 诱导的线粒体功能障碍。
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