Hydrogen sulfide increases copper-dependent neurotoxicity via intracellular copper accumulation
Hydrogen sulfide increases copper-dependent neurotoxicity via intracellular copper accumulation
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DOI：
10.1039/d0mt00015a
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发表时间：
2020-06-01
期刊：
影响因子：
3.4
通讯作者：
Adachi, Tetsuo
中科院分区：
文献类型：
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作者：
Goto, Norika;Hara, Hirokazu;Adachi, Tetsuo
铜（Cu）是一种必需的微量元素，并作为许多酶的氧化还原辅因子;然而，过量的Cu对细胞是有毒的。硫化氢（H2S）是一种众所周知的有毒气体分子，但它具有多种生物学效应，如神经调节和血管舒张。H2S最近被证明参与重金属的解毒，包括锌和镉，这表明H2S有助于维持细胞内重金属的稳态。然而，目前还不清楚H2S如何影响细胞Cu动力学。在这项研究中，我们研究了硫化氢对铜细胞毒性的影响。在存在H2S供体NaHS的情况下，将人神经母细胞瘤SH-SY 5 Y细胞暴露于CuSO（4）。单独的CuSO（4）轻微地诱导细胞损伤，而CuSO（4）和NaHS（Cu/NaHS）的组合增加了Cu的细胞毒性。铜螯合剂浴铜灵二磺酸减轻Cu/NaHS诱导的细胞毒性。与单独的CuSO（4）相比，Cu/NaHS显著促进ROS产生，线粒体功能障碍和ATP产生的减少。此外，使用金属响应元件（MRE）驱动的报告质粒的报告分析显示，Cu/NaHS增强Cu依赖的MRE激活。Cu/NaHS处理的细胞内Cu的量显著高于单独用CuSO（4）处理的细胞。此外，铜/NaHS显着抑制铜输出ATP 7A的水平，但不ATP 7 B，蛋白质，而组合不影响铜进口CTR 1蛋白。综上所述，我们得出结论，ATP 7A蛋白水平的显着下降，铜/NaHS促进细胞内铜积累，并导致铜细胞毒性增加。
Copper (Cu) is an essential trace element and acts as a redox cofactor for many enzymes; however, excess Cu is toxic to cells. Hydrogen sulfide (H2S) is a well-known toxic gaseous molecule, but it has various biological effects such as neuromodulation and vasodilation. H2S was recently demonstrated to be involved in the detoxification of heavy metals, including zinc and cadmium, suggesting that H2S helps to maintain the homeostasis of heavy metals in cells. However, it is unclear how H2S impacts cellular Cu dynamics. In this study, we examined the effects of H2S on Cu cytotoxicity. Human neuroblastoma SH-SY5Y cells were exposed to CuSO(4)in the presence of the H2S donor NaHS. CuSO(4)alone slightly induced cell injury, whereas the combination of CuSO(4)and NaHS (Cu/NaHS) increased Cu cytotoxicity. The Cu chelator bathocuproinedisulfonic acid mitigated Cu/NaHS-induced cytotoxicity. Compared with CuSO(4)alone, Cu/NaHS markedly promoted ROS generation, mitochondrial dysfunction, and a decrease in ATP production. In addition, reporter assay using the metal responsive element (MRE)-driven reporter plasmid revealed that Cu/NaHS augmented Cu-dependent MRE activation. The amount of intracellular Cu was significantly higher in cells treated with Cu/NaHS than in those treated with CuSO(4)alone. Moreover, Cu/NaHS markedly suppressed the level of the Cu exporter ATP7A, but not ATP7B, protein, whereas the combination did not affect that of the Cu importer CTR1 protein. Taken together, we conclude that the marked decrease in the ATP7A protein level by Cu/NaHS promotes intracellular Cu accumulation and leads to increased Cu cytotoxicity.