Cu(I)/Cu(II) Released by Cu Nanoparticles Revealed Differential Cellular Toxicity Related to Mitochondrial Dysfunction

作者：Wang, Xiangrui; Wang, Wen-Xiong^*

来源：Environmental Science and Technology, 2023, 57(26): 9548-9558.

DOI：10.1021/acs.est.3c00864

• Cu valence
• mitochondrial fragmentation
• cellcycle
• reactive oxygen species
• apoptosis

Differential tolerance to Cu(I)and Cu(II) accumulationwas due to their different toxicity mechanisms on mitochondrial function. @@@ Cu-basednanoparticles (NPs) have been increasingly fabricated,and different Cu species (i.e., Cu+ andCu(2+)) of these NPs are tuned to achieve differential physicochemicalproperties. Although ion release is one of the major toxic mechanismsof Cu-based NPs, differences in cytotoxicity between released Cu(I)and Cu(II) ions are largely unknown. In this study, the A549 cellsexhibited a lower tolerance to Cu(I) compared with Cu(II) accumulation.Bioimaging of labile Cu(I) indicated that the change of the Cu(I)level upon CuO and Cu2O exposure displayed different trends.We then developed a novel method to selectively release Cu(I) andCu(II) ions within the cells by designing Cu (x) S shells for Cu2O and CuO NPs, respectively. This methodconfirmed that Cu(I) and Cu(II) exhibited different cytotoxicity mechanisms.Specifically, excess Cu(I) induced cell death through mitochondrialfragmentation, which further led to apoptosis, whereas Cu(II) resultedin cell cycle arrest at the S phase and induced reactive oxygen speciesgeneration. Cu(II) also led to mitochondrial fusion, which was likelydue to the influence of the cell cycle. Our study first uncoveredthe difference between the cytotoxicity mechanisms of Cu(I) and Cu(II),which could be greatly beneficial for the green fabrication of engineeredCu-based NPs.