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

Abstract

Cu-based nanoparticles (NPs) have been increasingly fabricated, and different Cu species (i.e., Cu+ and Cu2+) of these NPs are tuned to achieve differential physicochemical properties. Although ion release is one of the major toxic mechanisms of Cu-based NPs, differences in cytotoxicity between released Cu­(I) and Cu­(II) ions are largely unknown. In this study, the A549 cells exhibited 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) and Cu­(II) ions within the cells by designing Cu x S shells for Cu2O and CuO NPs, respectively. This method confirmed that Cu­(I) and Cu­(II) exhibited different cytotoxicity mechanisms. Specifically, excess Cu­(I) induced cell death through mitochondrial fragmentation, which further led to apoptosis, whereas Cu­(II) resulted in cell cycle arrest at the S phase and induced reactive oxygen species generation. Cu­(II) also led to mitochondrial fusion, which was likely due to the influence of the cell cycle. Our study first uncovered the difference between the cytotoxicity mechanisms of Cu­(I) and Cu­(II), which could be greatly beneficial for the green fabrication of engineered Cu-based NPs.

Dynamic Regulation of Intracellular Labile Cu(I)/Cu(II) Cycle in Microalgae Chlamydomonas reinhardtii: Disrupting the Balance by Cu Stress

“…The labile Cu­(I) content in cells at each cell cycle stage did not exhibit a uniform increasing trend under heightened Cu stress, suggesting a functional difference between those two forms (Figure S5). A recent study also found differential cellular toxicity of labile Cu­(I) and Cu­(II) using Cu-based nanoparticles, suggesting that labile Cu­(II) may influence the cell cycle regulation . Thus, we proposed that the heterogeneous resistance of algae at different cell cycle stages to Cu stress stems from their disparate sensitivities to the labile Cu­(II) pool.…”

In vitro and in vivo biocompatibility assessment of chalcogenide thermoelectrics as implants

“…The elevated Cu ion levels were found to interfere with essential cellular processes, including mitochondrial function and signaling pathways, culminating in apoptosis or necrosis. 28 Moreover, the Cu could catalyze the production of reactive oxygen species (ROS) through Fenton-like reactions, 29 leading to oxidative stress, 30 cellular damage, and a disruption of homeostasis.…”

Light-Activatable Ionic and Photothermal Therapy by CuAu Nanorods for Treating Wounds and Keratitis Caused by Methicillin-Resistant Staphylococcus aureus

“…As shown in Scheme , these NRs could effectively ablate bacteria under 808 nm laser irradiation. In normal environments, CuAu NRs released fewer copper ions, however, which were largely released in the acidic infection microenvironment, − further enhancing the antibacterial effect and improving re-epithelialization. We further proved the effectiveness of CuAu NRs in methicillin-resistant Staphylococcus aureus (MRSA) affected chronic wounds model in mice and MRSA-affected keratitis model in rabbits.…”