Nanosilver Incurs an Adaptive Shunt of Energy Metabolism Mode to Glycolysis in Tumor and Nontumor Cells

Due to its significant antimicrobial properties, nanosilver (nAg) has been substantially used in a wide spectrum of areas. This has raised the concerns on the detrimental effects on environment and human health. Although numerous studies have documented nAg-mediated toxicity to cells or organisms, little attempt has been made to study the biological impacts of nAg on cells at nontoxic concentrations, namely, the distinct biological effects that can be separated from direct cytotoxicity. Here, we studied nAg-mediated effects on energy metabolism in cells under sublethal exposure. Treatment of nAg at nontoxic concentrations resulted in a decline of ATP synthesis and attenuation of respiratory chain function in nontumor HEK293T cells and tumor cells with differential respiration rate, including HepG2, HeLa, A498, and PC3 cells. Cellular energy homeostasis was switched from oxidative phosphorylation-based aerobic metabolism to anaerobic glycolysis, which is an adaption process to satisfy the energy demand for cell survival. Nanospheres with smaller size showed greater capability to alter cellular energy metabolism than those with larger size or nanoplates. Mechanistic investigation manifested that inhibition of PGC-1 alpha by nAg was, at least partially, accountable for the transition from oxidative phosphorylation to glycolysis. Additionally, altered expression of a few energy metabolism-related genes (such as PFKFB3 and PDHA1) was also involved in the transition process. We further showed nAg-induced depolarization of mitochondrial membrane potential and reduction of respiratory chain complex activity. Together, our combined results uncovered the mechanisms by which nAg induced energy metabolism reprogramming in both tumor and nontumor cells under sublethal dosage.