Crucial physicochemical factors mediating mitochondrial toxicity of nanoparticles at noncytotoxic concentration

Abstract

Nanomaterials have been extensively applied in multiple industries, among which silver nanoparticles (AgNPs), silicon dioxide nanoparticles (SiNPs), and gold nanoparticles (AuNPs) have become representative of widely consumed NPs. Limited knowledge is available regarding the subcellular responses of NPs with different physicochemical properties, i.e. material type and size, under the noncytotoxic concentrations. Macrophages are important sensitive cells exposed to NPs, and mitochondria are sensitive organelles that respond at the subcellular level. Herein, we found that sublethal concentrations of AgNPs and SiNPs, not AuNPs, decreased the mitochondrial membrane potential (MMP) and tubular mitochondria, and further resulted in an increase of ROS level and a decrease of ATP generation. AgNPs and SiNPs can also disturb mitochondrial dynamics manifested as increasing Mfn2 expression and decreasing Drp1 expression. Further assessments for mitochondrial function showed that AgNPs and SiNPs exposure led to a decrease in the gene expressions related to complex I (Ndufa8 and Ndufs2), complex III (Uqcrc2 and Uqcrfs1), complex IV (Cox6b1), and activity of complex I, suggesting their potential roles in impairing cellular respiration. In terms of the effects of NPs with different sizes, stronger toxicity was observed in smaller-sized nanoparticles. Among the above mitochondrial changes, we identified that ROS, ATP, MMP, tubular mitochondria, and expression of Drp1 were relatively sensitive indicators in subcellular response to NPs. With the above sensitive indicators, the comparison of heterogeneity between material type and size of the NPs showed that material type occupied a main influence on subcellular mitochondrial effects. Our finding provided important data on the potential subcellular risks of NPs, and indicated the vital role of material type for a better understanding of the nanomaterial biological safety.