Silica nanoparticles induce autophagy dysfunction via lysosomal impairment and inhibition of autophagosome degradation in hepatocytes

Abstract

Ji Wang,1,2 Yongbo Yu,1,2 Ke Lu,1 Man Yang,1,2 Yang Li,1,2 Xianqing Zhou,1,2 Zhiwei Sun1,2 1Department of Toxicology and Sanitary Chemistry, School of Public Health, 2Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People’s Republic of China Abstract: Autophagy dysfunction is considered as a potential toxic mechanism of nanomaterials. Silica nanoparticles (SiNPs) can induce autophagy, but the specific mechanism involved remains unclear. Therefore, the aim of this study was to confirm the effects of SiNPs on autophagy dysfunction and explore the possible underlying mechanism. In this article, we reported that cell-internalized SiNPs exhibited dose- and time-dependent cytotoxicity in both L-02 and HepG2 cells. Multiple methods verified that SiNPs induced autophagy even at the noncytotoxic level and blocked the autophagic flux at the high-dose level. Notably, SiNPs impaired the lysosomal function through damaging lysosomal ultrastructures, increasing membrane permeability, and downregulating the expression of lysosomal proteases, cathepsin B, as evidenced by transmission electron microscopy, acridine orange staining, quantitative reverse transcription-polymerase chain reaction, and Western blot assays. Collectively, these data concluded that SiNPs inhibited autophagosome degradation via lysosomal impairment in hepatocytes, resulting in autophagy dysfunction. The current study not only discloses a potential mechanism of autophagy dysfunction induced by SiNPs but also provides novel evidence for the study of toxic effect and safety evaluation of SiNPs. Keywords: silica nanoparticles, autophagosome, lysosome, autophagy dysfunction, hepatocytes

Keywords

• Silica nanoparticles
• Autophagosome
• Lysosome
• Autophagy dysfunction
• Hepatocytes