Mechanisms of silver nanoparticle-induced toxicity and important role of autophagy

Abstract

Safety concerns have been raised over the extensive applications of silver nanoparticles (AgNPs) because nano dimensions make them highly bioactive, being potentially harmful to the exposed humans. Surface physico-chemistry (shape, surface charge, chemical composition, etc.) that mainly dictates nano-bio interactions is relevant for influencing their biocompatibility and toxicity. Although the hazardousness of AgNPs has been demonstrated in vitro and in vivo, mechanistic understanding of the toxicity particularly at the molecular and organismal levels, in addition to oxidative stress and silver ion dissolution, has remained unclear. A growing body of research has elucidated that autophagy, being activated in response to exposure to various nanomaterials, may serve as a cellular defense mechanism against nanotoxicity. Recently, autophagy activation was shown to correlate with AgNPs exposure; however, the subsequent autophagosome–lysosome fusion was defective. As autophagy plays a crucial role in selective removal of stress-mediated protein aggregates and injured organelles, AgNPs-induced autophagic flux defect may consequently lead to aggravated cytotoxic responses. Furthermore, we suggest that p62 accumulation resulting from defective autophagy may also potentially account for AgNPs cytotoxicity. Intriguingly, AgNPs have been shown to interfere with ubiquitin modifications, either via upregulating levels of enzymes participating in ubiquitination, or through impairing the biological reactivity of ubiquitin (due to formation of AgNPs-ubiquitin corona). Ubiquitination both confers selectivity to autophagy as well as modulates stabilization, activation, and trafficking of proteins involved in autophagic clearance pathways. In this regard, we offer a new perspective that interference of AgNPs with ubiquitination may account for AgNPs-induced defective autophagy and cytotoxic effects.

• AgNPs-ubiquitin corona
• blockade of autophagosome–lysosome fusion
• selective autophagy

Acknowledgements

The authors would like to thank Paul Saunders (Research Specialist, National Cheng Kung University College of Medicine(South East Asian Health Education Center in Taiwan) for his valuable assistance in English editing and proofreading of this manuscript.

Declaration of interest

The authors declare no competing personal or financial conflicts. This work was supported by the Institute of Labor, Occupational Safety and Health, Ministry of Labor (1033059 and 1040005) and the Ministry of Science and Technology, Taiwan (MOST 103-2314-B-006-060-MY2 and MOST 103-2320-B-006-022-MY3). The viewpoints and opinions expressed in this article are those of the authors and do not necessarily represent those of the Institute of Labor, Occupational Safety and Health, Ministry of Labor and the Ministry of Science and Technology.