Zinc Oxide Particles Induce Activation of the Lysosome–Autophagy System

Abstract

Metal-oxide-based materials are highly versatile and used in a wide variety of applications ranging from medical technology to personal care products. Generally recognized as safe by the US Food and Drug Administration, zinc oxide (ZnO) has been increasingly used in pharmaceutical, cosmetic, food, and commodity chemical industries. As a result, exposure to nano- and micron-sized ZnO particles through occupational processes and consumer products is increasing and has raised concerns over the health effects associated with the large-scale production and commercialization of ZnO-based materials. It is therefore important to investigate the interaction of ZnO particles with biological systems and elucidate the consequent effect on cell physiology. Of particular interest is the autophagic response to zinc oxide particles, as autophagy is the first line of defense activated in response to the uptake of foreign materials. As the main cellular catabolic pathway, the lysosome–autophagy system plays an important homeostatic function and defects or deficiency of this degradation system is associated with the cellular pathogenesis of a number of human diseases, ranging from neurodegenerative disorders to cancer. In this study, we investigated the response of the lysosome–autophagy system to three relevant types of ZnO particles, namely, a polydisperse mixture of bare, micron-sized particles (100–1000 nm) and monodisperse, bare, and coated (with triethoxycaprylylsilane) ZnO nanoparticles (85 nm). To investigate the molecular mechanisms mediating the response of the lysosome–autophagy system to these ZnO particles, we examined a complete set of markers of this pathway and characterized each step, from transcriptional activation to clearance of autophagic cargo. To evaluate the effect of the different types of ZnO particles on the lysosome–autophagy system, biological assays were conducted under conditions that do not cause considerable cytotoxicity. All three types of ZnO particles were found to result in activation of the transcription factor EB, a master regulator of autophagy and lysosomal biogenesis. Cellular exposure to bare and coated nano-sized ZnO enhanced the formation and turnover of autophagosomes and cellular clearance. Cellular exposure to the polydisperse mixture of ZnO particles, however, resulted in enhancement of autophagosome formation, but also in blockage of the autophagic flux. Results from this study underscore the importance of characterizing the autophagic response to ZnO-based materials and contribute significant engineering principles for the future design of nano- and micron-sized ZnO materials with the desired autophagy-modulating properties.

Aggregation Behavior of Nanoparticle-Peptide Systems Affects Autophagy

“…This wide range of applications is due to the unique and tunable physicochemical properties of nanoparticles that shape the interactions at the interface between nanoparticles and biological systems. , Interactions at the nanobio interface, however, can also have bioadverse effects beyond those already characterized for materials at the bulk or molecular scales. ,, Specifically, mechanistic studies have pointed to the key role of nanoparticle-induced impairment and disruption of lysosomal function, formation of reactive oxygen species, and activation of inflammatory responses in mediating the observed cytotoxic effect of nanoparticles. Notably, the autophagic response induced upon internalization of a variety of nanoparticles presenting different physicochemical properties − has a profound effect on the fate of internalized nanoparticles and the ultimate outcome of the interaction of nanoparticles with cellular components, including their potentially toxic effect. − …”

The impact of nanomaterials on autophagy across health and disease conditions

“…Further, entry of foreign particles triggers autophagy which in response acts as a first line of defense [ 33 ]. Nevertheless, it is possible that the autophagy activated in response to the entry of foreign particles or by the foreign particles can be both pro-survival and pro-death [ 34 ].…”

Understanding cellular interactions with nanomaterials: towards a rational design of medical nanodevices

“…The other endocytosis pathways used were highly dependent on the cell and material types, but it is possible to distinguish common NP uptake mechanisms, which are schematized in figure 1. Popp and Segatori (2019) studied the effect of zinc oxide particles and found that both NP and microparticles (100-1000 nm) induce autophagy, but only microparticles block the autophagic flux. It is worth highlighting that current knowledge suggests that NP size is not the only factor that determines the NP uptake mechanism, and that several endocytic pathways have a synergistic role in NP internalization.…”