Lysosome-dependent cell death and deregulated autophagy induced by amine-modified polystyrene nanoparticles.

Fengjuan Wang,Anna Salvati,Patricia Boya

doi:10.1098/rsob.170271

Abstract

Nanoparticles (NPs) typically accumulate in lysosomes. However, their impact on lysosomal function, as well as autophagy, a lysosomal degradative pathway, is still not well known. We have previously reported in the 1321N1 cell line that amine-modified polystyrene (NH2-PS) NPs induce apoptosis through damage initiated in the lysosomes leading ultimately to release of lysosomal content in the cytosol, followed by apoptosis. Here, by using a combination of biochemical and cell biological approaches, we have characterized in a mouse embryonic fibroblast cell line that the lysosomal alterations induced by NH2-PS NPs is progressive, initiating from mild lysosomal membrane permeabilization (LMP), to expansion of lysosomal volume and intensive LMP before the summit of cell death. Though the cells initially seem to induce autophagy as a surviving mechanism, the damage of NH2-PS NPs to lysosomes probably results in lysosomal dysfunctions, leading to blockage of autophagic flux at the level of lysosomes and the eventual cell death.

Highlights

Damage to lysosomes has recently been proposed as an emerging mechanism of nanotoxicity [1,2], as most endocytosed nanoparticles (NPs) accumulate within the lysosomal compartments without evident exit [3,4,5]
By using a combination of biochemical and cell biological approaches, we have characterized in a mouse embryonic fibroblast cell line that the lysosomal alterations induced by NH2-PS NPs is progressive, initiating from mild lysosomal membrane permeabilization (LMP), to expansion of lysosomal volume and intensive LMP before the summit of cell death
mouse embryonic fibroblast (MEF) cells were stained with the lysosomotropic dye-LysoTracker Red (LTR) that selectively accumulates in the cellular acidic compartments

Summary

Introduction

Damage to lysosomes has recently been proposed as an emerging mechanism of nanotoxicity [1,2], as most endocytosed nanoparticles (NPs) accumulate within the lysosomal compartments without evident exit [3,4,5]. Using amine-modified polystyrene (NH2-PS) NPs as an example, we have previously shown that the NP/corona complexes enter cells together and home in lysosomes [9,13]. Several reports have proposed the so-called ‘proton sponge’ effect as the mechanism of lysosomal damage by nanomaterials [16,17], similar effects have been reported for materials not capable of buffering the lysosomal pH [9,18]. Other mechanisms have been proposed, involving for instance damage to chloride channels [19]

Methods

Results

Discussion

Conclusion