Cationic gold nanoparticles elicit mitochondrial dysfunction: a multi-omics study

Sergio Moya,Tiina Skoog,Juha Kere,Jaime Ruiz,Ding Xue,Nataliya Östberg,Didier Astruc,Jimmy Ytterberg,Katharina Klöditz,Bengt Fadeel,Roman Zubarev,Audrey Gallud,Yu-Zen Chen,Shintaro Katayama,Vladimir Gogvadze

doi:10.1038/s41598-019-40579-6

Abstract

Systems biology is increasingly being applied in nanosafety research for observing and predicting the biological perturbations inflicted by exposure to nanoparticles (NPs). In the present study, we used a combined transcriptomics and proteomics approach to assess the responses of human monocytic cells to Au-NPs of two different sizes with three different surface functional groups, i.e., alkyl ammonium bromide, alkyl sodium carboxylate, or poly(ethylene glycol) (PEG)-terminated Au-NPs. Cytotoxicity screening using THP-1 cells revealed a pronounced cytotoxicity for the ammonium-terminated Au-NPs, while no cell death was seen after exposure to the carboxylated or PEG-modified Au-NPs. Moreover, Au-NR3+ NPs, but not the Au-COOH NPs, were found to trigger dose-dependent lethality in vivo in the model organism, Caenorhabditis elegans. RNA sequencing combined with mass spectrometry-based proteomics predicted that the ammonium-modified Au-NPs elicited mitochondrial dysfunction. The latter results were validated by using an array of assays to monitor mitochondrial function. Au-NR3+ NPs were localized in mitochondria of THP-1 cells. Moreover, the cationic Au-NPs triggered autophagy in macrophage-like RFP-GFP-LC3 reporter cells, and cell death was aggravated upon inhibition of autophagy. Taken together, these studies have disclosed mitochondria-dependent effects of cationic Au-NPs resulting in the rapid demise of the cells.

Highlights

Systems biology is increasingly being applied in nanosafety research for observing and predicting the biological perturbations inflicted by exposure to nanoparticles (NPs)
Systems biology approaches based on computational modelling of systems-wide molecular changes at the gene or protein level are increasingly being applied in the field of nanosafety research for observing and predicting the biological perturbations inflicted by nanomaterials[18]
The primary particle sizes of the NPs were determined by transmission electron microscopy (TEM) whereas the size distribution profiles and zeta potentials of the NPs suspended in cell culture medium supplemented with serum were determined by dynamic light scattering (DLS) (Fig. 1, Supplementary Table S1)

Summary

Introduction

Systems biology is increasingly being applied in nanosafety research for observing and predicting the biological perturbations inflicted by exposure to nanoparticles (NPs). The intrinsic physicochemical properties remain an important determinant of the biological effects of NPs. Systems biology approaches based on computational modelling of systems-wide molecular changes at the gene or protein level are increasingly being applied in the field of nanosafety research for observing and predicting the biological perturbations inflicted by nanomaterials[18]. We addressed the role of particle size and surface functionalization for cytotoxicity of Au-NPs using the human monocytic THP-1 cell line as a model These cells are widely used to study the impact of NPs on immune-competent cells[17,26]. To obtain a detailed understanding of the cellular effects of Au-NPs, we applied a combined transcriptomics and proteomics approach coupled with cell-based validation studies. The results showed that ammonium-functionalized Au-NPs elicited mitochondrial dysfunction leading to cell death with features of both necrosis and apoptosis, and inhibition of autophagy was found to aggravate cell death suggesting that autophagy acts as a defence mechanism in this model

Methods

Results

Conclusion