An acetyl-L-carnitine switch on mitochondrial dysfunction and rescue in the metabolomics study on aluminum oxide nanoparticles.

Xiaobo Li,Chengcheng Zhang,Xin Zhang,Hongbao Yang,Shizhi Wang,Shenshen Wu,Rui Chen,Yankai Xia,Qingtao Meng

doi:10.1186/s12989-016-0115-y

Abstract

BackgroundDue to the wide application of engineered aluminum oxide nanoparticles and increased aluminum containing particulate matter suspending in air, exposure of human to nano-scale aluminum oxide nanoparticles (Al2O3 NPs) is becoming inevitable.MethodsIn the present study, RNA microarray coupled with metabolomics analysis were used to uncover mechanisms underlying cellular responses to Al2O3 NPs and imply the potential rescue.ResultsWe found that Al2O3 NPs significantly triggered down-regulation of mitochondria-related genes located in complex I, IV and V, which were involved in oxidative phosphorylation and neural degeneration pathways, in human bronchial epithelial (HBE) cells. Subsequent cell- and animal- based assays confirmed that Al2O3 NPs caused mitochondria-dependent apoptosis and oxidative stress either in vitro or in vivo, which were consistent with the trends of gene regulation. To rescue the Al2O3 NPs induced mitochondria dysfunction, disruption of small molecular metabolites of HBE were profiled using metabolomics analysis, which facilitates identification of potential antagonizer or supplement against nanoparticle-involved damages. Supplementation of an antioxidant, acetyl-L-carnitine, completely or partially restored the Al2O3 NPs modulated gene expression levels in mitochondrial complex I, IV and V. It further reduced apoptosis and oxidative damages in both Al2O3 NPs treated HBE cells and animal lung tissues.ConclusionThus, our results demonstrate the potential mechanism of respiratory system damages induced by Al2O3 NPs. Meanwhile, based on the metabolomics profiling, application of acetyl-L-carnitine is suggested to ameliorate mitochondria dysfunction associated with Al2O3 NPs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0115-y) contains supplementary material, which is available to authorized users.

Highlights

Due to the wide application of engineered aluminum oxide nanoparticles and increased aluminum containing particulate matter suspending in air, exposure of human to nano-scale aluminum oxide nanoparticles (Al2O3 NPs) is becoming inevitable
The Gene Ontology (GO) analysis revealed that genes encoding proteins necessary for mitochondrial function were differentially expressed
Of the genes differentially regulated, 23/ 154 genes involved in cell components (CC) (Fig. 1b); 11/85 genes involved in molecular function (MF) (Fig. 1c), and 14/183 in biological process (Fig. 1d)

Summary

Introduction

Due to the wide application of engineered aluminum oxide nanoparticles and increased aluminum containing particulate matter suspending in air, exposure of human to nano-scale aluminum oxide nanoparticles (Al2O3 NPs) is becoming inevitable. Nano-scale aluminum oxide (Al2O3) particles are widely used in insulator layers, powder coating, and fluorescent lamp material. Apoptosis is an endpoint to assess toxicity of metal oxide nanomaterial, providing a benchmark against which to evaluate the potential toxicity of engineered nanoparticles [2,3,4]. Studies investigating ambient particulate matter or nanoparticles suggest apoptosis or mitochondrial dysfunction are sufficient end-points to monitor toxicity [11,12,13], but conventional toxicity assays may not suffice to fully understand the cellular responses of ultrafine particle exposure. A more comprehensive approach to determining how cells respond to ultrafine particles is required

Methods

Results

Discussion

Conclusion