Journal of Nanomedicine & Nanotechnology

Abstract

The Immediate Mitochondrial Stress Response in Coping with Systemic Exposure of Silver Nanoparticles in Rat Liver

Tzu-Ying Lee, Maw-Shung Liu, Li-Ju Huang, Sheng-I Lue, Tsen-Ni Tsai, Lung-Chang Lin, Aij-Lie Kwan and Rei-Cheng Yang

Silver nanoparticles (Ag-nps) induce hepatotoxicities via oxidative stress. The oxidative stress-induced mitochondrial damages are known to be regulated by mitochondrial unfolded protein response (mtUPR) and autophagy/mitophagy systems. The present study was undertaken to investigate role of mtUPR and autophagy/mitophagy on the Ag-nps induced mitochondrial dysfunction. Experiments consisted of two groups of Sprague Dawley rats: control and Ag-nps treated. The Ag-nps treated group received an intraperitoneally injection of 1.5 ml deionized water containing 500 mg/ kg of Ag-nps. Control group received equal volume of deionized water. All animals were sacrificed at different time points (6, 12, 18 and 24 hr post treatment), followed by removal of livers for determination of ATP content and protein expression. The results show that multi-ubiquitinated proteins (Ub-proteins) in liver mitochondria were increased at 12 hr and the increases were sustained up to 24 hr following Ag-nps treatment. Expressions of mtUPR-associated proteins including transcriptional factors (C/EBP homologous protein (CHOP) and CAAT/enhancer-binding protein-β (C/EBPβ)), molecular chaperones (heat shock protein (Hsp) 70 and Hsp60) and protease (caseinolytic Clp protease (ClpP)) remained unchanged during the entire experimental period, except that Hsp10 was upregulated. Expression of LC3-II (autophagy marker) and BNIP3 (mitophagy marker) were upregulated at 6 hr and the upregulation remained throughout the experimental period. ATP content was reduced at 6 hr after Ag-nps exposure and the reductions were sustained during the entire experimental period. These results demonstrate that activation of autophagy/mitophagy markers co-existed with upregulation of Ub-proteins and reduction of ATP content without changing mtUPR in rat liver following Ag-nps administration. These findings indicate that protective effects of autophagy/mitophagy markers were overwhelmed by detrimental actions of Ub-proteins on the control of mitochondrial function, and the counter-balance of the two systems eventually resulting in impaired mitochondrial function, i.e., reduction of ATP content.