Disturbed mitochondrial quality control involved in hepatocytotoxicity induced by silica nanoparticles

Abstract

The extensive application of silica nanoparticles (SiNPs) brings about inevitable occupational, environmental, and even iatrogenic exposure for human beings. The liver, which is rich in mitochondria, is one of the target organs of SiNPs, but the underlying mechanisms by which these nanoparticles (NPs) interact with liver mitochondria and affect their functions still remain unclear. In the present study, we examined silicon nanoparticle (SiNP)-induced mitochondrial dysfunction, and further revealed its negative effects on mitochondrial quality control (MQC) in the human liver cell line L-02, including mitochondrial dynamics, mitophagy and biogenesis. Consequently, SiNPs induced cellular injury, accompanied by mitochondrial dysfunction, including mitochondrial reactive oxygen generation and mitochondrial membrane potential collapse. In line with the transmission electron microscopy (TEM)-observed abnormalities in the mitochondrial morphology and length distribution, a fission phenotype was manifested in the mitochondria of SiNP-exposed cells, and up-regulated DRP1 and FIS1, and down-regulated MFN1, were detected. Furthermore, the enhanced LC3II level, colocalization of the mitochondria and lysosomes, activated PINK1/Parkin signaling, and accumulated p62 in the SiNP-exposed cells suggested mitophagy disorder triggered by SiNPs. In addition, SiNPs inhibited mito-biogenesis, as evidenced by the reduced mitochondrial mass and mtDNA copy number, as well as the suppressed PGC1α-NRF1-TFAM signaling pathway. Overall, the study demonstrates that SiNPs trigger hepatocytotoxicity through interfering with the MQC process, bringing in excessive mitochondrial fission, mitophagy disorder and suppressed mito-biogenesis, leading to mitochondrial dysfunction and ensuing cell damage, and ultimately contributing to the occurrence and development of liver diseases. Our research could provide important experimental evidence related to safety assessments of SiNPs, especially in the field of biomedical applications.