Persistency of Enlarged Autolysosomes Underscores Nanoparticle‐Induced Autophagy in Hepatocytes

Abstract

The diverse biological effects of nanomaterials form the basis for their applications in biomedicine but also cause safety issues. Induction of autophagy is a cellular response after nanoparticles exposure. It may be beneficial in some circumstances, yet autophagy-mediated toxicity raises an alarming concern. Previously, it has been reported that upconversion nanoparticles (UCNs) elicit liver damage, with autophagy contributing most of this toxicity. However, the detailed mechanism is unclear. This study reveals persistent presence of enlarged autolysosomes in hepatocytes after exposure to UCNs and SiO nanoparticles both in vitro and in vivo. This phenomenon is due to anomaly in the autophagy termination process named autophagic lysosome reformation (ALR). Phosphatidylinositol 4-phosphate (PI(4)P) relocates onto autolysosome membrane, which is a key event of ALR. PI(4)P is then converted into phosphatidylinositol 4,5-bisphosphate (PI(4,5)P ) by phosphatidylinositol-4-phosphate 5-kinase. Clathrin is subsequently recruited by PI(4,5)P and leads to tubule budding of ALR. Yet it is observed that PI(4)P cannot be converted in nanoparticle-treated hepatocytes cells. Exogenous supplement of PI(4,5)P suppresses the enlarged autolysosomes in vitro. Abolishment of these enlarged autolysosomes by autophagy inhibitor relieves the hepatotoxicity of UCNs in vivo. The results provide evidence for disrupted ALR in nanoparticle-treated hepatocytes, suggesting that the termination of nanoparticle-induced autophagy is of equal importance as the initiation.

Silica nanoparticles induce autophagosome accumulation via activation of the EIF2AK3 and ATF6 UPR pathways in hepatocytes

“…In addition, Stern et al reported that nanoparticles could disrupt the cytoskeleton and prevent lysosomal trafficking, leading to autophagic flux blockage. 1 Moreover, a recent study indicated that upconversion nanoparticles (UCNs) induce autolysosomal membrane turnover anomalies leading to abnormal autophagy [52]. However, the contributions of autophagy initiation and autophagosome synthesis to autophagy dysfunction are rarely investigated.…”

Review of toxicological effect of quantum dots on the liver

“…There are some studies confirming that hepatocyte toxicity caused by nanomaterials was mediated by autophagy. (Fan et al, ; Paesano et al, ; Zhang et al, ; Zhu et al, ). Studies have shown that low‐dose (3 μg ml −1 ) CdS QDs can lead to upregulation of autophagy related genes ATG3, ATG7, ATG13 and ATG14, whereas in high doses (14 μg/ml), there is no such inducement effect in HepG2 cells (Paesano et al, ), which suggest the significance of autophagy in preventing intracellular damage.…”

“…There are some studies confirming that hepatocyte toxicity caused by nanomaterials was mediated by autophagy. (Fan et al, 2016;Paesano et al, 2016;Zhang et al, 2017;Zhu et al, 2017). Studies have shown that low-dose (3 μg ml −1 ) CdS QDs can lead to upregulation of autophagy related genes ATG3, ATG7, ATG13 and ATG14, whereas in high doses (14 μg/ml),…”

Midazolam Enhances Mutant Huntingtin Protein Accumulation via Impairment of Autophagic Degradation In Vitro

“…Trehalose and CQ are commonly used as an autophagy inducer and blocker, respectively [18,23]. Trehalose significantly attenuated the elevation of GFP-Htt (Q74) puncta following midazolam treatment, but CQ had the opposite effect (Fig.…”

“…3c) suggested the blockade of autophagic flux [23,29]; thus, we measured autophagic degradation. The effect of sequestosome 1 (SQSTM1/p62), a protein substrate that is selectively incorporated during the formation of autophagosomes and degraded by autophagy, was investigated first [30].…”