Persistency of Enlarged Autolysosomes Underscores Nanoparticle‐Induced Autophagy in Hepatocytes |
| |
| Authors: | Ji‐Qian Zhang Wei Zhou Sha‐Sha Zhu Jun Lin Peng‐Fei Wei Fen‐Fen Li Pei‐Pei Jin Han Yao Yun‐Jiao Zhang Yi Hu Yi‐Ming Liu Ming Chen Zheng‐Quan Li Xue‐sheng Liu Li Bai Long‐ping Wen |
| |
| Affiliation: | 1. The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, P. R. China;2. Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, P. R. China;3. School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui, P. R. China;4. Center for Biomedical Engineering, Department of Electronic Science and Technology, University of Science and Technology of China, Hefei, Anhui, P. R. China;5. Department of Pharmacology, Anhui University of Chinese Medicine, Hefei, Anhui, P.R. China;6. Anhui Anke Biotechnology (Group) Co., Ltd, Hefei, Anhui, P. R. China;7. Department of Materials Physics, Zhejiang Normal University, Jinhua, Zhejiang, P. R. China |
| |
| 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 SiO2 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)P2) by phosphatidylinositol‐4‐phosphate 5‐kinase. Clathrin is subsequently recruited by PI(4,5)P2 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)P2 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. |
| |
| Keywords: | autolysosomes autophagy phosphatidylinositol 4‐phosphate phosphatidylinositol‐4‐phosphate 5‐kinase upconversion nanoparticles |
|
|
