title: 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 SiO2nanoparticles 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)P2and 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)P2suppresses 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.
authors.affiliation: 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, 230027, P. R. China.|Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, 230022, P. R. China.
authors.forename: Ji-Qian
authors.initials: JQ
authors.lastname: Zhang
authors.affiliation: 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, 230027, P. R. China.|School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui, 230009, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Zhu
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wei
authors.affiliation: Center for Biomedical Engineering, Department of Electronic Science and Technology, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Li
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Jin
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Han
authors.initials: H
authors.lastname: Yao
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Yun-Jiao
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Liu
authors.affiliation: 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, 230027, P. R. China.|Department of Pharmacology, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, P.R. China.|Anhui Anke Biotechnology (Group) Co., Ltd, Hefei, Anhui, 230088, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Materials Physics, Zhejiang Normal University, Jinhua, Zhejiang, 321004, P. R. China.
authors.forename: Zheng-Quan
authors.initials: ZQ
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, 230022, P. R. China.
authors.forename: Xue-Sheng
authors.initials: XS
authors.lastname: Liu
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Bai
authors.affiliation: 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, 230027, P. R. China.
authors.forename: Long-Ping
authors.initials: LP
authors.lastname: Wen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002478:Cells, Cultured; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism
chemical_list: D018129:Phosphatidylinositol Phosphates; C037178:phosphatidylinositol 4-phosphate
keywords: autolysosomes; autophagy; phosphatidylinositol 4-phosphate; phosphatidylinositol-4-phosphate 5-kinase; upconversion nanoparticles