Cyclooxygenase-2 modulates ER-mitochondria crosstalk to mediate superparamagnetic iron oxide nanoparticles induced hepatotoxicity: an in vitro and in vivo study

被引:29
作者
Che, Lin [1 ]
Yao, Huan [1 ]
Yang, Chuan-Li [1 ]
Guo, Ni-Jun [1 ]
Huang, Jing [1 ]
Wu, Zi-Li [1 ]
Zhang, Li-Yin [1 ]
Chen, Yuan-Yuan [1 ]
Liu, Gang [1 ]
Lin, Zhong-Ning [1 ]
Lin, Yu-Chun [1 ]
机构
[1] Xiamen Univ, State Key Lab Mol Vaccinol & Mol Diagnost, Sch Publ Hlth, Xiangan South Rd, Xiamen 361102, Fujian, Peoples R China
基金
中国国家自然科学基金;
关键词
Superparamagnetic iron oxide nanoparticles; cyclooxygenase-2; mitochondria-associated endoplasmic reticulum membranes; interorganelle Ca2+ transfer; hepatotoxicity; ENDOPLASMIC-RETICULUM; CONTACT SITES; IMMUNE CELLS; TOXICITY; DYSFUNCTION; HOMEOSTASIS; ACTIVATION; APOPTOSIS; CELECOXIB; MEMBRANES;
D O I
10.1080/17435390.2019.1683245
中图分类号
TB3 [工程材料学];
学科分类号
0805 ; 080502 ;
摘要
Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are central microdomains of the ER that interact with mitochondria. MAMs provide an essential platform for crosstalk between the ER and mitochondria and play a critical role in the local transfer of calcium (Ca2+) to maintain cellular functions. Despite the potential uses of superparamagnetic iron oxide nanoparticles (SPIO-NPs) in biomedical applications, the hepatotoxicity of these nanoparticles (NPs) is not well characterized and little is known about the involvement of MAMs in ER-mitochondria crosstalk. We studied SPIO-NPs-associated hepatotoxicity in vitro and in vivo. In vitro, human normal hepatic L02 cells were exposed to SPIO-NPs (2.5, 7.5, and 12.5 mu g/mL) for 6 h and SPIO-NPs (12.5 mu g/mL) was found to induce apoptosis. In vivo, SPIO-NPs induced liver injury when mice were intravenously injected with 20 mg/kg body weight SPIO-NPs for 24 h. Based on both in vitro and in vivo studies, we found that the structure and Ca2+ transport function of MAMs were perturbated and an accumulation of cyclooxygenase-2 (COX-2) in MAMs fractions was increased upon treatment of SPIO-NPs. The interaction between COX-2 and the components of MAMs, in terms of IP3R-GRP75-VDAC1 complex, was also revealed. Furthermore, the role of COX-2 in SPIO-NPs-associated hepatotoxicity was investigated by modifying the expression of COX-2. We demonstrated that COX-2 increases the structural and functional ER-mitochondria coupling and enhances the efficacy of ER-mitochondria Ca2+ transfer through the MAMs, thus sensitizing hepatocytes to a mitochondrial Ca2+ overload-dependent apoptosis. Taken together, our findings link SPIO-NPs-triggered hepatotoxicity with ER-mitochondria Ca2+ crosstalk which is mediated by COX-2 and provide mechanistic insight into the impact of interorganelle ER-mitochondria communication on hepatic nanotoxicity.
引用
收藏
页码:162 / 180
页数:19
相关论文
共 61 条
[21]   Proteomic Analysis of Mitochondrial-Associated ER Membranes (MAM) during RNA Virus Infection Reveals Dynamic Changes in Protein and Organelle Trafficking [J].
Horner, Stacy M. ;
Wilkins, Courtney ;
Badil, Samantha ;
Iskarpatyoti, Jason ;
Gale, Michael, Jr. .
PLOS ONE, 2015, 10 (03) :1-20
[22]   Endoplasmic reticulum stress stimulates the expression of cyclooxygenase-2 through activation of NF-κB and pp38 mitogen-activated protein kinase [J].
Hung, JH ;
Su, IJ ;
Lei, HY ;
Wang, HC ;
Lin, WC ;
Chang, WT ;
Huang, WY ;
Chang, WC ;
Chang, YS ;
Chen, CC ;
Lai, MD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (45) :46384-46392
[23]   Targeting of Primary Breast Cancers and Metastases in a Transgenic Mouse Model Using Rationally Designed Multifunctional SPIONs [J].
Kievit, Forrest M. ;
Stephen, Zachary R. ;
Veiseh, Omid ;
Arami, Hamed ;
Wang, Tingzhong ;
Lai, Vy P. ;
Park, James O. ;
Ellenbogen, Richard G. ;
Disis, Mary L. ;
Zhang, Miqin .
ACS NANO, 2012, 6 (03) :2591-2601
[24]   Silicon dioxide nanoparticles induce COX-2 expression through activation of STAT3 signaling pathway in HaCaT cells [J].
Kundu, Juthika ;
Kim, Do-Hee ;
Chae, In Gyeong ;
Lee, Jong Kwon ;
Lee, Sooyeun ;
Jeong, Chul-Ho ;
Chun, Kyung-Soo .
TOXICOLOGY IN VITRO, 2018, 52 :235-242
[25]   The porin VDAC2 is the mitochondrial platform for Bax retrotranslocation [J].
Lauterwasser, Joachim ;
Todt, Franziska ;
Zerbes, Ralf M. ;
Thanh Ngoc Nguyen ;
Craigen, William ;
Lazarou, Michael ;
van der Laan, Martin ;
Edlich, Frank .
SCIENTIFIC REPORTS, 2016, 6
[26]   Silver nanoparticles induce SH-SY5Y cell apoptosis via endoplasmic reticulum- and mitochondrial pathways that lengthen endoplasmic reticulum-mitochondria contact sites and altelr inositol-3-phosphate receptor function [J].
Li, Lin ;
Cui, Jiahui ;
Liu, Zi ;
Zhou, Xuejiao ;
Li, Zengqiang ;
Yu, Yang ;
Jia, Yuanyuan ;
Zuo, Daiying ;
Wu, Yingliang .
TOXICOLOGY LETTERS, 2018, 285 :156-167
[27]   In Vitro Response of Immune Cells on Metal Oxide Nanoparticles with Different Solubility [J].
Liang, Zhongyan ;
Zhang, Fengbin ;
Zhang, Hua .
JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY, 2016, 16 (06) :5546-5552
[28]   Applications and Potential Toxicity of Magnetic Iron Oxide Nanoparticles [J].
Liu, Gang ;
Gao, Jinhao ;
Ai, Hua ;
Chen, Xiaoyuan .
SMALL, 2013, 9 (9-10) :1533-1545
[29]   Endoplasmic reticulum stress eIF2α-ATF4 pathway-mediated cyclooxygenase-2 induction regulates cadmium-induced autophagy in kidney [J].
Luo, B. ;
Lin, Y. ;
Jiang, S. ;
Huang, L. ;
Yao, H. ;
Zhuang, Q. ;
Zhao, R. ;
Liu, H. ;
He, C. ;
Lin, Z. .
CELL DEATH & DISEASE, 2016, 7 :e2251-e2251
[30]   Vitexin inhibits Aβ25-35 induced toxicity in Neuro-2a cells by augmenting Nrf-2/HO-1 dependent antioxidant pathway and regulating lipid homeostasis by the activation of LXR-α [J].
Malar, Dicson Sheeja ;
Suryanarayanan, Venkatesan ;
Prasanth, Mani Iyer ;
Singh, Sanjeev Kumar ;
Balamurugan, Krishnaswamy ;
Devi, Kasi Pandima .
TOXICOLOGY IN VITRO, 2018, 50 :160-171