期刊
NANOTOXICOLOGY
卷 14, 期 2, 页码 162-180出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/17435390.2019.1683245
关键词
Superparamagnetic iron oxide nanoparticles; cyclooxygenase-2; mitochondria-associated endoplasmic reticulum membranes; interorganelle Ca2+ transfer; hepatotoxicity
资金
- National Natural Science Foundation of China [81773465, 81573181, 81874272, 81472997]
- Natural Science Foundation of Fujian Province of China [2014J01372, 2015J01344]
- Regional Demonstration of Marine Economy Innovative Development Project [16PYY007SF17]
- Scientific Research Foundation of State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics [2017ZY003]
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.
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