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Ferritinophagy Is Critical for Deoxynivalenol-Induced Liver Injury in Mice
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-03-19 , DOI: 10.1021/acs.jafc.4c00556 Junze Jiang 1 , Yongbao Ruan 1 , Xiaohui Liu 1 , Jun Ma 1, 2 , Hao Chen 3
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2024-03-19 , DOI: 10.1021/acs.jafc.4c00556 Junze Jiang 1 , Yongbao Ruan 1 , Xiaohui Liu 1 , Jun Ma 1, 2 , Hao Chen 3
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Background: Deoxynivalenol (DON) contamination, pervasive throughout all stages of food production and processing, presents a significant threat to human health. The degradation of ferritin mediated by nuclear receptor coactivator 4 (NCOA4), termed ferritinophagy, plays a crucial role in maintaining iron homeostasis and regulating ferroptosis. Aim: This study aims to elucidate the role of ferritinophagy and ferroptosis in DON-induced liver injury. Methods: Male mice and AML12 cells were subjected to varying doses of DON, serving as in vivo and in vitro models, respectively. Protein expression was assessed by using immunofluorescence and western blot techniques. Co-immunoprecipitation was employed to investigate the protein–protein interactions. Results: Our findings demonstrate that DON triggers hepatocyte ferroptosis in a ferritinophagy-dependent manner. Specifically, DON impedes the activation of the mammalian target of rapamycin complex 1 (mTORC1) by inhibiting RAC1’s binding to mTOR, thereby ultimately inducing autophagy. Concurrently, DON amplifies NCOA4’s affinity for ferritin by facilitating NCOA4 phosphorylation through the ataxia-telangiectasia mutated kinase (ATM), thus promoting the autophagy-dependent degradation of ferritin. Both autophagy inhibition and NCOA4 expression suppression ameliorate DON-induced ferroptosis. Conclusion: Our study concludes that DON facilitates NCOA4-mediated ferritinophagy via the ATM–NCOA4 pathway, subsequently inducing ferroptosis in the liver.
中文翻译：
铁蛋白吞噬对于脱氧雪腐镰刀菌烯醇诱导的小鼠肝损伤至关重要
背景：脱氧雪腐镰刀菌烯醇 (DON) 污染普遍存在于食品生产和加工的各个阶段，对人类健康构成重大威胁。由核受体共激活剂 4 (NCOA4) 介导的铁蛋白降解（称为铁蛋白自噬）在维持铁稳态和调节铁死亡中发挥着至关重要的作用。目的：本研究旨在阐明铁蛋白自噬和铁死亡在 DON 诱导的肝损伤中的作用。方法：雄性小鼠和 AML12 细胞接受不同剂量的 DON，分别作为体内和体外模型。通过使用免疫荧光和蛋白质印迹技术评估蛋白质表达。采用免疫共沉淀研究蛋白质-蛋白质相互作用。结果：我们的研究结果表明，DON 以铁蛋白吞噬依赖性方式触发肝细胞铁死亡。具体来说，DON 通过抑制 RAC1 与 mTOR 的结合来阻碍哺乳动物雷帕霉素复合物 1 (mTORC1) 的激活，从而最终诱导自噬。同时，DON 通过共济失调毛细血管扩张突变激酶 (ATM) 促进 NCOA4 磷酸化，从而放大 NCOA4 对铁蛋白的亲和力，从而促进铁蛋白的自噬依赖性降解。自噬抑制和 NCOA4 表达抑制均可改善 DON 诱导的铁死亡。结论：我们的研究得出结论，DON 通过 ATM-NCOA4 途径促进 NCOA4 介导的铁蛋白自噬，随后诱导肝脏铁死亡。
更新日期：2024-03-19
中文翻译：
铁蛋白吞噬对于脱氧雪腐镰刀菌烯醇诱导的小鼠肝损伤至关重要
背景：脱氧雪腐镰刀菌烯醇 (DON) 污染普遍存在于食品生产和加工的各个阶段，对人类健康构成重大威胁。由核受体共激活剂 4 (NCOA4) 介导的铁蛋白降解（称为铁蛋白自噬）在维持铁稳态和调节铁死亡中发挥着至关重要的作用。目的：本研究旨在阐明铁蛋白自噬和铁死亡在 DON 诱导的肝损伤中的作用。方法：雄性小鼠和 AML12 细胞接受不同剂量的 DON，分别作为体内和体外模型。通过使用免疫荧光和蛋白质印迹技术评估蛋白质表达。采用免疫共沉淀研究蛋白质-蛋白质相互作用。结果：我们的研究结果表明，DON 以铁蛋白吞噬依赖性方式触发肝细胞铁死亡。具体来说，DON 通过抑制 RAC1 与 mTOR 的结合来阻碍哺乳动物雷帕霉素复合物 1 (mTORC1) 的激活，从而最终诱导自噬。同时，DON 通过共济失调毛细血管扩张突变激酶 (ATM) 促进 NCOA4 磷酸化，从而放大 NCOA4 对铁蛋白的亲和力，从而促进铁蛋白的自噬依赖性降解。自噬抑制和 NCOA4 表达抑制均可改善 DON 诱导的铁死亡。结论：我们的研究得出结论，DON 通过 ATM-NCOA4 途径促进 NCOA4 介导的铁蛋白自噬，随后诱导肝脏铁死亡。
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