Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress
Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress
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DOI：
10.1016/j.freeradbiomed.2008.01.031
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发表时间：
2008-05-01
影响因子：
7.4
通讯作者：
Tsuji, Yoshiaki
中科院分区：
文献类型：
--
作者：
MacKenzie, Elizabeth L.;Ray, Paul D.;Tsuji, Yoshiaki
针对线粒体功能障碍而严格调节细胞内铁水平是防止氧化应激、从而限制细胞损伤的重要机制。在这里，我们描述了一种细胞保护反应，涉及铁蛋白 H 基因的转录激活，以响应线粒体复合物 I 抑制剂和神经毒性化合物鱼藤酮。鱼藤酮暴露增加了 NIH3T3 成纤维细胞和 SH-SY5Y 神经母细胞瘤细胞中铁蛋白 H mRNA 和蛋白质的合成。将铁蛋白 H 启动子-荧光素酶报告基因瞬时转染至 NIH3T3 细胞中，结果表明铁蛋白 H 通过抗氧化剂响应元件 (ARE) 被鱼藤酮转录激活。染色质免疫沉淀分析表明，鱼藤酮处理增强了 Nrf2 和 JunD 转录因子与 ARE 的结合。此外，鱼藤酮诱导活性氧 (ROS) 的产生，并且用 N-乙酰半胱氨酸预处理消除了鱼藤酮对铁蛋白 H mRNA 的诱导，表明这种反应是氧化应激介导的。此外，siRNA 降低铁蛋白 H 表达使细胞对鱼藤酮诱导的细胞凋亡敏感，同时增加 ROS 产生和膜联蛋白 V 阳性细胞。总而言之，这些结果表明，鱼藤酮通过氧化应激介导的途径激活铁蛋白 H 转录，从而导致 ARE 激活，并且可能对于保护细胞免受线粒体功能障碍和氧化应激至关重要。 (c) 2008 Elsevier Inc. 保留所有权利。
Tight regulation of intracellular iron levels in response to mitochondrial dysfunction is an important mechanism that prevents oxidative stress, thereby limiting cellular damage. Here, we describe a cytoprotective response involving transcriptional activation of the ferritin H gene in response to the mitochondrial complex I inhibitor and neurotoxic compound rotenone. Rotenone exposure increased ferritin H mRNA and protein synthesis in NIH3T3 fibroblasts and SH-SY5Y neuroblastoma cells. Transient transfection of a ferritin H promoter-luciferase reporter into NIH3T3 cells showed that ferritin H was transcriptionally activated by rotenone through an antioxidant-responsive element (ARE). Chromatin immunoprecipitation assays showed that rotenone treatment enhanced binding of Nrf2 and JunD transcription factors to the ARE. In addition, rotenone induced production of reactive oxygen species (ROS), and pretreatment with N-acetylcysteine abrogated ferritin H mRNA induction by rotenone, suggesting that this response is oxidative stress-mediated. Furthermore, reduced ferritin H expression by siRNA sensitized cells to rotenone-induced apoptosis with increased ROS production and annexin V-positive cells. Taken together, these results suggest that ferritin H transcription is activated by rotenone via an oxidative stress-mediated pathway leading to ARE activation and may be critically important to protect cells from mitochondrial dysfunction and oxidative stress. (c) 2008 Elsevier Inc. All rights reserved.