Pantopoulos K, Hentze M W
Gene Expression Programme, European Molecular Biology Laboratory, Heidelberg, Germany.
EMBO J. 1995 Jun 15;14(12):2917-24. doi: 10.1002/j.1460-2075.1995.tb07291.x.
Reactive oxygen intermediates (ROIs), including superoxide anion (O2.-) and hydrogen peroxide (H2O2), are by-products of aerobic metabolism with potential toxicity towards cellular macromolecules, including lipids, proteins and DNA. Excess ROIs, a condition referred to as oxidative stress, is considered to be a major contributor to ageing, degenerative diseases and reperfusion injury. The reactivity of H2O2 with iron (Fenton reaction) intimately connects oxidative stress and cellular iron metabolism. We have found a novel oxidative stress response pathway in mammalian cells which links oxidative stress to the regulation of iron metabolism. Exposure of cells to H2O2 leads to reduced synthesis of the intracellular iron storage protein ferritin and stimulates transferrin receptor (TfR) mRNA expression. Both responses are post-transcriptional and result from induction of iron regulatory protein (IRP) binding to iron-responsive elements (IREs) in ferritin and TfR mRNAs. IRP induction by H2O2 appears to involve the disassembly of its cubane 4Fe-4S cluster and occurs even in the presence of the protein synthesis inhibitor cycloheximide. The induction kinetics by H2O2 far exceed those by iron starvation. The response requires cellular integrity and cannot be elicited in cell extracts. Whereas the activation of IRP by iron depletion is insensitive to okadaic acid, the rapid induction by H2O2 is blocked by this inhibitor of type I/IIa protein phosphatases. Thus okadaic acid separates the activation pathways by iron depletion and oxidative stress, suggesting the involvement of stress-induced kinase/phosphatase pathways in the latter.
活性氧中间体（ROIs），包括超氧阴离子（O2.-）和过氧化氢（H2O2），是有氧代谢的副产物，对细胞大分子（包括脂质、蛋白质和DNA）具有潜在毒性。过量的ROIs，即氧化应激状态，被认为是衰老、退行性疾病和再灌注损伤的主要促成因素。H2O2与铁的反应（芬顿反应）将氧化应激与细胞铁代谢紧密联系起来。我们在哺乳动物细胞中发现了一条新的氧化应激反应途径，该途径将氧化应激与铁代谢的调节联系起来。细胞暴露于H2O2会导致细胞内铁储存蛋白铁蛋白的合成减少，并刺激转铁蛋白受体（TfR）mRNA的表达。这两种反应都是转录后反应，是由铁调节蛋白（IRP）与铁蛋白和TfR mRNA中的铁反应元件（IREs）结合诱导产生的。H2O2诱导IRP似乎涉及到其立方烷4Fe-4S簇的解体，即使在存在蛋白质合成抑制剂环己酰亚胺的情况下也会发生。H2O2的诱导动力学远远超过铁饥饿的诱导动力学。该反应需要细胞完整性，在细胞提取物中无法引发。虽然铁缺乏激活IRP对冈田酸不敏感，但H2O2的快速诱导被这种I/IIa型蛋白磷酸酶抑制剂阻断。因此，冈田酸将铁缺乏和氧化应激的激活途径分开，表明应激诱导的激酶/磷酸酶途径参与了后者。
