Institut für Zytobiologie und Zytopathologie, 35032 Marburg, Germany.
Fachbereich Chemie, Philipps-Universität Marburg, 35032 Marburg, Germany.
Cell Metab. 2010 Oct 6;12(4):373-385. doi: 10.1016/j.cmet.2010.08.001.
Iron is an essential nutrient for cells. It is unknown how iron, after its import into the cytosol, is specifically delivered to iron-dependent processes in various cellular compartments. Here, we identify an essential function of the conserved cytosolic monothiol glutaredoxins Grx3 and Grx4 in intracellular iron trafficking and sensing. Depletion of Grx3/4 specifically impaired all iron-requiring reactions in the cytosol, mitochondria, and nucleus, including the synthesis of Fe/S clusters, heme, and di-iron centers. These defects were caused by impairment of iron insertion into proteins and iron transfer to mitochondria, indicating that intracellular iron is not bioavailable, despite highly elevated cytosolic levels. The crucial task of Grx3/4 is mediated by a bridging, glutathione-containing Fe/S center that functions both as an iron sensor and in intracellular iron delivery. Collectively, our study uncovers an important role of monothiol glutaredoxins in cellular iron metabolism, with a surprising connection to cellular redox and sulfur metabolisms.
铁是细胞必需的营养物质。目前尚不清楚铁进入细胞质后，如何特异性地递送到各种细胞区室中的铁依赖性过程。在这里，我们发现保守的胞质单硫醇谷胱甘肽还原酶 Grx3 和 Grx4 在细胞内铁运输和感应中具有重要功能。Grx3/4 的耗竭特异性地损害了细胞质、线粒体和核中的所有铁需求反应，包括 Fe/S 簇、血红素和二铁中心的合成。这些缺陷是由于铁插入蛋白和铁向线粒体转移的受损引起的，表明尽管细胞质中的铁水平非常高，但细胞内的铁是不可用的。Grx3/4 的关键任务是通过含有谷胱甘肽的 bridging、Fe/S 中心介导的，该中心既作为铁传感器，又在细胞内铁递送上发挥作用。总的来说，我们的研究揭示了单硫醇谷胱甘肽还原酶在细胞铁代谢中的重要作用，与细胞氧化还原和硫代谢有惊人的联系。
