“Regulation of iron metabolism: Deciphering the biological functions of the iron responsive element of divalent-metal transporter 1”

“铁代谢的调节：破译二价金属转运蛋白 1 铁反应元件的生物学功能”

• 批准号: 402801855
• 负责人: Dr. Bruno Galy, Ph.D.
• 金额: --
• 依托单位: Abteilung Virus-assoziierte Karzinogenese
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/402801855?language=en
• 关键词: Regulation; iron; metabolism; Deciphering; biological

Iron is a co-factor required for numerous metabolic processes but toxic when present in excess, and imbalances of iron metabolism account for some of the most common diseases. Extensive research during the last two decades has uncovered key molecules of iron homeostasis. Among those molecules, the transmembrane proton-coupled iron importer DMT1 (divalent metal transporter 1) was shown to be essential for dietary iron assimilation as well as for iron acquisition by erythroid cells. To prevent both iron insufficiency and excess, the expression of DMT1 must be controlled very tightly. In mammals, cellular iron homeostasis is orchestrated by the iron regulatory proteins (IRP)-1 and -2, which control the fate of iron metabolism mRNAs by binding to cis-regulatory RNA structures named iron-responsive elements (IRE). The DMT1 mRNA bears a single, non-canonical IRE in its 3’ untranslated region, and is thus potentially regulated by the IRPs. However, the lack of adequate animal models has so far hampered a better comprehension of the in vivo functions of the DMT1 IRE. To fill this gap, we have created a mouse line with selective disruption of the 3’IRE of DMT1, which represents the first animal model with targeted mutagenesis of such RNA motifs. Our preliminary work indicates that the IRE of DMT1 is required for normal erythropoiesis and to prevent systemic iron overload in young adult mice maintained under standard laboratory conditions. Based on a detailed exploration of tissular and serological iron metabolism parameters, a study of hematological parameters, and a molecular analysis of iron metabolism genes, we propose to determine the cause of the iron imbalance observed in young adult DMT1-mutant mice. In addition, we will examine the iron phenotype at other stages of life asociated with distinct iron metabolism characteristics, more precisely during perinatal life when mice have high iron needs and rely on maternal milk, and in aged animals with high iron stores and feeding on a normal diet. Furthermore, we will assess whether and how the IRE of DMT1 impacts on the adaptative responses of the iron homeostasis machinery to fluctuations in dietary iron availability and in conditions of stress erythropoiesis. With this work we wish to unveil new facets of an essential iron transporter in the cell, and enhance our understanding of the role of posttranscriptional control mechanisms in metabolic regulations.

铁是许多代谢过程所需的辅助因子，但过量时会产生毒性，并且铁代谢失衡是一些最常见疾病的原因，在这些分子中发现了铁稳态的关键分子。跨膜质子耦合铁输入蛋白 DMT1（二价金属转运蛋白 1）被证明对于膳食铁同化以及红细胞获取铁至关重要。无论是不足还是过量，DMT1 的表达都必须受到严格控制。在哺乳动物中，细胞铁稳态是由铁调节蛋白 (IRP)-1 和 -2 协调的，它们通过与顺式调节蛋白结合来控制铁代谢 mRNA 的命运。称为铁反应元件 (IRE) 的 RNA 结构 DMT1 mRNA 在其 3' 非翻译区具有单个非规范 IRE，因此可能受到 IRP 的调节。然而，迄今为止，缺乏足够的动物模型阻碍了对 DMT1 IRE 体内功能的更好理解。为了填补这一空白，我们创建了一个选择性破坏 DMT1 3'IRE 的小鼠品系，它代表了 DMT1 的 3'IRE。我们的初步工作表明，在标准实验室条件下维持的年轻成年小鼠中，DMT1 的 IRE 是正常红细胞生成和防止全身铁超载所必需的。通过组织和血清铁代谢参数、血液学参数研究以及铁代谢基因的分子分析，我们建议确定在年轻成年 DMT1 突变小鼠中观察到的铁失衡的原因。此外，我们将检查铁表型。在与独特的铁代谢特征相关的生命的其他阶段，更确切地说，在围产期，当小鼠具有高铁需求并依赖母乳时，以及在铁储存量高且以正常饮食喂养的老年动物中，此外，我们将评估是否。以及如何DMT1 的 IRE 影响铁稳态机制对膳食铁可用性波动和应激红细胞生成条件的适应性反应，我们希望揭示细胞中重要铁转运蛋白的新方面，并增强我们对铁转运蛋白的了解。转录后控制机制在代谢调节中的作用。

项目成果

IRE-dependent Regulation of Intestinal Dmt1 Prevails During Chronic Dietary Iron Deficiency but is Dispensable in Conditions of Acute Erythropoietic Stress

肠道 Dmt1 的 IRE 依赖性调节在慢性膳食缺铁期间普遍存在，但在急性红细胞生成应激情况下是可有可无的

• DOI: 10.1097/hs9.0000000000000693
• 发表时间: 2022-03
• 期刊: HemaSphere
• 影响因子: 6.6
• 作者: Qatato M;Bonadonna M;Palais G;Ertl A;Schmidt G;Polycarpou-Schwarz M;Karim Z;Galy B
• 通讯作者: Galy B

Control of Systemic Iron Homeostasis by the 3’ Iron-Responsive Element of Divalent Metal Transporter 1 in Mice

小鼠体内二价金属转运蛋白 1 的 3â 铁响应元件对全身铁稳态的控制

• DOI: 10.1097/hs9.0000000000000459
• 发表时间: 2020-10
• 期刊: HemaSphere
• 影响因子: 6.6
• 作者: Tybl E;Gunshin H;Gupta S;Barrientos T;Bonadonna M;Celma Nos F;Palais G;Karim Z;Sanchez M;Andrews NC;Galy B
• 通讯作者: Galy B