Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos, Consejo Superior de Investigaciones Científicas, 46980 Paterna, Valencia, Spain.
Proc Natl Acad Sci U S A. 2018 Jul 3;115(27):E6291-E6300. doi: 10.1073/pnas.1804701115. Epub 2018 Jun 18.
Cells respond to iron deficiency by activating iron-regulatory proteins to increase cellular iron uptake and availability. However, it is not clear how cells adapt to conditions when cellular iron uptake does not fully match iron demand. Here, we show that the mRNA-binding protein tristetraprolin (TTP) is induced by iron deficiency and degrades mRNAs of mitochondrial Fe/S-cluster-containing proteins, specifically in complex I and in complex III, to match the decrease in Fe/S-cluster availability. In the absence of TTP, levels are not decreased in iron deficiency, resulting in nonfunctional complex III, electron leakage, and oxidative damage. Mice with deletion of display cardiac dysfunction with iron deficiency, demonstrating that TTP is necessary for maintaining cardiac function in the setting of low cellular iron. Altogether, our results describe a pathway that is activated in iron deficiency to regulate mitochondrial function to match the availability of Fe/S clusters.
细胞通过激活铁调节蛋白来响应缺铁，以增加细胞内铁的摄取和可用性。然而，目前尚不清楚细胞如何适应细胞铁摄取不能完全满足铁需求的情况。在这里，我们发现 RNA 结合蛋白 tristetraprolin（TTP）在缺铁时被诱导，其可降解含有线粒体 Fe/S 簇的蛋白质的 mRNA，特别是复合物 I 和复合物 III 中的 和 ，以匹配 Fe/S 簇可用性的降低。在缺乏 TTP 的情况下， 在缺铁时不会减少，导致复合物 III 功能失调、电子泄漏和氧化损伤。缺乏 的小鼠在缺铁时表现出心脏功能障碍，这表明 TTP 对于维持低细胞铁状态下的心脏功能是必需的。总之，我们的研究结果描述了一条在缺铁时被激活的途径，该途径可调节线粒体功能以匹配 Fe/S 簇的可用性。
