Copper deficiency- induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells
Copper deficiency- induced anemia is caused by a mitochondrial metabolic reprograming in erythropoietic cells
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DOI：
10.1039/c8mt00224j
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发表时间：
2019-02-01
期刊：
影响因子：
3.4
通讯作者：
Elorza, Alvaro A.
中科院分区：
文献类型：
--
作者：
Jensen, Erik L.;Gonzalez-Ibanez, Alvaro M.;Elorza, Alvaro A.
铜的缺乏与贫血、骨髓增生异常综合征和白血病以及复合物IV活性的丧失和线粒体形态的扩大有关。线粒体通过调节糖酵解代谢向氧化代谢的转变，在造血干细胞的分化过程中发挥关键作用。前者与细胞增殖有关，后者与细胞分化有关。氧化代谢发生在线粒体内，由呼吸链维持，其中复合物IV是铜依赖性的。我们假设，铜缺乏诱导线粒体代谢重编程，有利于红细胞生成中的细胞扩增而不是细胞分化。对喂食缺铜饮食的小鼠骨髓的红细胞系进展分析以及用浴铜灵（铜螯合剂）处理的人CD 34+细胞的体外红细胞生成分析显示，祖细胞大量扩增，分化减少。与对照组相比，铜缺乏时线粒体膜电位升高，耗氧速率降低，活性氧水平降低。此外，线粒体生物量增加，线粒体融合蛋白mitofusin 2上调。大多数铜缺乏的表型被模仿的药理学抑制复合物IV与叠氮化物。我们的结论是，铜缺乏诱导线粒体代谢重编程，使造血干细胞有利于祖细胞扩增细胞分化。
The lack of copper has been associated with anemia, myelodysplastic syndromes and leukemia as well as with a loss in complex IV activity and an enlarged mitochondrial morphology. Mitochondria play a key role during the differentiation of hematopoietic stem cells by regulating the passage from a glycolytic to oxidative metabolism. The former is associated with cell proliferation and the latter with cell differentiation. Oxidative metabolism, which occurs inside mitochondria, is sustained by the respiratory chain, where complex IV is copper-dependent. We have hypothesized that a copper deficiency induces a mitochondrial metabolic reprogramming, favoring cell expansion over cell differentiation in erythropoiesis. Erythroid progression analysis of the bone marrow of mice fed with a copper deficient diet and of the in vitro erythropoiesis of human CD34+ cells treated with a bathocuproine - a copper chelator - showed a major expansion of progenitor cells and a decreased differentiation. Under copper deficiency, mitochondria switched to a higher membrane potential, lower oxygen consumption rate and lower ROS levels as compared with control cells. In addition, mitochondrial biomass was increased and an up-regulation of the mitochondrial fusion protein mitofusin 2 was observed. Most copper-deficient phenotypes were mimicked by the pharmacological inhibition of complex IV with azide. We concluded that copper deficiency induced a mitochondrial metabolic reprogramming, making hematopoietic stem cells favor progenitor cell expansion over cell differentiation.