SOD2-deficiency anemia:: protein oxidation and altered protein expression reveal targets of damage, stress response, and antioxidant responsiveness
SOD2-deficiency anemia:: protein oxidation and altered protein expression reveal targets of damage, stress response, and antioxidant responsiveness
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DOI：
10.1182/blood-2003-11-3858
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发表时间：
2004-10-15
期刊：
影响因子：
20.3
通讯作者：
Burakoff, SJ
中科院分区：
文献类型：
--
作者：
Friedman, JS;Lopez, MF;Burakoff, SJ
Sod2是一种抗氧化蛋白质，可以保护细胞免受线粒体超氧化物的伤害。缺乏SOD2的造血干细胞(HSCs)能够挽救受到致命性照射的宿主，但重组动物表现出一种持续性溶血性贫血，其特征是对红细胞的氧化损伤增加，其形态类似于人类的铁粒母细胞贫血。我们报告了这种新的SOD2缺乏性贫血的进一步特征。SOD2缺陷型网织红细胞的电子显微镜下可见明显的线粒体增殖和线粒体膜增厚。外周血涂片显示成熟红细胞(铁血球)中有丰富的铁染色颗粒。用氧化敏感染料标记的细胞的荧光激活细胞分选(FACS)分析表明，SOD2缺陷细胞产生的超氧化物和过氧化氢增加。在SOD2缺乏的细胞中，对蛋白质的氧化损伤增加，大部分损伤影响到膜/不溶性蛋白质。红细胞蛋白质组分析表明，在SOD2缺乏的细胞中，参与折叠/伴侣功能、氧化还原调节、三磷酸腺苷(ATP)合成和红细胞代谢的几种蛋白质的表达发生了变化。这些数据与抗氧化剂治疗后蛋白质表达水平如何变化的信息相结合，将有助于在该模型中识别对氧化损伤敏感的蛋白质，进而可能在调节其他溶血性疾病的红细胞寿命方面发挥作用。
SOD2 is an antioxidant protein that protects cells against mitochondrial superoxide. Hematopoietic stem cells (HSCs) lacking SOD2 are capable of rescuing lethally irradiated hosts, but reconstituted animals display a persistent hemolytic anemia characterized by increased oxidative damage to red cells, with morphologic similarity to human "sideroblastic" anemia. We report further characterization of this novel SOD2-deficiency anemia. Electron micrographs of SOD2-deficient reticulocytes reveal striking mitochondrial proliferation and mitochondrial membrane thickening. Peripheral blood smears show abundant iron-stainable granules in mature red cells (siderocytes). Fluorescence-activated cell sorting (FACS) analysis of cells labeled with oxidation-sensitive dyes demonstrates enhanced production of superoxide and hydrogen peroxide by SOD2-deficient cells. Oxidative damage to proteins is increased in SOD2-deficient cells, with much of the damage affecting membrane/insoluble proteins. Red cell proteome analysis demonstrates that several proteins involved in folding/chaperone function, redox regulation, adenosine triphosphate (ATP) synthesis, and red cell metabolism show altered expression in SOD2-deficient cells. This data, combined with information on how protein expression levels change upon antioxidant therapy, will aid in identification of proteins that are sensitive to oxidative damage in this model, and by extension, may have a role in the regulation of red cell lifespan in other hemolytic disorders.