Manganese superoxide dismutase depletion in murine hematopoietic stem cells perturbs iron homeostasis, globin switching, and epigenetic control in erythrocyte precursor cells.
Manganese superoxide dismutase depletion in murine hematopoietic stem cells perturbs iron homeostasis, globin switching, and epigenetic control in erythrocyte precursor cells.
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DOI：
10.1016/j.freeradbiomed.2012.11.018
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发表时间：
2013-03
影响因子：
7.4
通讯作者：
Domann, Frederick E.
中科院分区：
文献类型：
--
作者：
Case, Adam J.;Madsen, Joshua M.;Motto, David G.;Meyerholz, David K.;Domann, Frederick E.
关键词：
血红素合成部分发生在线粒体基质中，因此在血红素生产中重要的酶和中间体很有可能暴露于包括活性氧的代谢副产物。此外，亚铁血红素的生产，Fe-S协调，和其他过程中发生的线粒体基质中的亚铁的需要表明，在这个隔间中的活性氧的异常流量可能会扰乱正常的铁稳态。锰超氧化物歧化酶（SOD 2）是一种抗氧化酶，控制线粒体基质中超氧化物的稳态水平。使用造血干细胞特异性条件性Sod 2基因敲除小鼠，我们观察到红细胞后代中超氧化物浓度增加，这导致显著的病理学，包括红细胞受损和亚铁螯合酶活性降低。在红系前体细胞中缺乏Sod 2表达的动物也表现出髓外造血和全身铁再分布。此外，红系前体细胞中超氧化物通量的增加导致造血转录因子、球蛋白和铁反应基因的基因调控异常。此外，红系前体细胞还显示组蛋白翻译后修饰的整体变化的证据，这可能是至少一些异常基因表达的原因。从治疗转化的角度来看，靶向的超氧化物清除抗氧化剂部分挽救了观察到的表型。总之，我们的研究结果阐明了红细胞前体细胞中正常铁稳态的超氧化物敏感性，并表明在哺乳动物红细胞生成过程中线粒体氧化还原代谢和核基因调控的表观遗传控制之间可能存在联系。
Heme synthesis partially occurs in the mitochondrial matrix, thus there is a high probability that enzymes and intermediates important in the production of heme will be exposed to metabolic byproducts including reactive oxygen species. In addition, the need for ferrous iron for heme production, Fe-S coordination, and other processes occurring in the mitochondrial matrix suggests that aberrant fluxes of reactive oxygen species in this compartment might perturb normal iron homeostasis. Manganese superoxide dismutase (Sod2) is an anti-oxidant enzyme that governs steady-state levels of the superoxide in the mitochondrial matrix. Using hematopoietic stem cell-specific conditional Sod2 knock-out mice we observed increased superoxide concentrations in red cell progeny which caused significant pathologies including impaired erythrocytes and decreased ferrochelatase activity. Animals lacking Sod2 expression in erythroid precursors also displayed extramedullary hematopoiesis and systemic iron redistribution. Additionally, the increase in superoxide flux in erythroid precursors caused abnormal gene regulation of hematopoietic transcription factors, globins, and iron-response genes. Moreover, the erythroid precursors also displayed evidence of global changes of histone post-translational modifications, a likely cause of at least some of the aberrant gene expression noted. From a therapeutic translational perspective, mitochondrially-targeted superoxide-scavenging anti-oxidants partially rescued the observed phenotype. Taken together, our findings illuminate the superoxide sensitivity of normal iron homeostasis in erythrocyte precursors and suggest a probable link between mitochondrial redox metabolism and epigenetic control of nuclear gene regulation during mammalian erythropoiesis.
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影响因子：
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