Aberrant iron accumulation and oxidized status of erythroid-specific δ-aminolevulinate synthase (ALAS2)-deficient definitive erythroblasts
Aberrant iron accumulation and oxidized status of erythroid-specific δ-aminolevulinate synthase (ALAS2)-deficient definitive erythroblasts
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DOI：
10.1182/blood-2002-01-0309
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发表时间：
2003-02-01
期刊：
影响因子：
20.3
通讯作者：
Sassa, S
中科院分区：
文献类型：
--
作者：
Harigae, H;Nakajima, O;Sassa, S
Alas 2编码红系特异性δ-氨基乙酰丙酸合酶（ALAS 2或ALAS-E），其是红系细胞中血红素生物合成中的第一个酶。Alas 2-null表型的小鼠在其原始成红细胞中表现出大量的细胞质而非线粒体铁积累。由于这些动物在子宫内第11.5天死亡，因此无法使用体内模型研究定形成红细胞中的铁代谢。在这项研究中，胚胎干（ES）细胞缺乏的Alas 2基因诱导进行分化的最终成红细胞阶段的文化，和Alas 2无效的最终成红细胞的表型进行了检查。Alas 2无效的定形成红细胞细胞团是完全无色的，由于显着缺乏血红素，虽然它们的细胞形态是类似的野生型成红细胞。Alas 2缺失的定形成红细胞中红细胞特异性基因的表达水平也与野生型成红细胞相似。这些发现表明，Alas 2-null定形成红细胞发育到与野生型成红细胞相似的阶段，其也显示出与体内骨髓成红细胞非常相似。相比之下，Alas 2-null的定形成红细胞含有15倍以上的非血红素铁比野生型成红细胞，电子显微镜发现这种铁分布在细胞质中，但不在线粒体。与铁的异常增加一致，Alas 2-null定形成红细胞比野生型成红细胞更过氧化。这些发现表明ALAS 2缺乏本身并不干扰定形红系细胞的发育，但它导致成红细胞中铁的大量积累和过氧化状态。(C)2003年，美国血液学会。
Alas2 encodes the erythroid-specific delta-aminolevulinate synthase (ALAS2 or ALAS-E), the first enzyme in heme biosynthesis in erythroid cells. Mice with the Alas2-null phenotype showed massive cytoplasmic, but not mitochondrial, iron accumulation in their primitive erythroblasts. Because these animals died by day 11.5 in utero, studies of iron metabolism in definitive erythroblasts were not possible using the in vivo model. In this study, embryonic stem (ES) cells lacking the Alas2 gene were induced to undergo differentiation to the definitive erythroblast stage in culture, and the phenotype of Alas2-null definitive erythroblasts was examined. Alas2-null definitive erythroblasts cell pellets were entirely colorless due to a marked deficiency of heme, although their cell morphology was similar to that of the wild-type erythroblasts. The level of expression of erythroid-specific genes in Alas2-null definitive erythroblasts was also similar to that of the wild-type erythroblasts. These findings indicate that Alas2-null definitive erythroblasts developed to a stage similar to that of the wild-type erythroblasts, which were also shown to be very similar to the bone marrow erythroblasts in vivo. In contrast, Alas2-null definitive erythroblasts contained 15 times more nonheme iron than did the wild-type erythroblasts, and electron microscopy found this iron to be distributed in the cytoplasm but not in mitochondria. Consistent with the aberrant increase in iron, Alas2-null definitive erythroblasts were more peroxidized than wild-type erythroblasts. These findings suggest that ALAS2 deficiency itself does not interfere with the development of definitive erythroid cells, but it results in a profound iron accumulation and a peroxidized state in erythroblasts. (C) 2003 by The American Society of Hematology.