Gattermann N, Retzlaff S, Wang Y L, Hofhaus G, Heinisch J, Aul C, Schneider W
Department of Hematology, Oncology, and Clinical Immunology, Institute of Biochemistry, Heinrich-Heine-University, Düsseldorf, Germany.
Blood. 1997 Dec 15;90(12):4961-72.
Mitochondrial iron overload in acquired idiopathic sideroblastic anemia (AISA) may be attributable to mutations of mitochondrial DNA (mtDNA), because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron (Fe3+) to ferrous iron (Fe2+). The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis. It is not yet understood to which part of the respiratory chain the reduction of ferric iron is linked. In two patients with AISA we identified point mutations of mtDNA affecting the same transmembrane helix within subunit I of cytochrome c oxidase (COX I; ie, complex IV of the respiratory chain). The mutations were detected by restriction fragment length polymorphism analysis and temperature gradient gel electrophoresis. One of the mutations involves a T --> C transition in nucleotide position 6742, causing an amino acid change from methionine to threonine. The other mutation is a T --> C transition at nt 6721, changing isoleucine to threonine. Both amino acids are highly conserved in a wide range of species. Both mutations are heteroplasmic, ie, they establish a mixture of normal and mutated mitochondrial genomes, which is typical of disorders of mtDNA. The mutations were present in bone marrow and whole blood samples, in isolated platelets, and in granulocytes, but appeared to be absent from T and B lymphocytes purified by immunomagnetic bead separation. They were not detected in buccal mucosa cells obtained by mouthwashes and in cultured skin fibroblasts examined in one of the patients. In both patients, this pattern of involvement suggests that the mtDNA mutation occurred in a self-renewing bone marrow stem cell with myeloid determination. Identification of two point mutations with very similar location suggests that cytochrome c oxidase plays an important role in the pathogenesis of AISA. COX may be the physiologic site of iron reduction and transport through the inner mitochondrial membrane.
获得性特发性铁粒幼细胞贫血（AISA）中的线粒体铁过载可能归因于线粒体DNA（mtDNA）突变，因为这些突变可导致呼吸链功能障碍，从而损害三价铁（Fe3+）向二价铁（Fe2+）的还原。还原形式的铁对于线粒体血红素生物合成的最后一步至关重要。目前尚不清楚三价铁的还原与呼吸链的哪一部分相关。在两名AISA患者中，我们鉴定出mtDNA的点突变，这些突变影响细胞色素c氧化酶（COX I；即呼吸链复合体IV）亚基I内的同一跨膜螺旋。通过限制性片段长度多态性分析和温度梯度凝胶电泳检测到这些突变。其中一个突变涉及核苷酸位置6742处的T→C转换，导致氨基酸从甲硫氨酸变为苏氨酸。另一个突变是核苷酸6721处的T→C转换，将异亮氨酸变为苏氨酸。这两种氨基酸在广泛的物种中高度保守。两种突变都是异质性的，即它们形成了正常和突变的线粒体基因组的混合物，这是mtDNA疾病的典型特征。这些突变存在于骨髓和全血样本、分离的血小板和粒细胞中，但在通过免疫磁珠分离纯化的T和B淋巴细胞中似乎不存在。在通过漱口获得的颊黏膜细胞和其中一名患者检测的培养皮肤成纤维细胞中未检测到这些突变。在两名患者中，这种受累模式表明mtDNA突变发生在具有髓系定向的自我更新骨髓干细胞中。鉴定出两个位置非常相似的点突变表明细胞色素c氧化酶在AISA的发病机制中起重要作用。COX可能是铁还原和通过线粒体内膜转运的生理位点。
