Unique iron binding and oxidation properties of human mitochondrial ferritin: A comparative analysis with human H-chain ferritin
Unique iron binding and oxidation properties of human mitochondrial ferritin: A comparative analysis with human H-chain ferritin
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DOI：
10.1016/j.jmb.2005.01.007
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发表时间：
2005-04-01
影响因子：
5.6
通讯作者：
Chasteen, ND
中科院分区：
文献类型：
--
作者：
Bou-Abdallah, F;Santambrogio, P;Chasteen, ND
铁蛋白是一种普遍存在的铁矿化和储存蛋白，在铁稳态中发挥着重要作用。虽然多余的铁储存在细胞质中，但大多数代谢活跃的铁是在细胞的线粒体中处理的。人们对这些细胞器如何调节铁的动态平衡和毒性知之甚少。新近发现的人线粒体铁蛋白(MTF)与其他哺乳动物铁蛋白不同，是一种由24个亚基组成的均聚体，与人H链铁蛋白(HUHF)具有高度的序列同源性。本文报道的MTF和HUHF的平行实验表明，尽管它们的铁氧化铁酶中心相似，但它们的铁氧化和水解化学存在显著差异。与HUHF不同的是，MTF在其初始补充Fe(II)氧化后不会再生其铁氧合酶活性，而且通常也具有相当慢的铁氧化和矿化活性。MTF的矿化动力学表现出更多的L链特征，而不是H链铁蛋白。定点突变表明，丝氨酸144是这种活性受损的一个参与者，它位于MTF铁氧基酶中心附近，但HUHF中没有丝氨酸144。此外，MTF的24个铁氧基酶中心中只有一半是功能的，这进一步导致了其活性较低。在MTF中，O-2氧化Fe(II)的停流吸收光谱表明，在HUHF中，以O-2为氧化剂，在MTF中铁的氧化沉积过程中，生成了瞬时的双铁(III)过氧物种(gimel(Max)=650 nm)。然而，在HUHF中发现的2Fe(II)+H_2O_2解毒反应在MTF中没有发生。根据这些结果，讨论了MTF独特的铁氧化特性的结构差异和生理意义。(C)2005爱思唯尔有限公司。保留所有权利。
Ferritins are ubiquitous iron mineralizing and storage proteins that play an important role in iron homeostasis. Although excess iron is stored in the cytoplasm, most of the metabolically active iron is processed in the mitochondria of the cell. Little is known about how these organelles regulate iron homeostasis and toxicity. The recently discovered human mitochondrial ferritin (MtF), unlike other mammalian ferritins, is a homopolymer of 24 subunits that has a high degree of sequence homology with human H-chain ferritin (HuHF). Parallel experiments with MtF and HuHF reported here reveal striking differences in their iron oxidation and hydrolysis chemistry despite their similar diFe ferroxidase centers. In contrast to HuHF, MtF does not regenerate its ferroxidase activity after oxidation of its initial complement of Fe(II) and generally has considerably slower ferroxidation and mineralization activities as well. MtF exhibits sigmoidal kinetics of mineralization more characteristic of an L-chain than an H-chain ferritin. Site-directed mutagenesis reveals that serine 144, a residue situated near the ferroxidase center in MtF but absent from HuHF, is one player in this impairment of activity. Additionally only one-half of the 24 ferroxidase centers of MtF are functional, further contributing to its lower activity. Stopped-flow absorption spectrometry of Fe(II) oxidation by O-2 in MtF shows the formation of a transient diiron(III) mu-peroxo species (gimel(max) = 650 nm) as observed in HuHE Also, as for HuHF, minimal hydroxyl radical is produced during the oxidative deposition of iron in MtF using O-2 as the oxidant. However, the 2Fe(II) + H2O2 detoxification reaction found in HuHF does not occur in MtF. The structural differences and the physiological implications of the unique iron oxidation properties of MtF are discussed in light of these results. (c) 2005 Elsevier Ltd. All rights reserved.