The expression of human mitochondrial ferritin rescues respiratory function infrataxin-deficient yeast
The expression of human mitochondrial ferritin rescues respiratory function infrataxin-deficient yeast
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DOI：
10.1093/hmg/ddh232
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发表时间：
2004-10-01
影响因子：
3.5
通讯作者：
Levi, S
中科院分区：
文献类型：
--
作者：
Campanella, A;Isaya, G;Levi, S
线粒体铁蛋白（MtF）在结构和功能上与胞质铁蛋白相似，胞质铁蛋白是设计用于储存和解毒细胞铁的分子。MtF在人类和小鼠中的表达仅限于睾丸和少数组织，并且在铁粒幼细胞性贫血患者的成红细胞中丰富，认为其保护线粒体免受铁负荷引起的损伤。线粒体铁过载也发生在缺乏共济失调蛋白的细胞中，共济失调蛋白是一种参与铁处理并与弗里德赖希共济失调有关的线粒体蛋白。我们在fraataxin缺陷的酵母细胞中表达人MtF，这是线粒体铁过载和氧化损伤的良好表征模型。人类MtF前体被酵母线粒体有效输入，并加工成功能性铁蛋白，可主动将铁螯合在细胞器中。MtF表达挽救了由共济失调蛋白的损失引起的呼吸缺陷，保护铁硫酶的活性，并使共济失调蛋白缺陷的细胞能够在不可发酵的碳源上生长。此外，MtF的表达阻止了线粒体铁过载的发展，保持了线粒体DNA的完整性，并增加了细胞对H2O2的抵抗力。数据显示，MtF可以替代酵母中的大多数共济失调蛋白功能，表明共济失调蛋白直接参与线粒体铁结合和解毒。
Mitochondrial ferritin (MtF) is structurally and functionally similar to the cytosolic ferritins, molecules designed to store and detoxify cellular iron. MtF expression in human and mouse is restricted to the testis and few tissues, and it is abundant in the erythroblasts of patients with sideroblastic anemia, where it is thought to protect the mitochondria from the damage caused by iron loading. Mitochondria iron overload occurs also in cells deficient in frataxin, a mitochondrial protein involved in iron handling and implicated in Friedreich ataxia. We expressed human MtF in frataxin-deficient yeast cells, a well-characterized model of mitochondrial iron overload and oxidative damage. The human MtF precursor was efficiently imported by yeast mitochondria and processed to functional ferritin that actively sequestered iron in the organelle. MtF expression rescued the respiratory deficiency caused by the loss of frataxin protecting the activity of iron-sulfur enzymes and enabling frataxin-deficient cells to grow on non-fermentable carbon sources. Furthermore, MtF expression prevented the development of mitochondrial iron overload, preserved mitochondrial DNA integrity and increased cell resistance to H2O2. The data show that MtF can substitute for most frataxin functions in yeast, suggesting that frataxin is directly involved in mitochondrial iron-binding and detoxification.