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Frataxin deficiency and mitochondrial dysfunction
Mitochondrion ( IF 4.4 ) Pub Date : 2002-11-01 , DOI: 10.1016/s1567-7249(02)00039-9
Massimo Pandolfo 1
Affiliation  

Friedreich ataxia (FA) is an inherited recessive disorder characterized by progressive neurological disability and heart abnormalities. The Friedreich ataxia gene (FRDA) encodes a small mitochondrial protein, frataxin, which is produced in insufficient amounts in the disease as a consequence of a GAA triplet repeat expansion in the first intron of the gene. Frataxin deficiency leads to excessive free radical production, dysfunction of Fe-S center containing enzymes (in particular respiratory complexes I, II and III, and aconitase), and progressive iron accumulation in mitochondria. Frataxin may be a mitochondrial iron-binding protein that prevents this metal from participating in Fenton chemistry to generate toxic hydroxyl radicals. We investigated whether frataxin deficiency may in addition interfere with signaling pathways. First, we showed that exposure of FA fibroblasts to iron fails to produce the normally observed increase in expression of the stress defense protein manganese superoxide dismutase. This impaired induction involves a nuclear factor-kappaB-independent pathway that does not require free radical signaling intermediates. We also examined the role of frataxin in neuronal differentiation by using stably transfected clones of P19 embryonic carcinoma cells with antisense or sense frataxin constructs. We found that during retinoic acid-induced neurogenesis frataxin deficiency enhances apoptosis and reduces the number of terminally differentiated neuronal-like cells. The addition of the antioxidant N-acetyl-cysteine only rescues cells non-committed to the neuronal lineage, indicating that frataxin deficiency impairs differentiation mechanisms and survival responses through different mechanisms. Both studies suggest that some abnormalities in frataxin-deficient cells are related to free radical independent signaling pathways.

中文翻译:

Frataxin缺乏和线粒体功能障碍

Friedreich 共济失调 (FA) 是一种遗传性隐性障碍,其特征是进行性神经功能障碍和心脏异常。Friedreich 共济失调基因 (FRDA) 编码一种小的线粒体蛋白 frataxin,由于基因的第一个内含子中的 GAA 三重重复扩增,该蛋白在疾病中产生的量不足。Frataxin 缺乏会导致过多的自由基产生、含有 Fe-S 中心的酶(特别是呼吸复合物 I、II 和 III 以及乌头酸酶)的功能障碍,以及线粒体中进行性铁积累。Frataxin 可能是一种线粒体铁结合蛋白,可防止这种金属参与芬顿化学以产生有毒的羟基自由基。我们调查了 frataxin 缺乏是否还会干扰信号通路。第一的,我们表明,FA 成纤维细胞暴露于铁不能产生通常观察到的应激防御蛋白锰超氧化物歧化酶表达的增加。这种受损的感应涉及不需要自由基信号中间体的独立于核因子 kappaB 的通路。我们还通过使用具有反义或有义 frataxin 构建体的 P19 胚胎癌细胞的稳定转染克隆检查了 frataxin 在神经元分化中的作用。我们发现在视黄酸诱导的神经发生过程中,frataxin 缺乏会增强细胞凋亡并减少终末分化的神经元样细胞的数量。添加抗氧化剂 N-乙酰-半胱氨酸只会拯救非神经元谱系的细胞,表明 frataxin 缺乏通过不同的机制损害分化机制和生存反应。这两项研究都表明,frataxin 缺陷细胞中的一些异常与自由基独立的信号通路有关。
更新日期:2002-11-01
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