Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia
Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia
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DOI：
10.1073/pnas.96.20.11492
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发表时间：
1999-09-28
影响因子：
11.1
通讯作者：
Schapira, AHV
中科院分区：
文献类型：
--
作者：
Lodi, R;Cooper, JM;Schapira, AHV
弗里德赖希共济失调 (FRDA) 是最常见的遗传性共济失调，是一种常染色体隐性退行性疾病，临床特征为 25 岁之前发病，进行性步态和肢体共济失调，深腱反射、足底伸肌反应缺失，下肢位置感和振动感丧失。 97% 的患者中，FRDA 是由染色体 9q13 上 FRDA 基因第一个内含子的 GAA 三联体扩增引起的。 FRDA 基因编码一种广泛表达的 210 个氨基酸蛋白 frataxin，该蛋白位于线粒体中，在 FRDA 患者中严重减少。 Frataxin 的功能仍不清楚，但酵母 frataxin 同源基因 (YFH1) 的敲除显示线粒体呼吸的严重缺陷以及与线粒体内铁升高相关的 mtDNA 丢失。在此，我们报告了 FRDA 患者骨骼肌线粒体呼吸受损的体内证据。使用磷磁共振波谱，我们证明了所有 12 名 FRDA 患者的肌肉线粒体 ATP 产生最大速率 (V(max)) 均低于正常范围，并且线粒体 V(max) 与较小等位基因中的 GAA 重复次数之间存在很强的负相关性。我们的结果表明 FRDA 是一种影响氧化磷酸化的核编码线粒体疾病，并为旨在改善这种情况下线粒体功能的治疗提供了理论依据。
Friedreich ataxia (FRDA), the most common of the inherited ataxias, is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs. FRDA is caused by a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 in 97% of patients. The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria and is severely reduced in FRDA patients. Frataxin function is still unknown but the knockout of the yeast frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration and loss of mtDNA associated with elevated intramitochondrial iron. Here we report in vivo evidence of impaired mitochondrial respiration in skeletal muscle of FRDA patients. Using phosphorus magnetic resonance spectroscopy we demonstrated a maximum rate of muscle mitochondrial ATP production (V(max)) below the normal range in all 12 FRDA patients and a strong negative correlation between mitochondrial V(max) and the number of GAA repeats in the smaller allele. Our results show that FRDA is a nuclear-encoded mitochondrial disorder affecting oxidative phosphorylation and give a rationale for treatments aimed to improve mitochondrial function in this condition.