Rustin P, von Kleist-Retzow J C, Chantrel-Groussard K, Sidi D, Munnich A, Rötig A
Unité de Recherches sur les Handicaps Génétiques de l'Enfant (INSERM U393), Paris, France.
Lancet. 1999 Aug 7;354(9177):477-9. doi: 10.1016/S0140-6736(99)01341-0.
Friedreich's ataxia is caused by a deficiency of frataxin, a protein involved in regulation of mitochondrial iron content. We have reported a combined deficiency of a Krebs-cycle enzyme, aconitase, and three mitochondrial respiratory-chain complexes in endomyocardial biopsy samples from patients with this disorder. All four enzymes share iron-sulphur cluster-containing proteins that are damaged by iron overload through generation of oxygen free radicals. We used an in-vitro system to elucidate the mechanism of iron-induced injury and to test the protective effects of various substances. On the basis of these results, we assessed the effect of idebenone (a free-radical scavenger) in three patients with Friedreich's ataxia.
Heart homogenates from patients with valvular stenosis were tested for respiratory-chain complex II activity, lipoperoxidation, and aconitase activity by spectrophotometric assays, in the presence of reduced iron (Fe2+), oxidised iron (Fe3+), desferrioxamine, ascorbic acid, and idebenone. The Friedreich's ataxia patients (aged 11 years, 19 years, and 21 years) underwent ultrasonographic heart measurements at baseline and after 4-9 months of idebenone (5 mg/kg daily).
Fe2+ (but not Fe3+) decreased complex II activity and increased lipoperoxidation in heart homogenate. Addition of ascorbate or desferrioxamine increased some of the iron-induced adverse effects. Idebenone protected against these effects. In the three patients, left-ventricular mass index decreased from baseline to 4-9 months of idebenone treatment (patient 1, 145 g to 114 g; patient 2, 215 g to 151 g; patient 3, 408 g to 279 g).
Our in-vitro data suggest that both iron chelators and antioxidant drugs that may reduce iron are potentially harmful in patients with Friedreich's ataxia. Conversely, our preliminary findings in patients suggest that idebenone protects heart muscle from iron-induced injury.
弗里德赖希共济失调由铁调素缺乏引起，铁调素是一种参与调节线粒体铁含量的蛋白质。我们曾报道，在该疾病患者的心内膜心肌活检样本中，一种三羧酸循环酶——乌头酸酶以及三种线粒体呼吸链复合物存在联合缺陷。这四种酶均含有铁硫簇蛋白，这些蛋白会因铁过载产生的氧自由基而受损。我们使用体外系统来阐明铁诱导损伤的机制，并测试各种物质的保护作用。基于这些结果，我们评估了艾地苯醌（一种自由基清除剂）对三名弗里德赖希共济失调患者的疗效。
通过分光光度法测定，在存在还原铁（Fe2+）、氧化铁（Fe3+）、去铁胺、抗坏血酸和艾地苯醌的情况下，检测瓣膜狭窄患者心脏匀浆中的呼吸链复合物II活性、脂质过氧化和乌头酸酶活性。三名弗里德赖希共济失调患者（年龄分别为11岁、19岁和21岁）在基线时以及接受艾地苯醌（每日5 mg/kg）治疗4 - 9个月后接受心脏超声测量。
Fe2+（而非Fe3+）降低了心脏匀浆中的复合物II活性并增加了脂质过氧化。添加抗坏血酸或去铁胺会增加一些铁诱导的不良反应。艾地苯醌可防止这些效应。在这三名患者中，左心室质量指数从基线到接受艾地苯醌治疗4 - 9个月后有所下降（患者1，从145 g降至114 g；患者2，从215 g降至151 g；患者3，从408 g降至279 g）。
我们的体外数据表明，铁螯合剂和可能减少铁的抗氧化药物对弗里德赖希共济失调患者可能具有潜在危害。相反，我们在患者中的初步研究结果表明，艾地苯醌可保护心肌免受铁诱导的损伤。
