Mitochondrial iron overload and Friedreich's ataxia: The role of frataxin in iron and haem metabolism

弗里德赖希共济失调（FA）是由于缺乏一种称为共济失调蛋白的蛋白质。最近使用面包酵母的研究表明，frataxin的缺失导致有毒铁在酵母中的积累。最近，各种研究表明FA患者的细胞内有铁负载。铁的积累可能会造成严重的损害。目前，frataxin在哺乳动物线粒体铁代谢中的作用尚不清楚。我们的初步研究表明，共济失调蛋白是下调的红细胞分化或血红素前体原卟啉IX（贝克尔和理查森，提交）。这些数据有力地表明了共济失调蛋白在铁代谢中的作用。在本研究中，我们将继续评估frataxin是否在细胞处理铁的方式中发挥作用。使用在我的实验室中开发的线粒体铁过载的独特模型（Richardson等人（1996）BLOOD 87：3477），我们将广泛地研究线粒体的铁代谢，以确定共济失调蛋白的功能及其在弗里德赖希共济失调中的作用。此外，我们已经开发了一系列被称为铁螯合剂的新药，由于其高脂溶性，其可以进入线粒体（Becker和Richardson 1999 J. Lab. 134：510）。这些后一种药物比目前用于治疗铁过载的螯合剂去铁胺（DFO）有效得多。事实上，我们的螯合剂已经被设计成导致高铁螯合功效但低毒性（参见Becker和Richardson，1999）。这项令人兴奋的研究可能对理解FA的发展和创造新的疗法（如使用铁螯合剂）至关重要。

Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin is down-regulated by either erythroid differentiation or the haem precursor protoporphyrin IX (Becker and Richardson, submitted). These data strongly suggest a role for frataxin in iron metabolism. In the present study we will continue to assess if frataxin plays a role in the way cells handle iron. Using a unique model of mitochondrial iron overload developed in my lab (Richardson et al. (1996) BLOOD 87:3477), we will extensively investigate the iron metabolism of the mitochondrion in order to determine the function of frataxin and its role in Friedreich's ataxia. In addition, we have developed a series of new drugs known as iron chelators that can enter the mitochondrion due to their high lipid solubility (Becker and Richardson 1999 J. Lab. Clin. Med. 134:510). These latter drugs are far more effective than the chelator currently used to treat iron overload, desferrioxamine (DFO). Indeed, our chelators have been designed to result in high iron chelation efficacy but low toxicity (see Becker and Richardson, 1999). This exciting research may be crucial in understanding the development of FA and in creating new therapies such as the use of iron chelators.