Iron-sulfur cluster synthesis, iron homeostasis and oxidative stress in Friedreich ataxia.
Iron-sulfur cluster synthesis, iron homeostasis and oxidative stress in Friedreich ataxia.
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DOI：
10.1016/j.mcn.2012.08.003
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Isaya G
中科院分区：
文献类型：
--
作者：
Vaubel RA;Isaya G
弗里德赖希共济失调（FRDA）是一种常染色体隐性、多系统退行性疾病，由线粒体蛋白frataxin合成减少引起。自1996年发现Frataxin缺乏与FRDA有关以来，人们对其进行了深入研究。frataxin的定义性质- (i)结合铁的能力，（ii）与其他铁结合蛋白相互作用并将铁提供给其他铁结合蛋白的能力，以及（iii）寡聚、储存铁和控制铁氧化还原化学的能力-已经被不同的frataxin同源物及其相互作用的蛋白质伙伴广泛表征。大量的生物化学和结构数据[见]支持同样广泛的生物学证据，即卵黄蛋白对线粒体铁代谢、整体细胞铁稳态和抗氧化保护至关重要。然而，酪黄蛋白的确切生物学作用仍然是一个有争议的问题。在这里，我们回顾了开创性的和最近的数据，这些数据强烈地将frataxin与铁硫簇辅因子（ISC）的合成联系起来，以及有争议的数据，尽管如此，将frataxin与其他铁相关过程联系起来。最后，我们讨论了ISC合成缺陷如何通过(i) ISC依赖性酶的丧失，（ii）线粒体和细胞铁调节失调，以及（iii）铁介导的氧化应激增强，成为FRDA病理生理的主要（尽管可能不是唯一的）因素。
Friedreich ataxia (FRDA) is an autosomal recessive, multi-systemic degenerative disease that results from reduced synthesis of the mitochondrial protein frataxin. Frataxin has been intensely studied since its deficiency was linked to FRDA in 1996. The defining properties of frataxin—(i) the ability to bind iron, (ii) the ability to interact with, and donate iron to, other iron-binding proteins, and (iii) the ability to oligomerize, store iron and control iron redox chemistry—have been extensively characterized with different frataxin orthologues and their interacting protein partners. This very large body of biochemical and structural data [reviewed in ] supports equally extensive biological evidence that frataxin is critical for mitochondrial iron metabolism and overall cellular iron homeostasis and antioxidant protection [reviewed in ]. However, the precise biological role of frataxin remains a matter of debate. Here, we review seminal and recent data that strongly link frataxin to the synthesis of iron-sulfur cluster cofactors (ISC), as well as controversial data that nevertheless link frataxin to additional iron-related processes. Finally, we discuss how defects in ISC synthesis could be a major (although likely not unique) contributor to the pathophysiology of FRDA via (i) loss of ISC-dependent enzymes, (ii) mitochondrial and cellular iron dysregulation, and (iii) enhanced iron-mediated oxidative stress.
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影响因子：
4.8
作者：
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