Pandolfo Massimo, Pastore Annalisa
Service de Neurologie, Hôpital Erasme - Université Libre de Bruxelles, Brussels, Belgium.
J Neurol. 2009 Mar;256 Suppl 1:9-17. doi: 10.1007/s00415-009-1003-2.
Understanding the role of frataxin in mitochondria is key to an understanding of the pathogenesis of Friedreich ataxia. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, which include oxidative stress, deficit of iron-sulphur clusters, and defects in heme synthesis, sulfur amino acid and energy metabolism, stress response, and mitochondrial function. Structural studies carried out on different orthologues have shown that the frataxin fold consists of a flexible N-terminal region present only in eukaryotes and in a highly conserved C-terminal globular domain. Frataxins bind iron directly but with very unusual properties: iron coordination is achieved solely by glutamates and aspartates exposed on the protein surface. It has been suggested that frataxin function is that of a ferritin-like protein, an iron chaperone of the iron sulphur cluster machinery and heme metabolism and/or a controller of cellular oxidative stress. To understand FRDA pathogenesis and to design novel therapeutic strategies, we must first precisely identify the cellular role of frataxin.
了解铁调素在线粒体中的作用是理解弗里德赖希共济失调发病机制的关键。铁调素是一类必需的小蛋白，其缺乏会导致一系列代谢紊乱，包括氧化应激、铁硫簇缺乏、血红素合成缺陷、含硫氨基酸和能量代谢异常、应激反应以及线粒体功能障碍。对不同直系同源物进行的结构研究表明，铁调素折叠结构由仅存在于真核生物中的柔性N端区域和高度保守的C端球状结构域组成。铁调素直接结合铁，但具有非常独特的特性：铁的配位仅通过暴露在蛋白质表面的谷氨酸和天冬氨酸来实现。有人提出，铁调素的功能类似于铁蛋白样蛋白，是铁硫簇机制和血红素代谢的铁伴侣和/或细胞氧化应激的调节者。为了理解弗里德赖希共济失调（FRDA）的发病机制并设计新的治疗策略，我们必须首先精确确定铁调素的细胞作用。
