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The pathogenesis of Friedreich ataxia and the structure and function of frataxin

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Abstract

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 ironsulphur 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.

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  1. Service de Neurologie, Hôpital Erasme – Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium

    Massimo Pandolfo MD

  2. The National Institute for Medical Research, The Ridgeway, London, NW7 1AA, UK

    Annalisa Pastore PhD

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Pandolfo, M., Pastore, A. The pathogenesis of Friedreich ataxia and the structure and function of frataxin. J Neurol 256 (Suppl 1), 9–17 (2009). https://doi.org/10.1007/s00415-009-1003-2

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