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

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 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.

The Role of Hydration in Protein Stability: Comparison of the Cold and Heat Unfolded States of Yfh1

“…4 Yfh1 is the yeast ortholog of frataxin, a mitochondrial human protein involved in Friedreich's ataxia, a severe neurodegenerative disease. 5 The frataxin family is highly conserved in both sequence and structure from bacteria to humans and is essential for life. Despite the high conservation, the thermodynamic stability of different frataxin orthologs varies appreciably and is strongly influenced by iron and other cations.…”

Cells Lacking Pfh1, a Fission Yeast Homolog of Mammalian Frataxin Protein, Display Constitutive Activation of the Iron Starvation Response

“…Homologs to human frataxin have been found in bacteria, fungi, and plants (14). In particular, unicellular model systems are being exploited to determine the origin of the pleiotropic phenotypes displayed by patients.…”

Frataxin Depletion in Yeast Triggers Up-regulation of Iron Transport Systems before Affecting Iron-Sulfur Enzyme Activities

“…Homologues of this protein are found in bacteria, fungi, and plants (1). The gene encoding frataxin was identified 14 years ago (2).…”