Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?

Abstract

Friedreich ataxia is a neurodegenerative disease with an autosomal recessive inheritance. In most patients, the disease is caused by the presence of trinucleotide GAA expansions in the first intron of the frataxin gene. These expansions cause the decreased expression of this mitochondrial protein. Many evidences indicate that frataxin deficiency causes the deregulation of cellular iron homeostasis. In this review, we will discuss several hypotheses proposed for frataxin function, their caveats, and how they could provide an explanation for the deregulation of iron homeostasis found in frataxin-deficient cells. We will also focus on the potential mechanisms causing cellular dysfunction in Friedreich Ataxia and on the potential use of the iron chelator deferiprone as a therapeutic agent for this disease.

Keywords: Friedreich Ataxia; Iron chelators; Iron-sulfur; Oxidative stress.

Figure 1

Structures of human frataxin (hFxn, pdb code 3s4m) and Yeast Frataxin Homologue 1 (Yfh1, pdb code 2fql). Top, ribbons representations showing the conserved alpha-beta-alpha structure. Structures are colored according to sequence, from dark blue (N-terminal) to red (C-terminal). In human frataxin the C-terminal region folds over the hydrophobic cavity formed between both alpha helices. Below, coulumbic surface coloring of the same structures. The red color indicates the presence of a marked acidic ridge, which may be involved in iron binding. Molecular graphics and analyses were performed with the UCSF Chimera package [11].

Figure 2

Potential contribution of frataxin to iron homeostasis and cellular consequences of its deficiency. (A), physiological: frataxin (FXN) binds Fe²⁺ and contributes to its controlled oxidation to Fe³⁺ and/or to incorporate it into Fe-containing proteins. These Fe-containing proteins (notably FeS proteins) keep the iron sensor inactive and genes involved in iron uptake are not expressed. Oxidized iron (Fe³⁺) is stored in the form of ferric-phosphate nanoparticles. (B), frataxin-deficient: loss of frataxin leads to decreased incorporation of iron into Fe-proteins and/or uncontrolled oxidation of Fe²⁺ by O₂. Such events lead to reactive oxygen species (ROS) generation, decreased phosphate availability, and mitochondrial dysfunction. Iron sensors and other cell signaling pathways are activated and regulate the expression of genes involved in iron uptake and/or other cell-specific pathways involved on metabolic remodeling, hypertrophy or neurodegeneration.