Review
Friedreich ataxia: a paradigm for mitochondrial diseases

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Abstract

Friedreich ataxia (FRDA), a progressive neurodegenerative disease, is due to the partial loss of function of frataxin, a mitochondrial protein of unknown function. Loss of frataxin causes mitochondrial iron accumulation, deficiency in the activities of iron-sulfur (Fe–S) proteins, and increased oxidative stress. Mouse models for FRDA demonstrate that the Fe–S deficit precedes iron accumulation, suggesting that iron accumulation is a secondary event. Furthermore, increased oxidative stress in FRDA patients has been demonstrated, and in vitro experiments imply that the frataxin defect impairs early antioxidant defenses. These results taken together suggest that frataxin may function either in mitochondrial iron homeostasis, in Fe–S cluster biogenesis, or directly in the response to oxidative stress. It is clear, however, that the pathogenic mechanism in FRDA involves free-radical production and oxidative stress, a process that appears to be sensitive to antioxidant therapies.

Introduction

Friedreich ataxia (FRDA) — the most common autosomal recessive ataxia (1 individual in 30,000) — is a neuro-degenerative disease characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes 1., 2., 3•.. FRDA is caused by severely reduced levels of frataxin as a result of a large GAA triplet repeat expansion within the first intron of the frataxin gene [4], leading to a reduction of frataxin expression by inhibiting transcription 5., 6., 7..

Frataxin is a ubiquitously expressed mitochondrial protein, highly conserved through evolution (from γ-purple bacteria to human). However, frataxin shows no similarity with protein domains of known function, and therefore its biochemical function cannot be deduced from its sequence. Both the physiological function of frataxin, and the pathophysiological process of the disease are controversial. In the present review, we discuss the recent advances that have been made in deciphering the function of frataxin and the predominant hypotheses in the field. The generation of mouse models in order to help understand the patho-physiology and test pharmacological therapy are described. Finally, we conclude with promising prospect for therapy. The recent increased understanding of the effect of the GAA expansion on transcription and replication, as well as insight into the biogenesis of frataxin will not be discussed as it has recently been reviewed thoroughly [8].

Section snippets

The function of frataxin

Although the exact physiological function of frataxin is not known, there are at least four predominant hypotheses for its role (Fig. 1): mitochondrial iron transport, iron–sulfur (Fe–S) cluster biogenesis, iron binding/sequestration, and response to oxidative stress. In this review, we discuss the experimental data leading to these four different hypotheses.

Frataxin and iron homeostasis

Yeast as a model organism proved to be an invaluable system for unraveling frataxin mitochondrial function. Deletion of the frataxin yeast homologue 1 (YFH1) results in mutant strains that show a growth defect on fermentable carbon source, accumulate mitochondrial iron and exhibit a high sensitivity to oxidative stress induced by oxidant agents such as hydrogen peroxide or iron, as well as a reduction in oxidative phosphorylation 9., 10., 11., 12., 13.. In parallel, not only is the

Frataxin and the biogenesis of iron–sulfur clusters

A selective deficiency of the respiratory chain complexes I–III and of both mitochondrial and cytosolic aconitases activities in the heart biopsy and autopsy material of patients has been reported 16., 21.. All the deficient enzymes and complexes contain Fe–S clusters in their active sites. Fe–S proteins are remarkably sensitive to free radicals, and their inactivation further suggests oxidative stress in FRDA-affected tissues which could be a consequence of iron accumulation. However, data

Frataxin as an iron-storage protein

An attractive hypothesis recently put forward by Isaya and co-workers suggests that the function of frataxin is to bind iron and keep it in a soluble and bioavailable form [32]. By gel-filtration experiments and analytical ultracentrifugation, the authors demonstrated that recombinant purified yeast frataxin is a soluble monomer that contains no iron, which assembles into a high molecular weight regular spherical multimer sequestering >3000 atoms of iron upon titration with increasing

Frataxin and oxidative stress

Whether frataxin is involved directly in iron homeostasis or Fe–S cluster biogenesis, the generation of reactive oxygen species plays an important role in the pathogenesis of FRDA. Consistent with this hypothesis, vitamin E deficiency produces a disease very similar to FRDA.

Although the speculation of oxidative stress involvement in FRDA has long been accepted, it was not until very recently that an increased oxidative stress has been demonstrated in individuals with FRDA. Schulz et al. [36•]

Mouse models for FRDA

To study further the disease pathology and to test pharmocological therapy, several mouse models have been generated. Our group generated a classical mouse model by constitutive inactivation of frataxin by homologous recombination [42]. Homozygous deletion of frataxin causes embryonic lethality a few days after implantation, demonstrating an important role for frataxin during early development. These results suggest that the milder phenotype in humans is caused by residual frataxin expression

Conclusion and prospect for therapy

On the basis of the recent discoveries of the potential function of frataxin, and more specifically on the consequences of frataxin reduction, therapeutic advances can be envisioned. Whether the mitochondrial iron accumulation is either a primary or a secondary effect of frataxin deficiency, all data suggest that intracellular iron imbalance and oxidative stress are involved in the pathogenesis of FRDA. This led to initial enthusiasm for the use of iron chelators, such as desferrioxamine, as

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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