Friedreich's ataxia: the vicious circle hypothesis revisited

Abstract

Friedreich's ataxia, the most frequent progressive autosomal recessive disorder involving the central and peripheral nervous systems, is mostly associated with unstable expansion of GAA trinucleotide repeats in the first intron of the FXN gene, which encodes the mitochondrial frataxin protein. Since FXN was shown to be involved in Friedreich's ataxia in the late 1990s, the consequence of frataxin loss of function has generated vigorous debate. Very early on we suggested a unifying hypothesis according to which frataxin deficiency leads to a vicious circle of faulty iron handling, impaired iron-sulphur cluster synthesis and increased oxygen radical production. However, data from cell and animal models now indicate that iron accumulation is an inconsistent and late event and that frataxin deficiency does not always impair the activity of iron-sulphur cluster-containing proteins. In contrast, frataxin deficiency appears to be consistently associated with increased sensitivity to reactive oxygen species as opposed to increased oxygen radical production. By compiling the findings of fundamental research and clinical observations we defend here the opinion that the very first consequence of frataxin depletion is indeed an abnormal oxidative status which initiates the pathogenic mechanism underlying Friedreich's ataxia.

Figure 1

Frataxin function in the mitochondria. The schema illustrates the iron-sulphur cluster (ISC) biosynthesis machinery present in the mitochondrial matrix encompassing the ISCU-NFS1 protein complex associating glutaredoxin 5 (GLRX5) with the frataxin protein. It makes use of iron possibly delivered by the mitochondrial ferritin to synthesize ISC also distributed among several of the mitochondrial proteins (including several membrane-bound respiratory chain components, complexes I, II and III and the matrix-soluble aconitase). In addition to its role in the biogenesis of ISC, the frataxin protein might be associated with ISC after their synthesis. The detoxifying role of vitamin E in the mitochondrial inner membrane is also indicated. ISP, ISC-containing protein; mt, mitochondrial.

Figure 2

The vicious circle hypothesis revisited in Friedreich's ataxia. (A) According to the vicious circle hypothesis, frataxin depletion results in impaired iron-sulphur cluster synthesis and/or stability with intramitochondrial accumulation of reactive iron. Reactive iron promotes Fenton chemistry, producing superoxide and hydrogen peroxide, which in turn destroys more iron-sulphur clusters. ISC, iron-sulphur cluster. (B) In frataxin-depleted cells, deficient signalling of antioxidant defences sensitises the frataxin-free iron-sulphur clusters to reactive oxygen species. This antioxidant sensitisation process results in intramitochondrial iron accumulation, mostly as amorphous nonreactive precipitates. ROS, reactive oxygen species.