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Friedreich's ataxia: the vicious circle hypothesis revisited.

Bayot A, Santos R, Camadro JM, Rustin P - BMC Med (2011)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inserm, U676, Physiopathology and Therapy of Mitochondrial Diseases Laboratory, CHU - Hôpital Robert Debré, 48, boulevard Sérurier, F-75019 Paris, France.

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.

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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.
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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.

Mentions: Friedreich's ataxia (FA), the most prevalent form of autosomal recessive cerebellar ataxia in Caucasians, is characterised by progressive ataxia and dysarthria [1]. The symptoms usually become apparent around puberty, although onset may occur much later in life (> 60 years old). The neurological features include sensory neuropathy, deep sensory impairment, signs of pyramidal tract involvement and progressive cerebellar dysfunction. The nonneurological manifestations vary, but among them hypertrophic cardiomyopathy is common. Diabetes mellitus occurs in approximately one-third of FA patients [1]. FA therefore appears to be a rather heterogeneous disorder. In the vast majority of cases, it is caused by a GAA trinucleotide repeat expansion in the first intron of the frataxin-encoding gene (FXN), which results in decreased gene expression and partial loss of function of the frataxin protein in the mitochondrial matrix [2]. Frataxin has been shown to interact with the iron-sulphur cluster (ISC) assembly machinery [3] (Figure 1). Frataxin loss of function therefore can result in ISC-containing protein (ISP) deficiency, decreasing aconitase and mitochondrial respiratory chain activity [4], but it also results in hypersensitivity to oxidative stress [5,6] and accumulation of iron in affected organs [7].


Friedreich's ataxia: the vicious circle hypothesis revisited.

Bayot A, Santos R, Camadro JM, Rustin P - BMC Med (2011)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198887&req=5

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.
Mentions: Friedreich's ataxia (FA), the most prevalent form of autosomal recessive cerebellar ataxia in Caucasians, is characterised by progressive ataxia and dysarthria [1]. The symptoms usually become apparent around puberty, although onset may occur much later in life (> 60 years old). The neurological features include sensory neuropathy, deep sensory impairment, signs of pyramidal tract involvement and progressive cerebellar dysfunction. The nonneurological manifestations vary, but among them hypertrophic cardiomyopathy is common. Diabetes mellitus occurs in approximately one-third of FA patients [1]. FA therefore appears to be a rather heterogeneous disorder. In the vast majority of cases, it is caused by a GAA trinucleotide repeat expansion in the first intron of the frataxin-encoding gene (FXN), which results in decreased gene expression and partial loss of function of the frataxin protein in the mitochondrial matrix [2]. Frataxin has been shown to interact with the iron-sulphur cluster (ISC) assembly machinery [3] (Figure 1). Frataxin loss of function therefore can result in ISC-containing protein (ISP) deficiency, decreasing aconitase and mitochondrial respiratory chain activity [4], but it also results in hypersensitivity to oxidative stress [5,6] and accumulation of iron in affected organs [7].

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inserm, U676, Physiopathology and Therapy of Mitochondrial Diseases Laboratory, CHU - Hôpital Robert Debré, 48, boulevard Sérurier, F-75019 Paris, France.

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.

Show MeSH
Related in: MedlinePlus