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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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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.
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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.

Mentions: The cellular consequences of frataxin loss of function were initially described as faulty iron handling, impaired ISC synthesis and increased reactive oxygen species production [4]. We and others hypothesized that a vicious circle might link these three abnormalities (Figure 2A) and that targeting any of the three would consequently be as effective in slowing disease progression as targeting one or both of the other two abnormalities.


Friedreich's ataxia: the vicious circle hypothesis revisited.

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

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

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

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.
Mentions: The cellular consequences of frataxin loss of function were initially described as faulty iron handling, impaired ISC synthesis and increased reactive oxygen species production [4]. We and others hypothesized that a vicious circle might link these three abnormalities (Figure 2A) and that targeting any of the three would consequently be as effective in slowing disease progression as targeting one or both of the other two abnormalities.

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