Deferiprone targets aconitase: Implication for Fridreich’s ataxia

Inserm, U676, Hôpital Robert Debré, Paris, F-75019 France and Université Paris 7, Faculté de Médecine Denis Diderot, IFR02, Paris, France.
BMC Neurology (Impact Factor: 2.49). 02/2008; 8:20. DOI: 10.1186/1471-2377-8-20
Source: PubMed

ABSTRACT Friedreich ataxia is a neurological disease originating from an iron-sulfur cluster enzyme deficiency due to impaired iron handling in the mitochondrion, aconitase being particularly affected. As a mean to counteract disease progression, it has been suggested to chelate free mitochondrial iron. Recent years have witnessed a renewed interest in this strategy because of availability of deferiprone, a chelator preferentially targeting mitochondrial iron.
Control and Friedreich's ataxia patient cultured skin fibroblasts, frataxin-depleted neuroblastoma-derived cells (SK-N-AS) were studied for their response to iron chelation, with a particular attention paid to iron-sensitive aconitase activity.
We found that a direct consequence of chelating mitochondrial free iron in various cell systems is a concentration and time dependent loss of aconitase activity. Impairing aconitase activity was shown to precede decreased cell proliferation.
We conclude that, if chelating excessive mitochondrial iron may be beneficial at some stage of the disease, great attention should be paid to not fully deplete mitochondrial iron store in order to avoid undesirable consequences.

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    • "However, these studies have to be considered along other experimental evidence suggesting that iron chelation, even by deferiprone, may be deleterious in FRDA under certain circumstances. A small study indicated that deferiprone at the concentration of 150 lM, but not at 25 lM, decreased aconitase activity in cultured fibroblasts by 70–80%, and at concentrations higher than 50 lM it could also inhibit cell proliferation (Goncalves et al. 2008). Another study demonstrated that frataxin mRNA levels decrease significantly in multiple human cell lines treated with desferoxamine (Li et al. 2008). "
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    ABSTRACT: Friedreich's ataxia (FRDA) is a neurological disease related to a deficiency of the protein frataxin involved in iron–sulfur (Fe–S) cluster biogenesis. This leads to an increased cellular iron uptake accumulating in mitochondria, and a subsequently disturbed iron homeostasis. The detailed mechanism of iron regulation of frataxin expression is yet unknown. Deferiprone, an iron chelator that may cross the blood–brain barrier, was shown to shuttle iron between subcellular compartments. It could also transfer iron from iron-overloaded cells to extracellular apotransferrin and pre-erythroid cells for heme synthesis. Here, clinical studies on Deferiprone are reviewed in the context of alternative agents such as desferoxamine, with specific regard to its mechanistic and clinical implications.
    Journal of Neurochemistry 08/2013; 126(s1). DOI:10.1111/jnc.12300 · 4.24 Impact Factor
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    • "This goal could be achieved through phlebotomy, iron chelation, overexpression of iron storage proteins or limitation of dietary iron (Polla et al. 2003;Saito et al. 2003;Sullivan 2009). Several studies have shown that iron chelation may be beneficial in the treatment of iron overload diseases, such as Alzheimer's disease (Weinberg and Miklossy 2008;Liu et al. 2010), Parkinson's disease (Kaur and Andersen 2004;Ghosh et al. 2010), Friedreich's ataxia (Whitnall et al. 2008;Goncalves et al. 2008) and retinal disease (Dunaief 2006;Lukinova et al. 2009). An important issue associated with iron chelation therapy is that compounds available to date do not possess enough selectivity for organs or macromolecular structures, and once penetrated in tissues chelate iron indiscriminately. "
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