Deferiprone targets aconitase: implication for Friedreich's ataxia treatment.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Inserm, U676, Hôpital Robert Debré, Paris, F-75019 France and Université Paris 7, Faculté de Médecine Denis Diderot, IFR02, Paris, France. goncalves@rdebre.inserm.fr
Sergio
S
Goncalves
Vincent
V
Paupe
Emmanuel P
EP
Dassa
Pierre
P
Rustin
D000154:Aconitate Hydratase / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D000077543:Deferiprone; D005347:Fibroblasts / Q000473:pathology; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008928:Mitochondria / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use
D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D007501:Iron; D000154:Aconitate Hydratase