Deferiprone targets aconitase: implication for Friedreich's ataxia treatment

Abstract

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.

Method: 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.

Conclusion: 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.

Figure 1

Deferiprone targets aconitase enzyme. Aconitase inhibition triggered by deferiprone in (A) cultured skin fibroblasts from control (open square) and two Friedreich's ataxia patients after 7 d of culture. Time-dependent aconitase inhibition by 150 μM deferiprone in (B) control (open square) and frataxin-depleted (shRNA treated) SK-N-AS cells. Error bars correspond to 1 SE (n = 3); *** denotes p < 0.001; n.s. non significant. Experimental conditions as described under Methods.

Figure 2

Deferiprone decreases cell proliferation. Effect of 7 d-treatment with deferiprone (0–150 μM) on (A) control (open symbol) and patient fibroblasts and on (C) control (open symbol) and frataxin-depleted SK-N-AS cells. A light microscope view (B) (×4) of control (a, b, c) and patient (d, e, f) fibroblasts, before treatment (18 h after seeding; a, d), or 7 d in the absence (b, e) or presence (c, f) of 150 μM deferiprone. Error bars correspond to 1 SE (n = 3); *** denotes p < 0.001; n.s. non significant. Experimental conditions as described under Methods.