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  • The specific role of NFAT alternative name of


    The specific role of NFAT3 (alternative name of the NFATc4 isoform) in promoting apoptosis has been reported, among others, in a model of lithium toxicity [66] and in a mouse model of brain ischemia as an activator of expression of the pro-apoptotic Fas ligand (FasL) [67]. Also it is worth mentioning that, in sensory neurons, Ca release from mitochondria clearly activates NFAT [23]. In agreement to these findings, dephosphorylation of NFAT3 clearly observed in our cardiomyocyte cultures (Fig. 8A) or in DRG neurons (Fig. 8C) gives important clues to understand why hearts could become hypertrophic as the disease progresses and to toxic effects observed in DRG neurons after frataxin-depletion. Another important result is the beneficial effects of CsA because in cardiomyocytes is able to restore mitochondrial morphology, reduce lipid droplets accumulation and deactivates the hypertrophic factor NFAT (Fig. 3, Fig. 4, Fig. 9, respectively). Lipid droplets accumulation has been reported in frataxin-deficient flies [68] and in mice models of the disease [69]. Such accumulation could be attributed to decreased mitochondrial fatty Relebactam utilization via β-oxidation pathway. Since one of the main sources for energy supply to cardiac cells comes from this pathway -reviewed in [70]- reduced lipid droplets found by CsA treatment would be highly beneficial and indicative of restoring energy production. Besides, it is well known that many FA patients develop cardiac hypertrophy and cardiac problems are one of the major causes of death (around 60%) among the affected patients [71], [72]. In this context, the cardioprotective role of CsA has been proposed because it targets MPTP [73] and because it can inhibit calcineurin pathway, a key player in myocardial hypertrophy [63]. Also, in cardiac cell models of Noonan and LEOPARD syndromes, CsA has proven to exert positive effects by attenuating incidence of NFAT/calcineurin pathways-mediated cardiac hypertrophy observed in these syndromes [74]. The neuro- and cardioprotector background of CsA mentioned above and the results obtained in this paper, suggest that this drug, or others targeting MPTP, would be a strong candidate to be repurposed for a new therapeutic approach to treat FA as it targets mitochondrial pore. Drugs such tacrolimus (Fig. 9D and F) targeting other downstream effects of frataxin deficiency, seem to be rather inefficient and not suitable candidate to treat FA. Finally, this paper provide evidences that decreased levels of NCLX and MPTP opening would impact on calcium homeostasis and constitute a central core to explain the downstream effects of frataxin deficiency. The involvement of MPTP opening suggests that drugs acting on the pore inhibition could be beneficial for treating the disease.
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