In primary cultures of dorsal root ganglia neurons, frataxin depletion results in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. This study shows that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1, a mitochondrial Fe/S cluster-containing protein that interacts with frataxin and, interestingly, is essential for the synthesis of calcitriol, the active form of vitamin D. Calcitriol supplementation, used at nanomolar concentrations, is able to reverse the molecular and cellular markers altered in DRG neurons. Calcitriol is able to recover both ferredoxin 1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction of apoptotic markers and neurite degeneration was observed and, as a result, cell survival was also recovered. All these beneficial effects would be explained by the finding that calcitriol is able to increase the mature frataxin levels in both frataxin-deficient DRG neurons and cardiomyocytes; remarkably, this increase also occurs in lymphoblastoid cell lines derived from Friedreich Ataxia (FA) patients. In conclusion, these results provide molecular bases to consider calcitriol as an easy and affordable therapeutic approach for FA patients.
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2021 (23)