Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia

Abstract

Friedreich ataxia (FA) is a neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. In primary cultures of dorsal root ganglia neurons, we showed that frataxin depletion resulted in decreased levels of the mitochondrial calcium exchanger NCLX, neurite degeneration and apoptotic cell death. Here, we describe that frataxin-deficient dorsal root ganglia neurons display low levels of ferredoxin 1 (FDX1), 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. We provide data that 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 FDX1 and NCLX levels and restores mitochondrial membrane potential indicating an overall mitochondrial function improvement. Accordingly, reduction in 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 FA patients. In conclusion, these results provide molecular bases to consider calcitriol for an easy and affordable therapeutic approach for FA patients.

Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

“…Frataxin deficiency has also been shown to impact different pathways related to mitochondrial function. These include the OXPHOS system [ 18 ], 19 ], mitochondrial calcium efflux [ 20 ], mitochondrial permeability pore opening [ 21 ], pyruvate dehydrogenase complex [ 22 ], and endoplasmic reticulum–mitochondria contacts [ 23 ], among others.…”

Curcumin-loaded graphene oxide quantum dots enhance otoprotective effects via blocking cuproptosis

“…We have previously performed experiments with isolated mitochondria without copper, thus hindering the identification of the essential role of this ion. Some studies have deciphered the mechanism of ROS induced by FDX1 in cancer cells ( Britti et al, 2021 ), which is a unique mode of action dependent on its copper chelating ability. After cellular uptake, the FDX1-Cu complex selectively and rapidly targets mitochondria.…”

Deficient mitochondrial respiration impairs sirtuin activity in dorsal root ganglia in Friedreich Ataxia mouse and cell models

“…After 1 h of pre-plating in a p60 tissue dish (Corning Incorporated, Cat# 35004) at 37°C/5%CO 2 , the cells were then plated in tissue dishes pre-treated with 0.1 mg/mL of collagen (Sigma, Cat# C7661-25) at a cell density of 14,000 cells/well. After 1–2 days, lentivirus transduction was performed with shRNA sequences targeting frataxin mRNA as described previously [31]. The RefSeq used was NM-008044, which corresponds to mouse frataxin.…”