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Tytuł pozycji:

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

Tytuł:
Calcitriol increases frataxin levels and restores mitochondrial function in cell models of Friedreich Ataxia.
Autorzy:
Britti E; Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, AV. Rovira Roure 80, 25198 Lleida, Spain.
Delaspre F; Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, AV. Rovira Roure 80, 25198 Lleida, Spain.
Sanz-Alcázar A; Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, AV. Rovira Roure 80, 25198 Lleida, Spain.
Medina-Carbonero M; Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, AV. Rovira Roure 80, 25198 Lleida, Spain.
Llovera M; Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, AV. Rovira Roure 80, 25198 Lleida, Spain.
Purroy R; Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, AV. Rovira Roure 80, 25198 Lleida, Spain.
Mincheva-Tasheva S; Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, AV. Rovira Roure 80, 25198 Lleida, Spain.
Tamarit J; Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, AV. Rovira Roure 80, 25198 Lleida, Spain.
Ros J; Dept. Ciències Mèdiques Bàsiques, Universitat de Lleida, IRBLleida, AV. Rovira Roure 80, 25198 Lleida, Spain.
Źródło:
The Biochemical journal [Biochem J] 2021 Jan 15; Vol. 478 (1), pp. 1-20.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: London, UK : Published by Portland Press on behalf of the Biochemical Society
MeSH Terms:
Calcitriol/*pharmacology
Ferredoxins/*metabolism
Friedreich Ataxia/*metabolism
Iron-Binding Proteins/*metabolism
Membrane Potential, Mitochondrial/*drug effects
Mitochondria/*drug effects
Neurons/*metabolism
25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism ; Apoptosis/drug effects ; Calcitriol/biosynthesis ; Calcitriol/metabolism ; Carrier Proteins/metabolism ; Cell Line ; Cell Survival/drug effects ; Ganglia, Spinal/cytology ; Ganglia, Spinal/metabolism ; Humans ; Microfilament Proteins/metabolism ; Mitochondria/metabolism ; Mitochondrial Proteins/metabolism ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Sodium-Calcium Exchanger/metabolism ; Vitamin D/metabolism ; Frataxin
Contributed Indexing:
Keywords: calcitriol; calcium homoeostasis; frataxin; mitochondrial dysfunction
Substance Nomenclature:
0 (Carrier Proteins)
0 (Ferredoxins)
0 (Iron-Binding Proteins)
0 (Microfilament Proteins)
0 (Mitochondrial Proteins)
0 (SLC8B1 protein, human)
0 (Sodium-Calcium Exchanger)
0 (fodrin)
1406-16-2 (Vitamin D)
EC 1.14.15.18 (25-Hydroxyvitamin D3 1-alpha-Hydroxylase)
FXC9231JVH (Calcitriol)
Entry Date(s):
Date Created: 20201211 Date Completed: 20210416 Latest Revision: 20231213
Update Code:
20240104
DOI:
10.1042/BCJ20200331
PMID:
33305808
Czasopismo naukowe
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.
(© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

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