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Tytuł pozycji:

Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models.

Tytuł :
Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models.
Autorzy :
Abeti R; Ataxia Centre, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
Baccaro A; Ataxia Centre, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
Esteras N; Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
Giunti P; Ataxia Centre, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
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Źródło :
Frontiers in cellular neuroscience [Front Cell Neurosci] 2018 Jul 17; Vol. 12, pp. 188. Date of Electronic Publication: 2018 Jul 17 (Print Publication: 2018).
Typ publikacji :
Journal Article
Język :
English
Imprint Name(s) :
Original Publication: Lausanne, Switzerland : Frontiers Research Foundation, 2007-
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Contributed Indexing :
Keywords: Friedreich’s ataxia; human fibroblasts; lipid peroxidation; mitochondrial dysfunction; nuclear factor (erythroid-derived 2)-like 2; reactive oxygen species
Entry Date(s) :
Date Created: 20180802 Latest Revision: 20210304
Update Code :
20210309
PubMed Central ID :
PMC6056642
DOI :
10.3389/fncel.2018.00188
PMID :
30065630
Czasopismo naukowe
Friedreich's Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, affecting dorsal root ganglia (DRG), cerebellar dentate nuclei and heart. It is caused by a GAA repeat expansion mutation within the frataxin gene ( FXN ). This impedes FXN transcription resulting in a progressive decrease of the mitochondrial protein, frataxin. Increased oxidative stress leading to a chronic depletion of endogenous antioxidants affects the survival of the cells and causes neurodegeneration. In particular, cerebellar granule neurons (CGNs) show a significant increase of reactive oxygen species (ROS), lipid peroxidation and lower level of reduced glutathione (GSH). In FRDA, one of the major pathways of oxidant scavengers, the Nrf2 antioxidant pathway, is defective. Previous studies on FRDA-like CGNs showed that the reduced level of frataxin and the oxidative stress induce mitochondrial impairments. By triggering the Nrf2 endogenous pathway pharmacologically we determined whether this could promote mitochondrial fitness and counteract oxidative stress. In this work, we sought to investigate the beneficial effect of a promising Nrf2-inducer, omaveloxolone (omav), in CGNs from two FRDA mouse models, KIKO and YG8R, and human fibroblasts from patients. We found that CGNs from both KIKO and YG8R presented Complex I deficiency and that omav was able to restore substrate availability and Complex I activity. This was also confirmed in human primary fibroblasts from FRDA patients. Although fibroblasts are not the major tissue affected, we found that they show significant differences recapitulating the disease; this is therefore an important tool to investigate patients' pathophysiology. Interestingly, we found that patient fibroblasts had an increased level of endogenous lipid peroxidation and mitochondrial ROS (mROS), and lower GSH at rest. Omav was able to reverse this phenotype, protecting the cells against oxidative stress. By stimulating the cells with hydrogen peroxide (H 2 O 2 ) and looking for potential mitochondrial pathophysiology, we found that fibroblasts could not maintain their mitochondrial membrane potential (ΔΨ m ). Remarkably, omav was protective to mitochondrial depolarization, promoting mitochondrial respiration and preventing cell death. Our results show that omav promotes Complex I activity and protect cells from oxidative stress. Omav could, therefore, be used as a novel therapeutic drug to ameliorate the pathophysiology of FRDA.

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