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

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 decreas...

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Autores principales: Abeti, Rosella, Baccaro, Annalisa, Esteras, Noemi, Giunti, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056642/
https://www.ncbi.nlm.nih.gov/pubmed/30065630
http://dx.doi.org/10.3389/fncel.2018.00188
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author Abeti, Rosella
Baccaro, Annalisa
Esteras, Noemi
Giunti, Paola
author_facet Abeti, Rosella
Baccaro, Annalisa
Esteras, Noemi
Giunti, Paola
author_sort Abeti, Rosella
collection PubMed
description 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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spelling pubmed-60566422018-07-31 Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models Abeti, Rosella Baccaro, Annalisa Esteras, Noemi Giunti, Paola Front Cell Neurosci Neuroscience 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. Frontiers Media S.A. 2018-07-17 /pmc/articles/PMC6056642/ /pubmed/30065630 http://dx.doi.org/10.3389/fncel.2018.00188 Text en Copyright © 2018 Abeti, Baccaro, Esteras Gallego and Giunti. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Abeti, Rosella
Baccaro, Annalisa
Esteras, Noemi
Giunti, Paola
Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models
title Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models
title_full Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models
title_fullStr Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models
title_full_unstemmed Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models
title_short Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models
title_sort novel nrf2-inducer prevents mitochondrial defects and oxidative stress in friedreich’s ataxia models
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056642/
https://www.ncbi.nlm.nih.gov/pubmed/30065630
http://dx.doi.org/10.3389/fncel.2018.00188
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