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Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects

Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mi...

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Autores principales: Zighan, Madleen, Arkadir, David, Douiev, Liza, Keller, Guy, Miller, Chaya, Saada, Ann
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9411646/
https://www.ncbi.nlm.nih.gov/pubmed/36032663
http://dx.doi.org/10.3389/fmolb.2022.890653
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author Zighan, Madleen
Arkadir, David
Douiev, Liza
Keller, Guy
Miller, Chaya
Saada, Ann
author_facet Zighan, Madleen
Arkadir, David
Douiev, Liza
Keller, Guy
Miller, Chaya
Saada, Ann
author_sort Zighan, Madleen
collection PubMed
description Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson’s disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreased. Mitochondrial mass and mitochondrial DNA (mtDNA) contents were significantly increased in the patient’s cells. These results were partially confirmed by the results of oxygen consumption studies which disclosed increased maximal oxygen consumption rates in most cells and increased energy status in all treated cells. Further investigation is required to explore the precise effect of omaveloxolone on mitochondrial function in disease.
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spelling pubmed-94116462022-08-27 Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects Zighan, Madleen Arkadir, David Douiev, Liza Keller, Guy Miller, Chaya Saada, Ann Front Mol Biosci Molecular Biosciences Omaveloxolone (RTA408) is a second-generation oleanane triterpenoid Nrf2 inducer with antioxidant and anti-inflammatory properties and was reported to improve mitochondrial bioenergetics. It is currently being tested in medical trials for Friedrich ataxia, a genetic, multi-organ disease involving mitochondrial dysfunction. Thus, omaveloxolone could potentially be beneficial for additional disorders involving mitochondrial dysfunction. To this end, we investigated its effect on primary fibroblasts derived from patients with mitochondrial complex I deficiency, mitochondrial cytochrome oxidase deficiency, and two recessive forms of Parkinson’s disease. Patients and control cells were incubated in the presence or absence of 50 nM omaveloxolone for 72 h prior to measurements. Generally, growth on galactose medium and ATP production were unaltered. Mitochondrial membrane potential was slightly but significantly decreased, while reactive oxygen species (ROS) production was variably decreased. Mitochondrial mass and mitochondrial DNA (mtDNA) contents were significantly increased in the patient’s cells. These results were partially confirmed by the results of oxygen consumption studies which disclosed increased maximal oxygen consumption rates in most cells and increased energy status in all treated cells. Further investigation is required to explore the precise effect of omaveloxolone on mitochondrial function in disease. Frontiers Media S.A. 2022-08-12 /pmc/articles/PMC9411646/ /pubmed/36032663 http://dx.doi.org/10.3389/fmolb.2022.890653 Text en Copyright © 2022 Zighan, Arkadir, Douiev, Keller, Miller and Saada. https://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 Molecular Biosciences
Zighan, Madleen
Arkadir, David
Douiev, Liza
Keller, Guy
Miller, Chaya
Saada, Ann
Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects
title Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects
title_full Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects
title_fullStr Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects
title_full_unstemmed Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects
title_short Variable effects of omaveloxolone (RTA408) on primary fibroblasts with mitochondrial defects
title_sort variable effects of omaveloxolone (rta408) on primary fibroblasts with mitochondrial defects
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9411646/
https://www.ncbi.nlm.nih.gov/pubmed/36032663
http://dx.doi.org/10.3389/fmolb.2022.890653
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