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Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction
Optic Atrophy 1 (OPA1) is a mitochondrially targeted GTPase that plays a pivotal role in mitochondrial health, with mutations causing severe mitochondrial dysfunction and typically associated with Dominant Optic Atrophy (DOA), a progressive blinding disease involving retinal ganglion cell loss and o...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726421/ https://www.ncbi.nlm.nih.gov/pubmed/33324145 http://dx.doi.org/10.3389/fnins.2020.571479 |
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author | Maloney, Daniel M. Chadderton, Naomi Millington-Ward, Sophia Palfi, Arpad Shortall, Ciara O’Byrne, James J. Cassidy, Lorraine Keegan, David Humphries, Peter Kenna, Paul Farrar, Gwyneth Jane |
author_facet | Maloney, Daniel M. Chadderton, Naomi Millington-Ward, Sophia Palfi, Arpad Shortall, Ciara O’Byrne, James J. Cassidy, Lorraine Keegan, David Humphries, Peter Kenna, Paul Farrar, Gwyneth Jane |
author_sort | Maloney, Daniel M. |
collection | PubMed |
description | Optic Atrophy 1 (OPA1) is a mitochondrially targeted GTPase that plays a pivotal role in mitochondrial health, with mutations causing severe mitochondrial dysfunction and typically associated with Dominant Optic Atrophy (DOA), a progressive blinding disease involving retinal ganglion cell loss and optic nerve damage. In the current study, we investigate the use of codon-optimized versions of OPA1 isoform 1 and 7 as potential therapeutic interventions in a range of in vitro and in vivo models of mitochondrial dysfunction. We demonstrate that both isoforms perform equally well in ameliorating mitochondrial dysfunction in OPA1 knockout mouse embryonic fibroblast cells but that OPA1 expression levels require tight regulation for optimal benefit. Of note, we demonstrate for the first time that both OPA1 isoform 1 and 7 can be used independently to protect spatial visual function in a murine model of retinal ganglion cell degeneration caused by mitochondrial dysfunction, as well as providing benefit to mitochondrial bioenergetics in DOA patient derived fibroblast cells. These results highlight the potential value of OPA1-based gene therapy interventions. |
format | Online Article Text |
id | pubmed-7726421 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-77264212020-12-14 Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction Maloney, Daniel M. Chadderton, Naomi Millington-Ward, Sophia Palfi, Arpad Shortall, Ciara O’Byrne, James J. Cassidy, Lorraine Keegan, David Humphries, Peter Kenna, Paul Farrar, Gwyneth Jane Front Neurosci Neuroscience Optic Atrophy 1 (OPA1) is a mitochondrially targeted GTPase that plays a pivotal role in mitochondrial health, with mutations causing severe mitochondrial dysfunction and typically associated with Dominant Optic Atrophy (DOA), a progressive blinding disease involving retinal ganglion cell loss and optic nerve damage. In the current study, we investigate the use of codon-optimized versions of OPA1 isoform 1 and 7 as potential therapeutic interventions in a range of in vitro and in vivo models of mitochondrial dysfunction. We demonstrate that both isoforms perform equally well in ameliorating mitochondrial dysfunction in OPA1 knockout mouse embryonic fibroblast cells but that OPA1 expression levels require tight regulation for optimal benefit. Of note, we demonstrate for the first time that both OPA1 isoform 1 and 7 can be used independently to protect spatial visual function in a murine model of retinal ganglion cell degeneration caused by mitochondrial dysfunction, as well as providing benefit to mitochondrial bioenergetics in DOA patient derived fibroblast cells. These results highlight the potential value of OPA1-based gene therapy interventions. Frontiers Media S.A. 2020-11-26 /pmc/articles/PMC7726421/ /pubmed/33324145 http://dx.doi.org/10.3389/fnins.2020.571479 Text en Copyright © 2020 Maloney, Chadderton, Millington-Ward, Palfi, Shortall, O’Byrne, Cassidy, Keegan, Humphries, Kenna and Farrar. 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 Maloney, Daniel M. Chadderton, Naomi Millington-Ward, Sophia Palfi, Arpad Shortall, Ciara O’Byrne, James J. Cassidy, Lorraine Keegan, David Humphries, Peter Kenna, Paul Farrar, Gwyneth Jane Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction |
title | Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction |
title_full | Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction |
title_fullStr | Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction |
title_full_unstemmed | Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction |
title_short | Optimized OPA1 Isoforms 1 and 7 Provide Therapeutic Benefit in Models of Mitochondrial Dysfunction |
title_sort | optimized opa1 isoforms 1 and 7 provide therapeutic benefit in models of mitochondrial dysfunction |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726421/ https://www.ncbi.nlm.nih.gov/pubmed/33324145 http://dx.doi.org/10.3389/fnins.2020.571479 |
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