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Opa1 Overexpression Protects from Early-Onset Mpv17(−/−)-Related Mouse Kidney Disease
Moderate overexpression of Opa1, the master regulator of mitochondrial cristae morphology, significantly improved mitochondrial damage induced by drugs, surgical denervation, or oxidative phosphorylation (OXPHOS) defects due to specific impairment of a single mitochondrial respiratory chain complex....
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403474/ https://www.ncbi.nlm.nih.gov/pubmed/32562616 http://dx.doi.org/10.1016/j.ymthe.2020.06.010 |
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author | Luna-Sanchez, Marta Benincá, Cristiane Cerutti, Raffaele Brea-Calvo, Gloria Yeates, Anna Scorrano, Luca Zeviani, Massimo Viscomi, Carlo |
author_facet | Luna-Sanchez, Marta Benincá, Cristiane Cerutti, Raffaele Brea-Calvo, Gloria Yeates, Anna Scorrano, Luca Zeviani, Massimo Viscomi, Carlo |
author_sort | Luna-Sanchez, Marta |
collection | PubMed |
description | Moderate overexpression of Opa1, the master regulator of mitochondrial cristae morphology, significantly improved mitochondrial damage induced by drugs, surgical denervation, or oxidative phosphorylation (OXPHOS) defects due to specific impairment of a single mitochondrial respiratory chain complex. Here, we investigated the effectiveness of this approach in the Mpv17(−/−) mouse, characterized by profound, multisystem mitochondrial DNA (mtDNA) depletion. After the crossing with Opa1(tg) mice, we found a surprising anticipation of the severe, progressive focal segmental glomerulosclerosis, previously described in Mpv17(−/−) animals as a late-onset clinical feature (after 12–18 months of life). In contrast, Mpv17(−/−) animals from this new “mixed” strain died at 8–9 weeks after birth because of severe kidney failure However, Mpv17(−/−)::Opa1(tg) mice lived much longer than Mpv17(−/−) littermates and developed the kidney dysfunction much later. mtDNA content and OXPHOS activities were significantly higher in Mpv17(−/−)::Opa1(tg) than in Mpv17(−/−) kidneys and similar to those for wild-type (WT) littermates. Mitochondrial network and cristae ultrastructure were largely preserved in Mpv17(−/−)::Opa1(tg) versus Mpv17(−/−) kidney and isolated podocytes. Mechanistically, the protective effect of Opa1 overexpression in this model was mediated by a block in apoptosis due to the stabilization of the mitochondrial cristae. These results demonstrate that strategies aiming at increasing Opa1 expression or activity can be effective against mtDNA depletion syndromes. |
format | Online Article Text |
id | pubmed-7403474 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-74034742020-09-17 Opa1 Overexpression Protects from Early-Onset Mpv17(−/−)-Related Mouse Kidney Disease Luna-Sanchez, Marta Benincá, Cristiane Cerutti, Raffaele Brea-Calvo, Gloria Yeates, Anna Scorrano, Luca Zeviani, Massimo Viscomi, Carlo Mol Ther Original Article Moderate overexpression of Opa1, the master regulator of mitochondrial cristae morphology, significantly improved mitochondrial damage induced by drugs, surgical denervation, or oxidative phosphorylation (OXPHOS) defects due to specific impairment of a single mitochondrial respiratory chain complex. Here, we investigated the effectiveness of this approach in the Mpv17(−/−) mouse, characterized by profound, multisystem mitochondrial DNA (mtDNA) depletion. After the crossing with Opa1(tg) mice, we found a surprising anticipation of the severe, progressive focal segmental glomerulosclerosis, previously described in Mpv17(−/−) animals as a late-onset clinical feature (after 12–18 months of life). In contrast, Mpv17(−/−) animals from this new “mixed” strain died at 8–9 weeks after birth because of severe kidney failure However, Mpv17(−/−)::Opa1(tg) mice lived much longer than Mpv17(−/−) littermates and developed the kidney dysfunction much later. mtDNA content and OXPHOS activities were significantly higher in Mpv17(−/−)::Opa1(tg) than in Mpv17(−/−) kidneys and similar to those for wild-type (WT) littermates. Mitochondrial network and cristae ultrastructure were largely preserved in Mpv17(−/−)::Opa1(tg) versus Mpv17(−/−) kidney and isolated podocytes. Mechanistically, the protective effect of Opa1 overexpression in this model was mediated by a block in apoptosis due to the stabilization of the mitochondrial cristae. These results demonstrate that strategies aiming at increasing Opa1 expression or activity can be effective against mtDNA depletion syndromes. American Society of Gene & Cell Therapy 2020-08-05 2020-06-12 /pmc/articles/PMC7403474/ /pubmed/32562616 http://dx.doi.org/10.1016/j.ymthe.2020.06.010 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Luna-Sanchez, Marta Benincá, Cristiane Cerutti, Raffaele Brea-Calvo, Gloria Yeates, Anna Scorrano, Luca Zeviani, Massimo Viscomi, Carlo Opa1 Overexpression Protects from Early-Onset Mpv17(−/−)-Related Mouse Kidney Disease |
title | Opa1 Overexpression Protects from Early-Onset Mpv17(−/−)-Related Mouse Kidney Disease |
title_full | Opa1 Overexpression Protects from Early-Onset Mpv17(−/−)-Related Mouse Kidney Disease |
title_fullStr | Opa1 Overexpression Protects from Early-Onset Mpv17(−/−)-Related Mouse Kidney Disease |
title_full_unstemmed | Opa1 Overexpression Protects from Early-Onset Mpv17(−/−)-Related Mouse Kidney Disease |
title_short | Opa1 Overexpression Protects from Early-Onset Mpv17(−/−)-Related Mouse Kidney Disease |
title_sort | opa1 overexpression protects from early-onset mpv17(−/−)-related mouse kidney disease |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403474/ https://www.ncbi.nlm.nih.gov/pubmed/32562616 http://dx.doi.org/10.1016/j.ymthe.2020.06.010 |
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