Cargando…

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....

Descripción completa

Detalles Bibliográficos
Autores principales: Luna-Sanchez, Marta, Benincá, Cristiane, Cerutti, Raffaele, Brea-Calvo, Gloria, Yeates, Anna, Scorrano, Luca, Zeviani, Massimo, Viscomi, Carlo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
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
_version_ 1783566948438638592
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
work_keys_str_mv AT lunasanchezmarta opa1overexpressionprotectsfromearlyonsetmpv17relatedmousekidneydisease
AT benincacristiane opa1overexpressionprotectsfromearlyonsetmpv17relatedmousekidneydisease
AT ceruttiraffaele opa1overexpressionprotectsfromearlyonsetmpv17relatedmousekidneydisease
AT breacalvogloria opa1overexpressionprotectsfromearlyonsetmpv17relatedmousekidneydisease
AT yeatesanna opa1overexpressionprotectsfromearlyonsetmpv17relatedmousekidneydisease
AT scorranoluca opa1overexpressionprotectsfromearlyonsetmpv17relatedmousekidneydisease
AT zevianimassimo opa1overexpressionprotectsfromearlyonsetmpv17relatedmousekidneydisease
AT viscomicarlo opa1overexpressionprotectsfromearlyonsetmpv17relatedmousekidneydisease