دورية أكاديمية
Opa1 Overexpression Protects from Early-Onset Mpv17−/−-Related Mouse Kidney Disease
| العنوان: | Opa1 Overexpression Protects from Early-Onset Mpv17−/−-Related Mouse Kidney Disease |
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| المؤلفون: | Luna-Sanchez M., Beninca C., Cerutti R., Brea-Calvo G., Yeates A., Scorrano L., Zeviani M., Viscomi C. |
| المساهمون: | Luna-Sanchez, M., Beninca, C., Cerutti, R., Brea-Calvo, G., Yeates, A., Scorrano, L., Zeviani, M., Viscomi, C. |
| بيانات النشر: | Cell Press |
| سنة النشر: | 2020 |
| المجموعة: | Padua Research Archive (IRIS - Università degli Studi di Padova) |
| مصطلحات موضوعية: | apoptosi, focal segmental glomerulosclerosi, mitochondrial cristae, mitochondrial DNA depletion, Mpv17, Opa1, oxidative phosphorylation |
| الوصف: | 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 Opa1tg 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−/−::Opa1tg mice lived much longer than Mpv17−/− littermates and developed the kidney dysfunction much later. mtDNA content and OXPHOS activities were significantly higher in Mpv17−/−::Opa1tg than in Mpv17−/− kidneys and similar to those for wild-type (WT) littermates. Mitochondrial network and cristae ultrastructure were largely preserved in Mpv17−/−::Opa1tg 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. No treatment is currently available to syndromes associated to mitochondrial DNA instability. We investigated the possibility to correct the kidney disease typical of Mpv17−/− mice by transgenically overexpressing Opa1, the master regulator of mitochondrial cristae shape. Mpv17−/−::Opa1 double recombinant mice showed a marked prolongation of the lifespan, with correction of the proteinuria and of the focal segmental glomerulosclerosis, by reducing apoptosis in podocytes. Accordingly, ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/32562616; info:eu-repo/semantics/altIdentifier/wos/WOS:000560007200020; journal:MOLECULAR THERAPY; http://hdl.handle.net/11577/3344055Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85086786617 |
| DOI: | 10.1016/j.ymthe.2020.06.010 |
| الإتاحة: | https://doi.org/10.1016/j.ymthe.2020.06.010Test http://hdl.handle.net/11577/3344055Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.F278FA4C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ymthe.2020.06.010 |
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