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Opa1 Overexpression Protects from Early-Onset Mpv17-/--Related Mouse Kidney Disease.
Mol Ther. 2020 Aug 05; 28(8):1918-1930.MT

Abstract

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.

Authors+Show Affiliations

University of Cambridge - MRC Mitochondrial Biology Unit, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.University of Cambridge - MRC Mitochondrial Biology Unit, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.University of Cambridge - MRC Mitochondrial Biology Unit, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.Centro Andaluz de Biología de Desarrollo and CIBERER, ISCIII, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.Medical Research Council - Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.Venetian Institute of Molecular Medicine, Via Orus 2, 35128 Padova, Italy; Department of Biology, University of Padova, via Ugo Bassi 58/B, 35131 Padova, Italy.Venetian Institute of Molecular Medicine, Via Orus 2, 35128 Padova, Italy; Department of Neurosciences, University of Padova, via Giustiniani 2, 35128 Padova, Italy. Electronic address: massimo.zeviani@unipd.it.Department of Biomedical Sciences, University of Padova, via Ugo Bassi 58/B, 35131 Padova, Italy. Electronic address: carlo.viscomi@unipd.it.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32562616

Citation

Luna-Sanchez, Marta, et al. "Opa1 Overexpression Protects From Early-Onset Mpv17-/--Related Mouse Kidney Disease." Molecular Therapy : the Journal of the American Society of Gene Therapy, vol. 28, no. 8, 2020, pp. 1918-1930.
Luna-Sanchez M, Benincá C, Cerutti R, et al. Opa1 Overexpression Protects from Early-Onset Mpv17-/--Related Mouse Kidney Disease. Mol Ther. 2020;28(8):1918-1930.
Luna-Sanchez, M., Benincá, C., Cerutti, R., Brea-Calvo, G., Yeates, A., Scorrano, L., Zeviani, M., & Viscomi, C. (2020). Opa1 Overexpression Protects from Early-Onset Mpv17-/--Related Mouse Kidney Disease. Molecular Therapy : the Journal of the American Society of Gene Therapy, 28(8), 1918-1930. https://doi.org/10.1016/j.ymthe.2020.06.010
Luna-Sanchez M, et al. Opa1 Overexpression Protects From Early-Onset Mpv17-/--Related Mouse Kidney Disease. Mol Ther. 2020 Aug 5;28(8):1918-1930. PubMed PMID: 32562616.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Opa1 Overexpression Protects from Early-Onset Mpv17-/--Related Mouse Kidney Disease. AU - Luna-Sanchez,Marta, AU - Benincá,Cristiane, AU - Cerutti,Raffaele, AU - Brea-Calvo,Gloria, AU - Yeates,Anna, AU - Scorrano,Luca, AU - Zeviani,Massimo, AU - Viscomi,Carlo, Y1 - 2020/06/12/ PY - 2020/03/23/received PY - 2020/05/06/revised PY - 2020/06/08/accepted PY - 2021/08/05/pmc-release PY - 2020/6/21/pubmed PY - 2020/6/21/medline PY - 2020/6/21/entrez KW - Mpv17 KW - Opa1 KW - apoptosis KW - focal segmental glomerulosclerosis KW - mitochondrial DNA depletion KW - mitochondrial cristae KW - oxidative phosphorylation SP - 1918 EP - 1930 JF - Molecular therapy : the journal of the American Society of Gene Therapy JO - Mol. Ther. VL - 28 IS - 8 N2 - 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. SN - 1525-0024 UR - https://www.unboundmedicine.com/medline/citation/32562616/Opa1_Overexpression_Protects_from_Early-Onset_Mpv17-/--Related_Mouse_Kidney_Disease L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-0016(20)30300-2 DB - PRIME DP - Unbound Medicine ER -
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