Opa1 Overexpression Protects from Early-Onset Mpv17-Related Mouse Kidney Disease.

TitleOpa1 Overexpression Protects from Early-Onset Mpv17-Related Mouse Kidney Disease.
Publication TypeJournal Article
Year of Publication2020
AuthorsLuna-Sanchez, M, Benincá, C, Cerutti, R, Brea-Calvo, G, Yeates, A, Scorrano, L, Zeviani, M, Viscomi, C
JournalMol Ther
Date Published2020 Jun 12

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 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 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 than in Mpv17 kidneys and similar to those for wild-type (WT) littermates. Mitochondrial network and cristae ultrastructure were largely preserved in Mpv17::Opa1 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.

Alternate JournalMol. Ther.
Citation Key10.1016/j.ymthe.2020.06.010
PubMed ID32562616