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bioRxiv · 10.1101/2020.03.18.996561

Opa1 overexpression protects from early onset Mpv17-/--related mouse kidney disease

Zeviani, M.·Luna-Sanchez, M.·Beninca, C.·Cerutti, R.·Yeats, A.·Scorrano, L.·Viscomi, C.·Brea Calvo, G.
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Abstract

Moderate overexpression of Opa1, encoding a master regulator of mitochondrial cristae morphology, has been shown to improve significantly mitochondrial damage induced by drugs, surgical denervation, or genetically determined OXPHOS defects. However, this approach has been so far demonstrated in a limited number of genetically defective OXPHOS models characterized by specific impairment of a single mitochondrial respiratory chain complex. Here, we investigated the effectiveness of moderate Opa1 overexpression in the Mpv17-/- mouse, characterized by profound, multisystem mtDNA depletion. In naive Mpv17-/- individuals, whose genetic background was crossed with individuals belonging to the Opa1tg strain, we found a surprising anticipation of severe, progressive focal segmental glomerulosclerosis, previously described in Mpv17-/- animals as a late-onset clinical feature (after 12-18 months of life). In contrast, kidney failure led Mpv17-/- individuals from this new "mixed" strain leading to death 8-9 weeks after birth. However, Mpv17-/-::Opa1tg mice lived much longer than Mpv17-/- littermates, and developed much later severe proteinuria associated with focal segmental glomerulosclerosis. MtDNA content and OXPHOS activities were significantly higher in Mpv17-/-::Opa1tg than in Mpv17-/- kidneys, and similar to WT littermates. Mitochondrial network and cristae ultrastructure were largely preserved in Mpv17-/-::Opa1tg vs. 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, consequently increasing the levels of mitochondrial morphology proteins like MFN2 and MIC19 as well as stabilizing ATP synthase oligomers. These results demonstrate that strategies aiming at increasing Opa1 expression or activity can be an effective aid against mtDNA depletion syndromes.

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Zeviani, M., Luna-Sanchez, M., Beninca, C., Cerutti, R., Yeats, A., Scorrano, L., Viscomi, C., Brea Calvo, G.. 2020-03-18. Opa1 overexpression protects from early onset Mpv17-/--related mouse kidney disease. https://doi.org/10.1101/2020.03.18.996561

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