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

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 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.

High-Dose Primaquine Induces Proximal Tubular Degeneration and Ventricular Cardiomyopathy Linked to Host Cells Mitochondrial Dysregulation

“…Subsequently, using a gold-labeled technique, the expression of OPA-1, HDHD-3, and Nrf-2 in renal and hepatic mitochondria was evaluated in this study. In a mouse model, the increase of OPA-1, a master regulator of mitochondrial cristae morphology, reduces mitochondrial damage from various causes, including mitochondrial DNA depletion-induced glomerulosclerosis [ 26 ] and sorafenib-induced (an anticancer agent) hepatocyte apoptosis [ 27 ]. In liver mitochondria treated with a high dose of PQ, our research revealed a downregulation of OPA-1, whereas renal mitochondria tended to exhibit a slight upregulation.…”

In-depth study of MPV17: a molecular travel unveiling a mitochondrial calcium regulation function

“…SYM1, the yeast ortholog of MPV17, exhibits strong evolutionary conservation as its depletion can be complemented by human MPV17 expression which can rescue the impaired OXPHOS activity and growth defect under non-fermentable condition (Dallabona et al, 2010). SYM1 depletion leads to mitochondrial ultrastructure defects (Dallabona et al, 2010), as also observed in glomeruli cells of MPV17 -/--related kidney disease mouse model (Luna-Sanchez et al, 2020) and in mpv17 -/zebrafish larvae muscle (Bian et al, 2021). The maintenance of the mitochondrial ultrastructure is mainly achieved by the MItochondrial contact site and Cristae Organizing System (MICOS) complex, which is part of the Mitochondrial Intermembrane space Bridging (MIB) supercomplex.…”

“…The MICOS complex is involved in the cristae formation and cristae junction stabilization and bridges the outer and inner membranes of mitochondria, by the interaction with the SAM50 outer membrane complex (reviewed in Kozjak-Pavlovic, 2017). Interestingly, MICOS disassembly and destabilization of the mitochondrial ultrastructure were reported in glomeruli cells from MPV17 -/mouse model, and OPA1 overexpression restored the mtDNA depletion observed in those cells (Luna-Sanchez et al, 2020). Additionally, MPV17 co-immunoprecipitates with the MICOS complex as well as with components of the ATP synthase complex and the membrane Permeability Transition Pore (mPTP) in mouse cardiomyocytes.…”

A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool

“…MPV17 protein and its mouse (Mpv17), zebrafish (tra/Mpv17) and Saccharomyces cerevisie (Sym1) orthologs show a high degree of conservation [6]. MPV17 takes part within a high molecular weight complex [7,8] and forms a non selective channel in the IMM affecting mitochondrial membrane potential, reactive oxygen species (ROS) production and cristae formation [7,[9][10][11]. However, the physiological role of the channel and the nature of the cargo remain elusive.…”

“…Therapeutic strategies with potential general applicability to several mitochondrial diseases have been proposed (reviewed in [15,16]). An effective strategy against the deleterious role of cristae disruption in mitochondrial pathogenic mechanisms has been successfully exploited in a mouse [11], thanks to a moderate overexpression of Opa1 [17], a master regulator of shape and function of mitochondrial cristae.…”