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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 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.

SUBMITTER: Luna-Sanchez M

PROVIDER: S-EPMC7403474 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Opa1 Overexpression Protects from Early-Onset Mpv17<sup>-/-</sup>-Related Mouse Kidney Disease.

Luna-Sanchez Marta M Benincá Cristiane C Cerutti Raffaele R Brea-Calvo Gloria G Yeates Anna A Scorrano Luca L Zeviani Massimo M Viscomi Carlo C

Molecular therapy : the journal of the American Society of Gene Therapy 20200612 8

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<sup>-/-</sup> mouse, characterized by profound, multisystem mitochondrial DNA (mtDNA) depletion. After the crossing with Opa1<sup ...[more]

PMID: 32562616

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Project description:Fibroblast growth factor 23 (FGF23) production is regulated by both calciotropic hormones and inflammation. Consistent with this, elevated FGF23 levels are associated with inflammatory markers as well as parathyroid hormone (PTH) in various disease states, including chronic kidney disease (CKD). However, the molecular mechanisms underpinning Fgf23 transcription in response to these regulators are largely unknown. We therefore utilized chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) data from an osteocyte cell line to identify potential regulatory regions of the Fgf23 gene. Based on ChIP-seq analysis of enhancer-associated histone modifications, including H3K4 methylation and H3K9 acetylation, we discovered several potential enhancers for Fgf23, one of which was located 16kb upstream of the gene's transcriptional start site. Deletion of this putative enhancer from the mouse genome using CRISPR-Cas9 technology led to lower bone, thymus, and spleen expression of Fgf23 mRNA without altering circulating levels of the intact hormone, although as previously reported, only bone displayed significant basal expression. Nevertheless, lack of the -16kb enhancer blunted FGF23 upregulation in a tissue-specific manner by the acute inflammatory inducers lipopolysaccharide (LPS), interleukin-1-beta (IL-1β), and tumor necrosis factor-alpha (TNFα) in bone, non-osseous tissues, and in circulation. Lack of the -16kb enhancer also inhibited PTH-induced bone Fgf23 mRNA. Moreover, the absence of this Fgf23 enhancer in an oxalate diet-induced murine CKD model prevented the early onset induction of osseous, renal, and thymic Fgf23 mRNA levels and led to a significant blunting of elevated circulating intact FGF23 levels. These results suggest that -16kb enhancer mediates the induction of Fgf23 by inflammation and PTH and facilitates the increase in FGF23 expression in a murine model of CKD. As exemplified herein, these Fgf23 enhancer-deleted mice will provide a unique model in which to study the role of FGF23 expression in inflammatory diseases.

Dataset Information

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

Publications

Opa1 Overexpression Protects from Early-Onset Mpv17<sup>-/-</sup>-Related Mouse Kidney Disease.

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