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Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondiral cardiomyopathy

ABSTRACT: The goal of this study was to analyze the molecular changes that occur over the time course of disease in a mutant CHCHD10-related mouse model of primary mitochondrial cardiomyopathy.

ORGANISM(S): Mus musculus

PROVIDER: GSE193801 | GEO | 2022/01/18

REPOSITORIES: GEO

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Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy

Project description:Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knock-in mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt.

2022-03-01 | PXD031444 | Pride

Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy.

Project description:Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses, leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt.

| S-EPMC9013208 | biostudies-literature

Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondiral cardiomyopathy

Project description:Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondiral cardiomyopathy

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Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy

2022-01-27 | ST002068 | MetabolomicsWorkbench

High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice

Project description:Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.

2024-03-23 | GSE261796 | GEO

High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice

Project description:High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice

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Tandem Mass Tag proteomics in CHCHD10 patient cells

Project description:Mutations in CHCHD10, coding for a mitochondrial intermembrane space protein, are a rare cause of autosomal dominant amyotrophic lateral sclerosis (ALS). Mutation-specific toxic gain of function or haploinsuffuciency models have been proposed to explain pathogenicity. To decipher the metabolic dysfunction associated with the haploinsufficient p.R15L variant we conducted a TMT labelling experiment. Fibroblasts with the CHCHD10 p.R15L variant (hereafter referred to as ‘patient’), were compared to the same cells expressing wild-type CHCHD10 cDNA (hereafter called ‘rescue’) under nutrient stress, in which galactose was substituted for glucose.

2022-04-04 | PXD018806 | Pride

CHCHD10 gene KO effect in iPSC drived motor neurons

Project description:We investigate the transcriptional changes caused by the knock-out of neuropathy linked gene CHCHD10.

2019-11-07 | GSE133763 | GEO

Effects of CHCHD10 G58R and S59L mutations on global gene expression in the presence and absence of OMA1

Project description:Differential gene expression in CHCHD10 mutants with OMA1 present or knocked out This experiment used the Clariom_S_Mouse Microarray from Affymetrix to analyze the effect of CHCHD10 mutations on gene expression, and the effect of congenital OMA1 KO on gene expression in these CHCHD10 mutants.

2022-06-30 | GSE189393 | GEO

Effects of acute OMA1 knockdown on global gene expression in CHCHD10 G58R mutants

Project description:Differential gene expression in CHCHD10 G58R mouse hearts treated with nontargeting or OMA1-targeting antisense oligomers (ASOs) provided by Ionis Pharmaceuticals (Carlsbad, CA) This experiment used the Clariom_S_Mouse Microarray from Affymetrix to analyze the effect of acute OMA1 KD on gene expression in CHCHD10 G58R mouse hearts.

2022-06-30 | GSE189396 | GEO

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