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AAV-mediated transduction of the nuclear-coded mitochondrial Ant1 gene ameliorates cardiomyopathy in Ant1-/- mouse: A step toward treating mitochondrial disease.

ABSTRACT: Primary mitochondrial disease (PMD) patients manifesting cardiomyopathy are twice as likely to die as other PMD patients. One PMD with cardiomyopathy is caused by null mutations in the heart-muscle isoform of the adenine nucleotide translocator (ANT1) gene, the severity of the cardiomyopathy being mediated by the mitochondrial DNA (mtDNA). To perfect strategies for addressing mitochondria cardiomyopathy, we generated an Ant1 null mouse and combined it with our ND6P25L mtDNA mutation to mimic the hypertrophic versus dilated cardiomyopathies observed in patients, respectively. We then transduced the neonatal Ant1-/- and Ant1-/-+ND6P25L mouse hearts with an AAV9-pDesmin-GFP-Ant1 cDNA vector. Restoration of just 10% Ant1 gene expression was sufficient to ameliorate the cardiomyopathies in these mice. Proteomics and single nucleus RNA sequencing (snRNA-seq) revealed the reversal of dysregulated mitochondrial metabolic genes including PGC1α as well as cardiac contractile and extracellular matrix proteins. Hence, modest increase in cardiac mitochondrial energetics can have profound benefits on cardiac function and is effective in treating mitochondrial cardiomyopathy.

ORGANISM(S): Mus musculus

PROVIDER: GSE280991 | GEO | 2025/06/01

REPOSITORIES: GEO

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Project description:Exercise is a fundamental component of human health that is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of endurance exercise on human health are well established, the molecular mechanisms responsible for these observations remain unclear. Endurance exercise reduces the accumulation of mitochondrial DNA (mtDNA) mutations, alleviates multisystem pathology, and increases the lifespan of the mtDNA mutator mouse model of aging, in which the proof-reading capacity of mitochondrial polymerase gamma (POLG1) is deficient. Clearly, exercise recruited a POLG1-independent mtDNA repair pathway to induce these adaptations, a novel finding as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here we investigate the identity of this pathway, and show that endurance exercise prevents mitochondrial oxidative damage, attenuates telomere erosion, and mitigates cellular senescence and apoptosis in mtDNA mutator mice. Unexpectedly, we observe translocation of tumour suppressor protein p53 to mitochondria in response to endurance exercise that facilitates mtDNA mutation repair. Indeed, endurance exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, and mitigate premature mortality in mtDNA mutator mice with muscle-specific deletion of p53. Our data establish an exciting new role for p53 in exercise-mediated maintenance of the mtDNA genome, and presents mitochondrially-targeted p53 as a novel therapeutic modality for aging-associated diseases of mitochondrial etiology. Microarray analysis of gene expression from skeletal muscle (quadriceps femoris) from Mus musculus. N=23 samples per treatment were analysed for whole transcriptiome gene expression profile using NimbleGen Arrays. The treatment groups included wild-type C57Bl/6J mice as the control group, then two treatment groups which both contained homozygous knock-in mtDNA mutator mice (PolG; PolgAD257A/D257A). Once group of these heterozygous knock out mice received regular endurance exercise sessions while the other group remained sedentraty for 6 months. The control group specimens were wild-type litter mates to the transgenic knockout mice.

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AAV-mediated transduction of the nuclear-coded mitochondrial Ant1 gene ameliorates cardiomyopathy in Ant1-/- mouse: A step toward treating mitochondrial disease.

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