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AAV-mediated transduction of the Ant1 gene restores heart function in the Ant1-/- mouse model of mitochondrial cardiomyopathy

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. We then transduced the neonatal Ant1-/- and Ant1-/-+ND6P25L mouse hearts with an AAV2/9-pDes-Gfp-mAnt1 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, a modest increase in cardiac mitochondrial energetics can have profound benefits on cardiac function and is effective in treating mitochondrial cardiomyopathy.Samples 1-3: WT (C57BL/6J).Samples 4-6: AAV (ANT1-/- treated with ANT1 AAV).Samples 7-9: ANT1-/-. Biological replicates were run once each.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Kevin A Janssen

LAB HEAD: Douglas Wallace

PROVIDER: PXD058090 | Pride | 2025-10-28

REPOSITORIES: Pride

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			Action	DRS
	231228_KJ_AA1_20231229230322.raw	Raw
	231228_KJ_AA2_20231230013244.raw	Raw
	231228_KJ_AA3_20231230040204.raw	Raw
	231228_KJ_AA4_20231230063127.raw	Raw
	231228_KJ_AA5_20231230090056.raw	Raw

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Project description: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 (SLC25A4, ANT1) gene, the severity of the cardiomyopathy being mediated by the mitochondrial DNA (mtDNA). To optimize strategies for addressing mitochondrial cardiomyopathy, we generated an Ant1 null mouse and combined it with the ND6P25L mtDNA mutation to mimic the hypertrophic versus dilated cardiomyopathies observed in patients. Here, we transduce the neonatal Ant1-/- and Ant1-/-+ND6P25L mouse hearts with an AAV2/9-pDes-Gfp-mAnt1 cDNA vector. We show that restoration of just 10% of Ant1 gene expression was sufficient to ameliorate the cardiomyopathies in these mice. Proteomics and single-nucleus RNA sequencing reveal the reversal of dysregulated mitochondrial metabolic genes, including PGC1α, as well as cardiac contractile and extracellular matrix proteins. Hence, a modest increase in cardiac mitochondrial energetics can have profound benefits on cardiac function and is effective in treating mitochondrial cardiomyopathy.

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