Abstract 15541: Potentially Adaptive Mt-trna Expression Regulation in Severe Metabolic Dysfunction
Circulation(2022)
摘要
Metabolic dysfunction is increasingly appreciated as characteristic of heart failure, particularly heart failure associated with advanced age. Mice harboring a mutant form of Polymerase Gamma (D257A, POLG), the mitochondrial DNA polymerase, display severe metabolic dysfunction, accelerated aging, and cardiac dysfunction. We recently reported sex specific aspects of cardiac remodeling in this model. We also proposed posttranscriptional/non-canonical activation of the mitochondrial unfolded protein response (mtUPR) in the POLG mutant based on analysis of nuclear encoded gene expression and available mass spectrometry data. Subsequent analysis of mitochondria encoded gene expression in the POLG mutant provides further support for the notion of alternate activation of the mtUPR in the POLG mutant heart. Specifically, we identify a pattern of differential mitochondrial tRNA (mt-tRNA) expression that shows surprising dependence on mt-tRNA chromosomal location as clusters of mt-tRNAs throughout the mitochondrial chromosome show similar expression change. Importantly, specific mt-tRNA expression changes negatively correlate (p=0.0017) with the propensity of the charged amino acid to be found in an amyloid fold. Thus, in addition to the mt-UPR impacting nuclear encoded gene expression, a yet unidentified mechanism exists to minimize protein missfolding in the mitochondria via regulation of mitochondrial tRNA expression.
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关键词
metabolic dysfunction,mt-trna
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