Abstract
BackgroundCoronary heart disease (CHD) is the most common cause of mortality globally, yet mitochondrial genetic mutations associated with CHD development remain incompletely understood.MethodsThe subjects from three Chinese families with LHON underwent clinical, genetic, molecular, and biochemical evaluations. Biochemical characterizations included measuring the effects of the15910C > T mutation on tRNAThr levels, enzymatic activity of electron transport chain complexes, membrane permeability, and the mitochondria-mediated generation of both reactive oxygen species (ROS) and adenosine triphosphate (ATP).ResultsWe characterize mitochondrial genetic mutations in a three-generation Chinese family exhibiting signs of maternally inherited CHD. Of the 24 different family members in this pedigree we assessed, CHD was detected in 6, with variable severity and age of first appearance. When we sequenced the mitochondrial genomes of these individuals, we found a tRNAThr 15910C > T mutation of the Eastern Asian haplogroup M7b’c. This mutation is predicted to destabilize the strongly conserved (24C-10G) base-pairing, thereby disrupting tRNAThr functionality. When we performed Northern blotting, we detected we observed a 37.5% reduction in tRNAThr levels at baseline in cybrid cell lines bearing the 15910C > T mutation. When we conducted western blot analysis, we detected a ~ 24.96% decrease in mitochondrial translation rates in these same cells.ConclusionsIn the present report, Together these findings suggest a possible link between this 15910C > T tRNAThr mutation and CHD, potentially offering new avenues for future disease intervention.
Highlights
Coronary heart disease (CHD) is the most common cause of mortality globally, yet mitochondrial genetic mutations associated with CHD development remain incompletely understood
We found that tRNAThr levels in these mutant cybrid lines were significantly reduced relative to control wild type cells (Fig. 2), with baseline tRNAThr levels in these mutant cells being 65.25% of those in control cells, with 5S RNA used for normalization purposes
Such reactive oxygen species (ROS) production can lead to significant damage to cellular macromolecules including DNA and proteins, potentially leading to cellular dysfunction or apoptotic cell death which, if it were to occur in cardiac muscle cells, could contribute to the observed CHD phenotype, potnetially explaining how these mutations contribute to the observed matrilineal CHD, as hypertension-associated mitochondrial tRNAAla m.5655A > G m
Summary
Coronary heart disease (CHD) is the most common cause of mortality globally, yet mitochondrial genetic mutations associated with CHD development remain incompletely understood. When we analyzed their mtDNA, we detected the presence of a tRNAThr 15910C > T mutation of the M7b’c haplogroup This mutation occurred in the stem region of this tRNA (conventional position 25) a site that is highly conserved and the mutation of which is predicted to result in structural and functional changes that have the potential to disrupt normal mitochondrial functionality. After identifying this mutation we followed up on its biological significance in cybrid cell lines bearing this mutation, measuring the effects of this15910C > T mutation on tRNAThr levels, enzymatic activity of electron transport chain complexes, membrane permeability, and the mitochondria-mediated generation of both reactive oxygen species (ROS) and adenosine triphosphate (ATP)
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