Maternally inherited coronary heart disease is associated with a novel mitochondrial tRNA mutation

Abstract

Background: Coronary heart disease (CHD) is the most common cause of mortality globally, yet mitochondrial genetic mutations associated with CHD development remain incompletely understood. Methods: The 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 tRNA Thr 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). Results: We 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 tRNA Thr 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 tRNA Thr functionality. When we performed Northern blotting, we detected we observed a 37.5% reduction in tRNA Thr 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. Conclusions: In the present report, Together these findings suggest a possible link between this 15910C > T tRNA Thr mutation and CHD, potentially offering new avenues for future disease intervention.

The Role of Mitochondrial DNA Mutations in Cardiovascular Diseases

“…Alone or in combination with LTL associated with recurrent MACEs and all-cause mortality in Caucasian CAD patients [38] Associated with MACEs and all-cause mortality in Italian CAD patients [39] In combination with low folate level associated with high CAD risk among Chinese diabetic patients [40] Mt15910 (C > T) tRNA Thr Han Chinese patients withLHON, signs of maternally inherited CHD [41] The mtDNA mutations associated with CAD could be grouped into several main categories, each with different mechanisms of action: (1) mutations in tRNA were predicted to destabilize the base pairing at the affected sites, potentially altering the secondary structure of this tRNA and causing its quicker degradation and the subsequent reduction in mitochondrial protein levels [41]; (2) mutations in the OXPHOS components were shown to reduce ATP synthesis and increase ROS production; and (3) mutations in the D-loop would interrupt the normal mtDNA replication process, resulting in the reduced mtDNA copy number [38]. Interestingly, the majority of identified mtDNA mutations were found to be non-pathogenic or mild; thus, they may not be able to cause a certain pathogenic phenotype development [42].…”

“…The cybrid cells carrying the Mt15910 (C > T) mutation (tRNA Thr ) had 37.5% lower levels of tRNA Thr in comparison to healthy control cells, suggesting that the Mt15910 (C > T) mutation speeds up its degradation [41]. Previously, similar results were described for other tRNA mutations, Mt3243 (A > G) tRNA Leu(UUR) [79], Mt5655 (T > C) tRNA Ala , Mt10003 (T > C) tRNA Gly , Mt3253 (T > C) tRNA Leu(UUR) , Mt7551 (A > G) tRNA Asp and Mt14692 (A > G) tRNA Glu [45].…”

“…Previously, similar results were described for other tRNA mutations, Mt3243 (A > G) tRNA Leu(UUR) [79], Mt5655 (T > C) tRNA Ala , Mt10003 (T > C) tRNA Gly , Mt3253 (T > C) tRNA Leu(UUR) , Mt7551 (A > G) tRNA Asp and Mt14692 (A > G) tRNA Glu [45]. Subsequently, alterations of the tRNA levels lead to the reduced rate of mitochondrial protein synthesis and a reduction in mitochondrial protein levels in the mutant cells, altered complex I/III activity, electron leakage and a rise in ROS production [41]. Elevated levels of ROS production could lead to the damage of cellular biomolecules and contribute to the disease-related phenotype (discussed in the following section).…”

Comments on: Outer retinal tubulation and inner retinal pseudocysts in a patient with maternally inherited diabetes and deafness evaluated with optical coherence tomography angiogram

“…In addition, we should be informed about the cause of ischemic heart disease,[ 1 ] that is, whether it was due to coronary heart disease from diabetes or a primary manifestation of the underlying genetic defect, as has been recently demonstrated. [ 5 ]…”

Response to comments on: Outer retinal tubulation and inner retinal pseudocysts in a patient with maternally inherited diabetes and deafness evaluated with optical coherence tomography angiogram

“… Various mtDNA mutations have been implicated in the pathogenesis of coronary heart disease/atherosclerotic vascular lesion including G12315A (gene MT-TL2), G15059A (gene MT-CYB), C3256T (gene MT-TL1),[ 4 ] and G13513A (gene MT-ND5),[ 5 ] and 15910C>T tRNA Thr . [ 6 ] However, whether the coronary artery disease in our index case was related to some mutation in the mtDNA or was due to diabetes is unknown. However, we do not agree with the comment[ 1 ] that 'Overall, this interesting case report has a number of shortcomings that need to be addressed before the conclusions drawn can be adopted.'…”