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- W2905156970 endingPage "2074" @default.
- W2905156970 startingPage "2056" @default.
- W2905156970 abstract "The tissue specificity of mitochondrial tRNA mutations remains largely elusive. In this study, we demonstrated the deleterious effects of tRNAThr 15927G>A mutation that contributed to pathogenesis of coronary artery disease. The m.15927G>A mutation abolished the highly conserved base-pairing (28C-42G) of anticodon stem of tRNAThr. Using molecular dynamics simulations, we showed that the m.15927G>A mutation caused unstable tRNAThr structure, supported by decreased melting temperature and slower electrophoretic mobility of mutated tRNA. Using cybrids constructed by transferring mitochondria from a Chinese family carrying the m.15927G>A mutation and a control into mitochondrial DNA (mtDNA)-less human umbilical vein endothelial cells, we demonstrated that the m.15927G>A mutation caused significantly decreased efficiency in aminoacylation and steady-state levels of tRNAThr. The aberrant tRNAThr metabolism yielded variable decreases in mtDNA-encoded polypeptides, respiratory deficiency, diminished membrane potential and increased the production of reactive oxygen species. The m.15927G>A mutation promoted the apoptosis, evidenced by elevated release of cytochrome c into cytosol and increased levels of apoptosis-activated proteins: caspases 3, 7, 9 and PARP. Moreover, the lower wound healing cells and perturbed tube formation were observed in mutant cybrids, indicating altered angiogenesis. Our findings provide new insights into the pathophysiology of coronary artery disease, which is manifested by tRNAThr mutation-induced alterations." @default.
- W2905156970 created "2018-12-22" @default.
- W2905156970 creator A5008897912 @default.
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- W2905156970 date "2018-12-12" @default.
- W2905156970 modified "2023-10-16" @default.
- W2905156970 title "A coronary artery disease-associated tRNAThr mutation altered mitochondrial function, apoptosis and angiogenesis" @default.
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- W2905156970 doi "https://doi.org/10.1093/nar/gky1241" @default.
- W2905156970 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6393294" @default.
- W2905156970 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30541130" @default.