A coronary artery disease-associated tRNAThr mutation altered mitochondrial function, apoptosis and angiogenesis. Issue 4 (12th December 2018)

• Record Type: Journal Article
• Authors: Jia, Zidong; Zhang, Ye; Li, Qiang; Ye, Zhenzhen; Liu, Yuqi; Fu, Changzhu; Cang, Xiaohui; Wang, Meng; Guan, Min-Xin
• Is Part Of: Nucleic acids research. Volume 47:Issue 4(2019)
• Page Start: 2056
• Page End: 2074
• Publication Date: 2018-12-12
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gky1241
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: The tissue specificity of mitochondrial tRNA mutations remains largely elusive. In this study, we demonstrated the deleterious effects of tRNA Thr 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 tRNA Thr . Using molecular dynamics simulations, we showed that the m.15927G>A mutation caused unstable tRNA Thr 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 tRNA Thr . The aberrant tRNA Thr 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 tRNA Thr mutation-induced alterations.