摘要 : Coronary heart disease (CHD) is the leading cause of death worldwide. Mitochondrial genetic determinant for the development of CHD remains poorly explored.We report there the clinical, genetic, molecular and biochemical characteri... 展开 Coronary heart disease (CHD) is the leading cause of death worldwide. Mitochondrial genetic determinant for the development of CHD remains poorly explored.We report there the clinical, genetic, molecular and biochemical characterization of a four-generation Chinese family with maternally inherited CHD. Thirteen of 32 adult members in this family exhibited variable severityandage-at-onset ofCHD.Mutational analysis of their mitochondrial genomes identified the tRNAThr 15927G>Amutation belonging to the Eastern Asian haplogroup B5. The anticipated destabilization of a highly conserved base-pairing (28C-42G) by the 15927G>Amutation affects structure and function of tRNAThr. Northern analysis revealed ≈80% decrease in the steady-state level of tRNAThr in the mutant cell lines carrying the 15927G>A mutation. The 15927G>A mutation changed the conformation of tThr, as suggested by slower electrophoretic mobility of mutated tRNA with respect to the wild-type molecule. In addition, ~39% reduction in aminoacylated efficiency of tRNAThr was observed in mutant cells derived from this Chinese family. An in vivo mitochondrial protein labeling analysis showed ~53% reduction in the rate of mitochondrial translation in mutant cells. The impaired mitochondrial protein synthesis leads to defects in overall respiratory capacity or malate/glutamate-promoted respiration or succinate/glycerol-3-phosphatepromoted respiration, or N,N,N',N'-tetramethyl-pphenylenediamine/ascorbate-promoted respiration in mutant cells. An increasing production of reactive oxygen species was observed in the mutant cells carrying the 15927G>A mutation. These results provide the direct evidence that the tRNAThr 15927G>A mutation is associated with CHD. Our findings may provide new insights into pathophysiology and intervention targets of this disorder. 收起