UC Irvine

In this report, we investigated the pathogenic mechanism underlying the deafness-associated mitochondrial(mt) tRNA^Asp 7551A > G mutation. The m.7551A > G mutation is localized at a highly conserved nucleotide(A37), adjacent (3') to the anticodon, which is important for the fidelity of codon recognition and stabilization in functional tRNAs. It was anticipated that the m.7551A > G mutation altered the structure and function of mt-tRNA^Asp The primer extension assay demonstrated that the m.7551A > G mutation created the m¹G37 modification of mt-tRNA^Asp Using cybrid cell lines generated by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mitochondrial DNA(mtDNA)-less (ρ^o) cells, we demonstrated the significant decreases in the efficiency of aminoacylation and steady-state level of mt-tRNA^Asp in mutant cybrids, compared with control cybrids. A failure in metabolism of mt-tRNA^Asp caused the variable reductions in mtDNA-encoded polypeptides in mutant cybrids. Impaired mitochondrial translation led to the respiratory phenotype in mutant cybrids. The respiratory deficiency lowed mitochondrial adenosine triphosphate production and increased the production of oxidative reactive species in mutant cybrids. Our data demonstrated that mitochondrial dysfunctions caused by the m.7551A > G mutation are associated with deafness. Our findings may provide new insights into the pathophysiology of maternally transmitted deafness that was manifested by altered nucleotide modification of mitochondrial tRNA.