Several mitochondrial
tRNA mutations have been associated with
maternally inherited diabetes and deafness. However, the pathophysiology of these
tRNA mutations remains poorly understood. In this report, we identified the novel homoplasmic 14692A→G mutation in the mitochondrial
tRNAGlu gene among three Han Chinese families with
maternally inherited diabetes and deafness. The m.14692A→G mutation affected a highly conserved
uridine at position 55 of the TΨC loop of
tRNAGlu The
uridine is modified to
pseudouridine (Ψ55), which plays an important role in the structure and function of this
tRNA. Using lymphoblastoid cell lines derived from a Chinese family, we demonstrated that the m.14692A→G mutation caused loss of Ψ55 modification and increased
angiogenin-mediated endonucleolytic cleavage in mutant
tRNAGlu The destabilization of base-pairing (18A-Ψ55) caused by the m.14692A→G mutation perturbed the conformation and stability of
tRNAGlu An approximately 65% decrease in the steady-state level of
tRNAGlu was observed in mutant cells compared with control cells. A failure in
tRNAGlu metabolism impaired mitochondrial translation, especially for
polypeptides with a high proportion of
glutamic acid codons such as ND1, ND6, and CO2 in mutant cells. An impairment of mitochondrial translation caused defective respiratory capacity, especially reducing the activities of complexes I and IV. Furthermore, marked decreases in the levels of mitochondrial
ATP and membrane potential were observed in mutant cells. These
mitochondrial dysfunctions caused an increasing production of
reactive oxygen species in the mutant cells. Our findings may provide new insights into the pathophysiology of
maternally inherited diabetes and deafness, which is primarily manifested by the deficient
nucleotide modification of mitochondrial
tRNAGlu.