A deafness and diabetes associated tRNA mutation caused the deficient pseudouridinylation at position 55 in tRNAGlu and mitochondrial dysfunction .

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A deafness and diabetes associated tRNA mutation caused the deficient pseudouridinylation at position 55 in tRNAGlu and mitochondrial dysfunction  .

J Biol Chem. 2016 Aug 12;

Authors: Wang M, Liu H, Zheng J, Chen B, Zhou M, Fan W, Wang H, Liang X, Zhou X, Eriani G, Jiang P, Guan MX

Abstract
Several mitochondrial tRNA mutations have been associated with maternally inherited diabetes and deafness (MIDD). 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 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 the loss of Ψ55 modification and increased the 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. Approximately 65% decrease in the steady-state level of tRNAGlu was observed in mutant cells, compared to control cells. A failure in tRNAGlu metabolism impaired mitochondrial translation, especially for polypeptides with high proportion of glutamic acid codons such as MT-ND1, MT-ND6 and MT-CO2 in mutant cells. An impairment of mitochondrial translation caused the defective respiratory capacity, especially reducing 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 pathophysiology of MIDD, which was primarily manifested by the deficient nucleotide modification of mitochondrial tRNAGlu.

PMID: 27519417 [PubMed - as supplied by publisher]

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