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A hypertension-associated mitochondrial DNA mutation alters the tertiary interaction and function of tRNALeu(UUR).
- Source :
-
Journal of Biological Chemistry . 8/25/2017, Vol. 292 Issue 34, p13934-13946. 13p. - Publication Year :
- 2017
-
Abstract
- Several mitochondrial tRNA mutations have been associated with hypertension, but their pathophysiology remains poorly understood. In this report, we identified a novel homoplasmic 3253T3C mutation in the mitochondrial tRNALeu(UUR) gene in a Han Chinese family with maternally inherited hypertension. The m.3253T→C mutation affected a highly conserved uridine at position 22 at the D-stem of tRNALeu(UUR), introducing a G-C base pairing (G13-C22) at the D-stem and a tertiary base pairing (C22-G46) between the D-stem and the variable loop.Wetherefore hypothesized that the m.3253T→C mutation altered both the structure and function of tRNALeu(UUR). Using cytoplasmic hybrid (cybrid) cell lines derived from this Chinese family, we demonstrated that the m.3253T→C mutation perturbed the conformation and stability of tRNALeu(UUR), as suggested by faster electrophoretic mobility of mutated tRNA relative to the wild-type molecule. Northern blot analysis revealed an ∼45% decrease in the steady-state level of tRNALeu(UUR) in the mutant cell lines carrying the m.3253T→C mutation, as compared with control cell lines. Moreover, an ∼35% reduction in aminoacylation efficiency of tRNALeu(UUR) was observed in the m.3253T→C mutant cells. These alterations in tRNALeu(UUR) metabolism impaired mitochondrial translation, especially for those polypeptides with a high proportion of Leu(UUR) codons, such as ND6. Furthermore, we demonstrated that the m.3253T→C mutation decreased the activities of mitochondrial complexes I and V, markedly diminished mitochondrial ATP levels and membrane potential, and increased the production of reactive oxygen species in the cells. In conclusion, our findings may provide new insights into the pathophysiology of maternally inherited hypertension. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PREHYPERTENSION
*DEOXYRIBOSE
*MITOCHONDRIAL DNA
*CELL lines
*TRANSFER RNA
Subjects
Details
- Language :
- English
- ISSN :
- 00219258
- Volume :
- 292
- Issue :
- 34
- Database :
- Academic Search Index
- Journal :
- Journal of Biological Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 124829002
- Full Text :
- https://doi.org/10.1074/jbc.M117.787028