In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 108, No. 7 ( 2011-04), p. 862-870
Abstract:
Despite maternal transmission of hypertension in some pedigrees, pathophysiology of maternally inherited hypertension remains poorly understood. Objective: To establish a causative link between mitochondrial dysfunction and essential hypertension. Method and Results: A total of 106 subjects from a large Chinese family underwent clinical, genetic, molecular, and biochemical evaluations. Fifteen of 24 adult matrilineal relatives exhibited a wide range of severity in essential hypertension, whereas none of the offspring of affected fathers had hypertension. The age at onset of hypertension in the maternal kindred varied from 20 years to 69 years, with an average of 44 years. Mutational analysis of their mitochondrial genomes identified a novel homoplasmic 4263A 〉 G mutation located at the processing site for the tRNA Ile 5′-end precursor. An in vitro processing analysis showed that the 4263A 〉 G mutation reduced the efficiency of the tRNA Ile precursor 5′-end cleavage catalyzed by RNase P. tRNA Northern analysis revealed that the 4263A 〉 G mutation caused ≈46% reduction in the steady-state level of tRNA Ile . An in vivo protein-labeling analysis showed ≈32% reduction in the rate of mitochondrial translation in cells carrying the 4263A 〉 G mutation. Impaired mitochondrial translation is apparently a primary contributor to the reductions in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate-promoted respiration, or N , N , N′ , N′ -tetramethyl- p -phenylenediamine/ascorbate–promoted respiration and the increasing level of reactive oxygen species in cells carrying the 4263A 〉 G mutation. Conclusions: These data provide direct evidence that mitochondrial dysfunction caused by mitochondrial tRNA Ile 4263A 〉 G mutation is involved in essential hypertension. Our findings may provide new insights into pathophysiology of maternally transmitted hypertension.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.110.231811
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2011
detail.hit.zdb_id:
1467838-X
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