The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNAIle A4263G mutation
The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNAIle A4263G mutation
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线粒体钙单向转运蛋白参与线粒体钙循环功能障碍：与线粒体 tRNA(Ile) A4263G 突变相关的高血压的潜在机制
DOI：
10.1016/j.biocel.2016.07.018
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发表时间：
2016-09-01
影响因子：
4
通讯作者：
Li, Yang
中科院分区：
文献类型：
--
作者：
Chen, Xi;Zhang, Yu;Li, Yang
近年来的研究表明，线粒体DNA突变参与了高血压的发病机制。本研究在一个母系遗传性高血压家系中发现了线粒体tRNA（Ile）A4263 G突变。该突变可能导致线粒体Ca ~（2+）循环功能障碍，但其机制尚不清楚。淋巴母细胞样细胞系来源于高血压和正常血压个体，有或没有tRNA（Ile）A4263 G突变。高血压患者tRNA（Ile）A4263 G突变的细胞线粒体Ca ~（2+）（m）低于正常血压者、高血压无突变者和正常血压有突变者（P < 0.05）。同时，高血压伴突变细胞组胞浆[Ca ~（2+）]（m）高于其他三组。咖啡因通过激活内质网ryanodine受体而使[Ca ~（2+）]（c）升高，[Ca ~（2+）]（c）/[Ca ~（2+）]（m）升高，高于其他三组突变细胞的高血压。高血压病细胞突变组MCU表达较其他3组明显降低（P < 0.05）。[Call Ru 360（MCU的抑制剂）或针对MCU的siRNA处理后，[Ca 2 +]（c）增加，[Ca 2 +]（c）降低。在这项研究中，我们发现高血压与突变细胞MCU表达减少导致线粒体Ca 2+摄取失调，胞浆Ca 2+超载。这种异常可能与携带线粒体tRNA（Ile）A4263 G突变的受试者中母系遗传性高血压的潜在机制有关。(C)2016爱思唯尔有限公司版权所有。
Recent studies have shown that the mitochondrial DNA mutations are involved in the pathogenesis of hypertension. Our previous study identified mitochondrial tRNA(Ile) A4263G mutation in a large Chinese Han family with maternally-inherited hypertension. This mutation may contribute to mitochondrial Ca2+ cycling dysfuntion, but the mechanism is unclear. Lymphoblastoid cell lines were derived from hypertensive and normotensive individuals, either with or without tRNA(Ile) A4263G mutation. The mitochondrial calcium ([Ca2+](m)) in cells from hypertensive subjects with the tRNA(Ile) A4263G mutation, was lower than in cells from normotension or hypertension without mutation, or normotension with mutation (P < 0.05). Meanwhile, cytosolic calcium ([Ca2+](m)) in hypertensive with mutation cells was higher than another three groups. After exposure to caffeine, which could increase the [Ca2+](c) by activating ryanodine receptor on endoplasmic reticulum, [Ca2+](c)/[Ca2+](m), increased higher than in hypertensive with mutation cells from another three groups. Moreover, MCU expression was decreased in hypertensive with mutation cells compared with in another three groups (P < 0.05). [Call, increased and [Ca2+](c) decreased after treatment with Ru360 (an inhibitor of MCU) or an siRNA against MCU. In this study we found decreased MCU expression in hypertensive with mutation cells contributed to dysregulated Ca2+ uptake into the mitochondria, and cytoplasmic Ca2+ overload. This abnormality might be involved in the underlying mechanisms of maternally inherited hypertension in subjects carrying the mitochondrial tRNA(Ile) A4263G mutation. (C) 2016 Elsevier Ltd. All rights reserved.