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首页> 外文期刊>Journal of cellular physiology. >A mutation in the Na-K-2CI cotransporter-1 leads to changes in cellular metabolism
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A mutation in the Na-K-2CI cotransporter-1 leads to changes in cellular metabolism

机译：一个突变Na-K-2CI cotransporter-1线索细胞代谢的改变

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The Na-K-CI cotransporter-1 (NKCC1), by mediating the electroneutral transport of Na+, K+, and Cl plays an important role in cell volume regulation, epithelial transport, and the control of neuronal excitability. Recently, we reported the first known human mutation in SLC12A2, the gene encoding NKCC1. The 17-year old patient suffers from multiorgan failure. Laboratory tests conducted on muscle and liver biopsies of the patient showed abnormal increase in mitochondrial DNA copy number and increased glycogen levels, indicating the possibility that the transporter may play a role in energy metabolism. Here, we show that fibroblasts isolated from the patient demonstrate a significant increase in mitochondrial respiration, compared to fibroblasts isolated from healthy individuals. Similarly, Madin Darby canine kidney (MDCK) cells transfected with enhanced green fluorescent protein (EGFP)-tagged mutant NKCC1 DNA demonstrated increased mitochondrial respiration when compared to MDCK cells expressing EGFP-tagged wild-type (WT) cotransporter. Direct inhibition of the cotransporter through addition of bumetanide did not change the rate of basal respiration, but led to increased maximal mitochondrial respiration. Fibroblasts extracted from NKCC1~(WT/DFX) and NKCC1~(DFX/DFX) mice also demonstrated a significant elevation in mitochondrial respiration, compared to fibroblasts isolated from their WT littermates. Expression of the mutant protein was associated with an increase in hydrogen peroxide and peroxidase activity and a decrease in messenger RNA transcript levels for protein involved in the unfolded protein response. These data reveal that cells expressing the mutant cotransporter demonstrate increased mitochondrial respiration and behave like they are experiencing a state of starvation.
机译：通过中介的Na-K-CI cotransporter-1 (NKCC1)Na +电中性的运输,K +和Cl扮演着一个重要的角色在细胞体积规定,上皮传输和控制神经元的兴奋性。第一个已知的人类SLC12A2的突变,基因编码NKCC1。患有multiorgan失败。进行肌肉和肝脏活组织检查的病人显示线粒体异常增加DNA拷贝数和糖原含量增加,表明运输的可能性可能在能量代谢中发挥作用。表明成纤维细胞隔离病人演示显著增加线粒体呼吸,相比成纤维细胞与健康的个体。同样,Madin Darby狗肾细胞(MDCK)转染与增强型绿色荧光蛋白(EGFP)标记突变NKCC1 DNA了增加线粒体呼吸相比MDCK细胞表达EGFP-tagged野生型(WT)转运蛋白。通过添加抑制的转运蛋白布美他尼没有变化的基础呼吸,但导致增加最大线粒体呼吸。从NKCC1 ~ (WT / DFX)和NKCC1 ~ (DFX / DFX)小鼠证明了显著提升线粒体呼吸,相比成纤维细胞与WT同窝出生的。突变蛋白的表达有关与过氧化氢和增加过氧化物酶活性和降低信使RNA转录水平对蛋白质参与展开的蛋白质反应。细胞表达突变的转运蛋白证明增加线粒体呼吸像他们正在经历的状态饥饿。

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