MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons.
MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons.
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DOI：
10.1523/jneurosci.3338-08.2008
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发表时间：
2008-11-19
期刊：
影响因子：
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通讯作者：
Kaplan BB
中科院分区：
文献类型：
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作者：
Aschrafi A;Schwechter AD;Mameza MG;Natera-Naranjo O;Gioio AE;Kaplan BB
MicroRNA (miR) 是进化上保守的非编码 RNA 分子，大约有 21 个核苷酸，可调节参与各种生物过程（例如细胞增殖和分化）的基因表达。此前，我们报道了初级交感神经元的轴突和神经末梢中存在异质 mRNA 群体，其中包括编码 COXIV 的核编码线粒体 mRNA。对该 mRNA 3'UTR 的序列分析揭示了 miR-338（一种大脑特异性 microRNA）的推定结合位点的存在。将前体 miR-338 转染到初级交感神经元的轴突中会降低 COXIV mRNA 和蛋白质水平，并导致线粒体活性降低（通过 ATP 水平降低来衡量）。相反，抑制 miR-338 的合成抗 miR 寡核苷酸的转染会增加 COXIV 水平，并导致轴突中氧化磷酸化和去甲肾上腺素摄取显着增加。我们的结果指出了这种 microRNA 通过调节 COXIV 水平参与轴突呼吸和功能调节的分子机制，COXIV 是一种在线粒体细胞色素 c 氧化酶复合物 IV 组装中起关键作用的蛋白质。
MicroRNAs (miRs) are evolutionarily conserved, non-coding RNA molecules of approximately 21 nucleotides that regulate the expression of genes that are involved in various biological processes, such as cell proliferation and differentiation. Previously, we reported the presence of a heterogeneous population of mRNAs present in the axons and nerve terminals of primary sympathetic neurons to include the nuclear-encoded mitochondrial mRNA coding for COXIV. Sequence analysis of the 3′UTR of this mRNA revealed the presence of a putative binding site for miR-338, a brain-specific microRNA. Transfection of precursor miR-338 into the axons of primary sympathetic neurons decreases COXIV mRNA and protein levels and results in a decrease in mitochondrial activity, as measured by the reduction of ATP levels. Conversely, the transfection of synthetic anti-miR oligonucleotides that inhibit miR-338 increases COXIV levels, and results in a significant increase in oxidative phosphorylation and also norepinephrine uptake in the axons. Our results point to a molecular mechanism by which this microRNA participates in the regulation of axonal respiration and function by modulating the levels of COXIV, a protein which plays a key role in the assembly of the mitochondrial cytochrome c oxidase complex IV.