Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription.
Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription.
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DOI：
10.1126/scisignal.2002712
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发表时间：
2012-07-03
影响因子：
7.3
通讯作者：
Gillespie MN
中科院分区：
文献类型：
--
作者：
Al-Mehdi AB;Pastukh VM;Swiger BM;Reed DJ;Patel MR;Bardwell GC;Pastukh VV;Alexeyev MF;Gillespie MN
线粒体可以控制第二信使的局部浓度，如活性氧（ROS），线粒体易位到离散的亚细胞区域可能有助于这种信号传导功能。在这里，我们报告说，暴露于缺氧的肺动脉内皮细胞引发的逆行线粒体运动，需要微管和微管运动蛋白动力蛋白，并导致在核周聚集的线粒体。线粒体的这种亚细胞再分布伴随着ROS在细胞核中的积累，这通过用诺考达唑抑制线粒体的核周聚集以使微管不稳定或用小干扰RNA介导的动力蛋白敲低来减弱。尽管抑制核周线粒体簇集并不影响缺氧诱导的缺氧诱导因子1α（HIF-1α）核丰度的增加或HIF-1α与缺氧反应元件（HRE）对应的寡核苷酸的结合，但它消除了VEGF（血管内皮生长因子）启动子的氧化修饰。此外，抑制核周线粒体聚集减少HIF-1α与VEGF启动子的结合，并减少VEGF mRNA的积累。这些研究结果支持缺氧诱导的转录调控模型，其中核周线粒体聚集导致细胞核中ROS积累，并导致VEGF HRE中的氧化碱基修饰，这对转录复合物组装和VEGF mRNA表达很重要。
Mitochondria can govern local concentrations of second messengers, such as reactive oxygen species (ROS), and mitochondrial translocation to discrete subcellular regions may contribute to this signaling function. Here, we report that exposure of pulmonary artery endothelial cells to hypoxia triggered a retrograde mitochondrial movement that required microtubules and the microtubule motor protein dynein and resulted in the perinuclear clustering of mitochondria. This subcellular redistribution of mitochondria was accompanied by the accumulation of ROS in the nucleus, which was attenuated by suppressing perinuclear clustering of mitochondria with nocodazole to destabilize microtubules or with small interfering RNA–mediated knockdown of dynein. Although suppression of perinuclear mitochondrial clustering did not affect the hypoxia-induced increase in the nuclear abundance of hypoxia-inducible factor 1α (HIF-1α) or the binding of HIF-1α to an oligonucleotide corresponding to a hypoxia response element (HRE), it eliminated oxidative modifications of the VEGF (vascular endothelial growth factor) promoter. Furthermore, suppression of perinuclear mitochondrial clustering reduced HIF-1α binding to the VEGF promoter and decreased VEGF mRNA accumulation. These findings support a model for hypoxia-induced transcriptional regulation in which perinuclear mitochondrial clustering results in ROS accumulation in the nucleus and causes oxidative base modifications in the VEGF HRE that are important for transcriptional complex assembly and VEGF mRNA expression.
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影响因子：
4.3
作者：
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通讯作者：
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影响因子：
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