mHGTD-P mediates hypoxic neuronal cell death via the release of apoptosis-inducing factor
mHGTD-P mediates hypoxic neuronal cell death via the release of apoptosis-inducing factor
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DOI：
10.1016/j.neulet.2007.01.073
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发表时间：
2007-04-12
影响因子：
2.5
通讯作者：
Park, Jae-Hoon
中科院分区：
文献类型：
--
作者：
Cho, Young-Eun;Ko, Jeong-Hun;Park, Jae-Hoon
HGTD-P 是缺氧诱导因子 1a (HIF-1 α) 的促凋亡靶蛋白。它定位于线粒体，并在过度表达时通过与电压依赖性阴离子通道的相互作用诱导线粒体通透性转变。然而，负责其诱导的分子机制以及细胞死亡过程中所需的下游效应分子，尤其是缺氧引起的神经元细胞死亡，在很大程度上尚不清楚。我们进行这项工作是为了阐明促凋亡蛋白 HGTD-P 对缺氧诱导的神经细胞死亡的影响，并研究在此过程中激活的细胞死亡机制。在本报告中，我们表明小鼠 HGTD-P (mHGTD-P) 因缺氧而转录增加，并且其过度表达会触发神经元细胞死亡，受影响的细胞以不依赖半胱天冬酶的方式表现出细胞质萎缩和核固缩。此外，通过 siRNA 抑制内源性 mHGTD-P 表达可挽救神经元细胞免受缺氧损伤。最后，我们发现 mHGTD-P 诱导线粒体将凋亡诱导因子释放到细胞质中。综上所述，我们的数据表明 mHGTD-P 参与不依赖 caspase 的缺氧神经元细胞死亡。未来的研究将是必要的，以确定缺氧诱导的 mHGTD-P 表达是否与缺血动物模型或临床缺氧诱导的疾病有任何相关性。 (c) 2007 Elsevier Ireland Ltd. 保留所有权利。
HGTD-P is a pro-apoptotic target protein of hypoxia-inducible factor 1 a (HIF-1 alpha). It localizes to mitochondria and induces the mitochondrial permeability transition through its interaction with voltage dependent anion channels when overexpressed. However, the molecular mechanisms responsible for its induction and its downstream effector molecules required during cell death, especially in neuronal cell death by hypoxia, are largely unknown. We performed this work to elucidate the effects of the pro-apoptotic protein HGTD-P on neuronal cell death induced by hypoxia and to investigate the cell death mechanisms activated during this process. In this report, we show that mouse HGTD-P (mHGTD-P) is transcriptionally increased by hypoxia and that its overexpression triggers neuronal cell death with affected cells displaying shrunken cytoplasm and condensed pyknotic nuclei in a caspase-independent manner. In addition, suppression of endogenous mHGTD-P expression by siRNA rescues neuronal cells from hypoxic injury. Finally, we show that mHGTD-P induces the mitochondrial release of apoptosis-inducing factor into the cytoplasm. Taken together, our data suggest that mHGTD-P participates in caspase-independent hypoxic neuronal cell death. Future studies will be necessary in order to determine whether hypoxia-induced mHGTD-P expression has any relevance in an ischemic animal model or clinical hypoxia-induced disorders. (c) 2007 Elsevier Ireland Ltd. All rights reserved.