Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation
Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation
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DOI：
10.1073/pnas.1213294110
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发表时间：
2013-04-09
影响因子：
11.1
通讯作者：
Sussman, Mark A.
中科院分区：
文献类型：
--
作者：
Din, Shabana;Mason, Matthew;Sussman, Mark A.
线粒体形态动力学影响缺血性心脏损伤的结果和发病机制。最近，线粒体分裂蛋白动力蛋白相关蛋白1（Drp 1）已被确定为心肌缺血损伤时线粒体形态学变化和细胞死亡的介导者。在这项研究中，我们报告了一个独特的关系Pim-1的活性和Drp 1调节心肌细胞的线粒体形态缺血应激的挑战。过表达心脏Pim-1的转基因心脏显示总Drp 1蛋白水平降低，Drp 1-（S637）磷酸化增加，以及Drp 1定位于线粒体的抑制。与这些发现一致，腺病毒诱导的Pim-1新生大鼠心肌细胞（NRCM）在模拟缺血（sl）后保留网状线粒体表型，并减少Drp 1线粒体隔离。有趣的是，腺病毒Pim显性阴性NRCM显示Bcl-2同源性3（BH 3）-唯一的蛋白p53上调凋亡调节因子（p53）的表达增加，先前已显示其诱导线粒体处Drp 1积累并增加对凋亡刺激的敏感性。p53上调的凋亡调节因子显性阴性腺病毒的过表达减弱了Drp 1在腺病毒中线粒体的定位Pim显性阴性NRCM促进网状线粒体形态并抑制sl.因此，Pim-1活性防止Drp 1区室化的线粒体和保留网状线粒体形态响应SL。
Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1-(S637), and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sl) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pim-dominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sl. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sl.