Evidence for p53 as guardian of the cardiomyocyte mitochondrial genome following acute adriamycin treatment
Evidence for p53 as guardian of the cardiomyocyte mitochondrial genome following acute adriamycin treatment
复制标题
DOI：
10.1369/jhc.6a7146.2007
复制
发表时间：
2007-06-01
影响因子：
3.2
通讯作者：
Oberley, Terry D.
中科院分区：
文献类型：
--
作者：
Nithipongvanitch, Rarnaneeya;Ittarat, Wanida;Oberley, Terry D.
本研究是p53是否可能作为心肌细胞线粒体基因组的监护人的初步分析，线粒体p53定位提出参与线粒体DNA（mtDNA）修复和凋亡。分析p53蛋白的亚细胞分布、蛋白水平及其在心肌细胞对阿霉素（ADR）反应中的可能功能。蛋白质水平和亚细胞定位通过Western印迹和免疫金超微结构分析技术确定。在这里，我们表明，压力引起的ADR诱导上调p53蛋白在心肌细胞线粒体和细胞核之间的3和24 hr. Increase A和Bax蛋白的表达，促凋亡的p53的目标，记录ADR治疗后，并伴随着细胞凋亡标志物的水平增加，与升高的细胞色素c在24小时和随后的caspase-3裂解在3天。线粒体p53水平与线粒体DNA氧化损伤相关。p53基因敲除小鼠心脏的缺失导致ADR治疗后线粒体DNA对损伤的脆弱性显著增加。我们的研究结果表明，线粒体p53可以参与线粒体DNA修复作为第一个反应的心肌细胞线粒体DNA的氧化损伤，并表现出增加的凋亡标志物作为线粒体/核p53定位的结果。
The present study is an initial analysis of whether p53 may function as guardian of the cardiomyocyte mitochondrial genome, with mitochondrial p53 localization proposed to be involved in both mitochondrial DNA (mtDNA) repair and apoptosis. Subcellular distribution, protein levels, and possible function(s) of p53 protein in the response of cardiomyocytes to adriamycin (ADR) were analyzed. Levels and subcellular localization of proteins were determined by Western blot and immunogold ultrastructural analysis techniques. Here we demonstrate that stress caused by ADR induced upregulation of p53 protein in cardiomyocyte mitochondria and nuclei between 3 and 24 hr. Increased expression of PUMA and Bax proteins, pro-apoptotic targets of p53, was documented following ADR treatment and was accompanied by increased levels of apoptotic markers, with elevation of cytosolic cytochrome c at 24 hr and subsequent caspase-3 cleavage at 3 days. Mitochondrial p53 levels correlated with mtDNA oxidative damage. Loss of p53 in knockout mouse heart resulted in a significant increase in mtDNA vulnerability to damage following ADR treatment. Our results suggest that mitochondrial p53 could participate in mtDNA repair as a first response to oxidative damage of cardiomyocyte mtDNA and demonstrate an increase of apoptotic markers as a result of mitochondrial/nuclear p53 localization.