Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress
Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress
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DOI：
10.1093/cvr/cvr274
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发表时间：
2012-01-01
影响因子：
10.8
通讯作者：
Rabinovitch, Peter S.
中科院分区：
文献类型：
--
作者：
Dai, Dao-Fu;Hsieh, Edward J.;Rabinovitch, Peter S.
目的我们研究线粒体氧化应激在线粒体蛋白质组重构中的作用，使用压力超负荷引起的心力衰竭的小鼠模型。方法和结果我们证明，小鼠过表达过氧化氢酶靶向线粒体（mCAT）减轻压力超负荷引起的心力衰竭。将一种改进的无标记无偏线粒体蛋白质组分析方法应用于横主动脉缩窄（TAC）所致心力衰竭小鼠模型。在接受TAC或假手术的野生型和mCAT小鼠之间比较了总共425种线粒体蛋白。心力衰竭中线粒体蛋白质组的变化包括参与脂肪酸代谢的蛋白质丰度减少，糖酵解、细胞凋亡、线粒体未折叠蛋白反应和蛋白质水解、转录和翻译控制以及发育过程中蛋白质丰度增加以及对刺激的反应。过表达的mCAT更好地保存蛋白质参与脂肪酸代谢和衰减的增加，细胞凋亡和蛋白水解酶。有趣的是，基因本体分析还表明，单糖代谢过程和蛋白质折叠/蛋白质水解只在mCAT中过度表达，而不是在野生型小鼠中响应于TAC。结论这是第一个研究表明，清除线粒体活性氧（ROS）的mCAT不仅减弱了大部分的线粒体蛋白质组的变化，在心力衰竭，但也引起了一个子集的独特的改变。这些变化代表了适应压力超负荷增加的工作和代谢要求的过程，但通常被线粒体ROS的过度产生抑制。
Aims We investigate the role of mitochondrial oxidative stress in mitochondrial proteome remodelling using mouse models of heart failure induced by pressure overload.Methods and results We demonstrate that mice overexpressing catalase targeted to mitochondria (mCAT) attenuate pressure overload-induced heart failure. An improved method of label-free unbiased analysis of the mitochondrial proteome was applied to the mouse model of heart failure induced by transverse aortic constriction (TAC). A total of 425 mitochondrial proteins were compared between wild-type and mCAT mice receiving TAC or sham surgery. The changes in the mitochondrial proteome in heart failure included decreased abundance of proteins involved in fatty acid metabolism, an increased abundance of proteins in glycolysis, apoptosis, mitochondrial unfolded protein response and proteolysis, transcription and translational control, and developmental processes as well as responses to stimuli. Overexpression of mCAT better preserved proteins involved in fatty acid metabolism and attenuated the increases in apoptotic and proteolytic enzymes. Interestingly, gene ontology analysis also showed that monosaccharide metabolic processes and protein folding/proteolysis were only overrepresented in mCAT but not in wild-type mice in response to TAC.Conclusion This is the first study to demonstrate that scavenging mitochondrial reactive oxygen species (ROS) by mCAT not only attenuates most of the mitochondrial proteome changes in heart failure, but also induces a subset of unique alterations. These changes represent processes that are adaptive to the increased work and metabolic requirements of pressure overload, but which are normally inhibited by overproduction of mitochondrial ROS.