Parkin Protein Deficiency Exacerbates Cardiac Injury and Reduces Survival following Myocardial Infarction
Parkin Protein Deficiency Exacerbates Cardiac Injury and Reduces Survival following Myocardial Infarction
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DOI：
10.1074/jbc.m112.411363
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发表时间：
2013-01-11
影响因子：
4.8
通讯作者：
Gustafsson, Asa B.
中科院分区：
文献类型：
--
作者：
Kubli, Dieter A.;Zhang, Xiaoxue;Gustafsson, Asa B.
已知编码帕金的基因中的功能丧失突变导致帕金森病的发展。最近，人们发现帕金在通过神经元自噬去除功能失调的线粒体方面发挥着重要作用。虽然帕金在心脏中表达，但其在该组织中的功能性作用在很大程度上未被探索。在这项研究中，我们研究了帕金在正常生理条件下的心肌和心肌梗死的反应中的作用。我们发现，通过超声心动图分析确定，帕金森病缺陷（帕金（-/-））小鼠在长达12个月的年龄内心脏功能正常。虽然超微结构分析显示，帕金森氏症缺乏的心脏有无序的线粒体网络和显着较小的线粒体，线粒体功能不受影响。然而，与野生型小鼠相比，Parkin（-/-）小鼠对心肌梗死更敏感。与野生型小鼠相比，Parkin（-/-）小鼠在梗死后存活率降低，并发生更大的梗死。有趣的是，在野生型小鼠的梗死边缘区，帕金蛋白水平和线粒体自噬（mitophagy）迅速增加。相比之下，Parkin（-/-）心肌细胞在梗死后线粒体自噬减少，线粒体肿胀，功能障碍。Parkin在离体心肌细胞中的过表达也可以保护心肌细胞免受缺氧介导的细胞死亡，而非功能性帕金森病相关突变体ParkinR 42 P和ParkinG 430 D则没有影响。我们的研究结果表明，帕金通过促进受损线粒体的清除在心肌适应应激中起着关键作用。
It is known that loss-of-function mutations in the gene encoding Parkin lead to development of Parkinson disease. Recently, Parkin was found to play an important role in the removal of dysfunctional mitochondria via autophagy in neurons. Although Parkin is expressed in the heart, its functional role in this tissue is largely unexplored. In this study, we have investigated the role of Parkin in the myocardium under normal physiological conditions and in response to myocardial infarction. We found that Parkin-deficient (Parkin(-/-)) mice had normal cardiac function for up to 12 months of age as determined by echocardiographic analysis. Although ultrastructural analysis revealed that Parkin-deficient hearts had disorganized mitochondrial networks and significantly smaller mitochondria, mitochondrial function was unaffected. However, Parkin(-/-) mice were much more sensitive to myocardial infarction when compared with wild type mice. Parkin(-/-) mice had reduced survival and developed larger infarcts when compared with wild type mice after the infarction. Interestingly, Parkin protein levels and mitochondrial autophagy (mitophagy) were rapidly increased in the border zone of the infarct in wild type mice. In contrast, Parkin(-/-) myocytes had reduced mitophagy and accumulated swollen, dysfunctional mitochondria after the infarction. Overexpression of Parkin in isolated cardiac myocytes also protected against hypoxia-mediated cell death, whereas nonfunctional Parkinson disease-associated mutants ParkinR42P and ParkinG430D had no effect. Our results suggest that Parkin plays a critical role in adapting to stress in the myocardium by promoting removal of damaged mitochondria.