Parkin does not prevent accelerated cardiac aging in mitochondrial DNA mutator mice.
Parkin does not prevent accelerated cardiac aging in mitochondrial DNA mutator mice.
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DOI：
10.1172/jci.insight.127713
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发表时间：
2019-05
期刊：
影响因子：
8
通讯作者：
B. Woodall;Amabel M. Orogo;Rita H. Najor;Melissa Q. Cortez;E. R. Moreno;Hongxia Wang;Ajit S. Divakaruni;A. Murphy;Å. Gustafsson
中科院分区：
文献类型：
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作者：
B. Woodall;Amabel M. Orogo;Rita H. Najor;Melissa Q. Cortez;E. R. Moreno;Hongxia Wang;Ajit S. Divakaruni;A. Murphy;Å. Gustafsson
E3泛素连接酶Parkin在调节包括心脏在内的组织中功能失调或不需要的线粒体的清除方面发挥着重要作用。然而，Parkin是否也通过维持健康的线粒体群体来防止心脏衰老仍不清楚。在这里，我们使用携带有缺陷的线粒体DNA聚合酶伽马(Polg)的小鼠模型，研究了Parkin在线粒体DNA损伤和心肌老化中的作用。我们观察到随着年龄的增长，Polg鼠心脏中Parkin蛋白水平降低和心肌肥厚的发展；然而，心脏特异性过表达或Parkin基因的整体缺失既不能挽救Polg鼠的心肌肥厚，也不能使其恶化。出乎意料的是，与WT相比，Polg小鼠的线粒体适合性并没有随着年龄的增长而大幅下降。我们发现，在老年Polg心脏中，基线有丝分裂受体介导的线粒体周转和生物发生增强。我们还观察到了老年Polg心脏中巨线粒体的存在。因此，这些过程可能限制功能障碍的线粒体的积累以及老化的Polg心脏的心脏功能损害的程度。总体而言，我们的结果表明，在心脏老化的mtDNA突变模型中，Parkin对于构成线粒体质量控制是必不可少的。
The E3 ubiquitin ligase Parkin plays an important role in regulating clearance of dysfunctional or unwanted mitochondria in tissues, including the heart. However, whether Parkin also functions to prevent cardiac aging by maintaining a healthy population of mitochondria is still unclear. Here, we have examined the role of Parkin in the context of mtDNA damage and myocardial aging using a mouse model carrying a proofreading defective mitochondrial DNA polymerase gamma (POLG). We observed both decreased Parkin protein levels and development of cardiac hypertrophy in POLG hearts with age; however, cardiac hypertrophy in POLG mice was neither rescued, nor worsened by cardiac specific overexpression or global deletion of Parkin, respectively. Unexpectedly, mitochondrial fitness did not substantially decline with age in POLG mice when compared to WT. We found that baseline mitophagy receptor-mediated mitochondrial turnover and biogenesis were enhanced in aged POLG hearts. We also observed the presence of megamitochondria in aged POLG hearts. Thus, these processes may limit the accumulation of dysfunctional mitochondria as well as the degree of cardiac functional impairment in the aging POLG heart. Overall, our results demonstrate that Parkin is dispensable for constitutive mitochondrial quality control in a mtDNA mutation model of cardiac aging.