Regulation of Mitochondrial Autophagy by Parkin

描述(由申请人提供)： 心肌细胞线粒体功能障碍在心力衰竭发病机制中起早期作用。在心脏中，线粒体的主要功能是通过氧化磷酸化提供ATP来满足心脏跳动的高能量需求。然而，线粒体也是细胞死亡的重要调节器，它们监测细胞内环境的变化，如活性氧物种的存在和DNA损伤。当线粒体受损或功能失调时，可作为活性氧物种的来源，从而对附近的线粒体造成进一步损害。因此，它们被自噬迅速移除，自噬是一种进化上保守的过程，涉及到长寿蛋白质和细胞器的降解。自噬在心脏中被用来清除功能失调的线粒体，研究表明，它的放松调控对心肌细胞有严重的后果。自噬去除线粒体的分子机制和调控机制还不是很清楚。然而，泛素连接酶Parkin最近被报道选择性地招募到功能失调的线粒体，从而促进它们的自噬。Park2基因的功能缺失突变在常染色体隐性遗传性帕金森病中起着重要作用。有趣的是，Parkin在心脏中也高度表达，但其在心肌中的功能和作用目前尚不清楚。我们的初步研究发现，有证据表明，帕金在适应压力方面发挥着重要作用，例如心肌梗死。因此，在这个提案中，我们将探索这样的假设，即Parkin在应激过程中通过自噬清除受损的线粒体是必不可少的，并且这一过程中的缺陷有助于心力衰竭的快速发展。这一假设将通过三个目标进行检验。目的1研究Parkin在线粒体自噬和心肌保护中的作用。在目标2中，我们将定义Parkin识别功能障碍线粒体的分子机制。最后，在目标3中，我们将确定新的Parkin底物，并表征它们在线粒体自噬和细胞生存中的作用。这些研究将为Parkin的功能作用以及心脏中功能障碍和潜在危险的线粒体如何清除提供重要的新信息。这些研究还将为这一途径中新的潜在治疗靶点提供洞察力。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction in cardiac myocytes occurs early in the pathogenesis of heart failure. In the heart, the primary function of mitochondria is to meet the high energy demand of the beating heart by providing ATP through oxidative phosphorylation. However, mitochondria are also important regulators of cell death and they monitor changes in the intracellular environment such as presence of reactive oxygen species and DNA damage. When mitochondria become damaged or dysfunctional, can serve as a source of reactive oxygen species which can cause further damage to nearby mitochondria. Therefore, they are rapidly removed by autophagy, an evolutionarily conserved process involved in the degradation of long-lived proteins and organelles. Autophagy is used in the heart to clear dysfunctional mitochondria and studies have shown that its deregulation has severe consequences to the myocytes. The molecular mechanism and regulation of mitochondrial removal via autophagy are not well characterized. However, the ubiquitin ligase Parkin was recently reported to be selectively recruited to dysfunctional mitochondria which subsequently promoted their autophagy. Loss-of-function mutations in Park2, the gene encoding Parkin, play a significant role in autosomal recessive Parkinson's disease. Interestingly, Parkin is also highly expressed in the heart, but its functiona role in the myocardium is currently unknown. Our preliminary studies have uncovered evidence that Parkin plays an important role in the adaptation to stress such as a myocardial infarction. Therefore, in this proposal, we will explore the hypothesis that Parkin is essential in clearing damaged mitochondria via autophagy during stress and that a defect in this process contributes to rapid development of heart failure. This hypothesis will be tested with three aims. Aim 1 will examine the role of Parkin in mitochondrial autophagy and cardioprotection. In aim 2, we will define the molecular mechanism by which Parkin recognizes dysfunctional mitochondria. Finally, in aim 3, we will identify novel Parkin substrates and characterize their roles in mitochondrial autophagy and cell survival. These studies will provide important new information into the functional role of Parkin and how dysfunctional and potentially dangerous mitochondria are cleared in the heart. These studies will also provide insights into new potential therapeutic targets in this pathway.