Mulan: a novel regulator of mitochondrial dynamics, mitophagy and heart function

Mulan：线粒体动力学、线粒体自噬和心脏功能的新型调节剂

• 批准号: 9789492
• 负责人: Ronglih Liao
• 金额: $ 68.63万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789492
• 关键词: Adult; Animal Model; Apoptosis; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cell Death; Cells; Cessation of life; Complex; Crista ampullaris; Data; Disease; Enzymes; Equilibrium; Genetic; Genetic Diseases; Health; Heart; Heart Diseases; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Impairment; In Vitro; Injury; Knockout Mice; Knowledge; Link; Maintenance; Mediating; Mediator of activation protein; Mitochondria; Molecular; Mus; Muscle; Myocardial dysfunction; Organ; Outer Mitochondrial Membrane; Pathologic; Pathology; Pathway interactions; Phenotype; Physiological; Play; Post-Translational Protein Processing; Process; Proteins; Quality Control; Reperfusion Injury; Reporting; Research Personnel; Role; Stress; Structure; Substrate Interaction; System; Techniques; Testing; Tissues; Ubiquitin; Up-Regulation; energy balance; fly; heart function; in vivo; mitochondrial dysfunction; mortality; novel; novel strategies; parkin gene/protein; recruit; repaired; sensor; ubiquitin-protein ligase

PROJECT SUMMARY . Mitochondria play a pivotal role in regulating cardiac function in health and disease by regulating energy balance, biosynthetic processes, and cellular survival. Mitochondrial quality control and homeostasis are maintained in part through fusion and fission of mitochondria as well as through autophagic clearance or mitophagy of damaged mitochondria. Disruption of mitochondrial homeostasis has been closely linked to a host of acquired and genetic disease states, characterized by cardiomyocyte death at the cell level and overt cardiac dysfunction at a systemic level. Thus, clearly a thorough understanding of the molecular regulators of mitochondrial homeostasis in the heart is critical for reducing cardiac dysfunction related mortality. Our preliminary data demonstrate that the mitochondrial E3 ubiquitin ligase, Mulan, is a novel regulator of mitochondrial dynamics and mitophagy in mammalian hearts. Mulan participates in the maintenance of mitochondrial integrity and function. While Parkin, a cytoplasmic E3 ligase, has been extensively studied in mitophagy, Mulan's proposed role as a mitochondrial injury sensor, mediator of mitophagy, and inducer of cell death is both novel and a significant departure from the current state of understanding in the field. Given that Mulan is upregulated in Parkin null mouse hearts, we postulate that Mulan's upregulation may serve to compensate for the loss of Parkin, thus maintaining the basal cardiac function of Parkin null mice. Employing state-of-the-art techniques, we will investigate the intricacies of protein-protein and protein-substrate interactions by Mulan as well as how modulation of Mulan's expression fundamentally alters mitochondrial dynamics. Ultimately, our data may provide the first glimpse of an unrecognized, yet significant role of Mulan as a “resident mitochondrial injury-sensor” in the heart. Furthermore, we intend to define the distinct contribution of Mulan in mitophagy, that is independent from Parkin, as well as Mulan's role in mitochondrial function, dynamics, and cell death in the heart. Given the emerging importance of mitochondrial dysfunction in cardiac pathology, the findings from our proposal will help define the role of Mulan as a key mitochondrial injury-sensor. In addition, the proposed studies will have broad implications for the understanding and treatment of heart disease.

项目总结。 线粒体通过以下途径在调节健康和疾病中的心脏功能方面发挥关键作用 调节能量平衡、生物合成过程和细胞存活。线粒体质量 控制和动态平衡在一定程度上是通过线粒体的融合和裂变来维持的 以及通过自噬清除或破坏的线粒体有丝分裂。中断 线粒体动态平衡与许多获得性和遗传性疾病密切相关 细胞水平的心肌细胞死亡和明显的心脏功能障碍 一个系统性的层面。因此，显然对分子调控因子有了透彻的了解 心脏线粒体动态平衡是减少心脏功能障碍的关键 死亡率。我们的初步数据表明，线粒体E3泛素连接酶，木兰， 是一种新的哺乳动物心脏线粒体动力学和有丝分裂的调节因子。木兰 参与维护线粒体的完整性和功能。而帕金，一个 细胞质E3连接酶在有丝分裂中被广泛研究，木兰被认为是一个 线粒体损伤感受器、有丝分裂的中介物和细胞死亡的诱导物都是新的 与该领域目前的理解状态有很大不同。考虑到 花木兰在Parkin零小鼠心脏中上调，我们推测花木兰的上调可能 用来弥补帕金的丧失，从而维持心脏的基础功能 帕金缺失的小鼠。利用最先进的技术，我们将调查错综复杂的 花木兰的蛋白质-蛋白质和蛋白质-底物相互作用及其调控 木兰的表达从根本上改变了线粒体的动力学。最终，我们的数据可能 让我们第一次看到花木兰作为居民所扮演的未被认可但意义重大的角色 线粒体损伤--心脏中的“传感器”。此外，我们打算定义不同的 木兰在有丝分裂中的贡献，这是独立于帕金的，以及木兰在 心脏线粒体的功能、动力学和细胞死亡。鉴于新出现的重要性 对于心脏病理中线粒体功能障碍，我们的建议的发现将有所帮助 明确花木兰作为线粒体损伤感受器的关键作用。此外，建议的 研究将对心脏病的理解和治疗产生广泛的影响。