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.

项目摘要。 线粒体在调节健康和疾病的心脏功能中起着关键作用， 调节能量平衡、生物合成过程和细胞存活。线粒体质量 控制和体内平衡部分通过线粒体的融合和分裂来维持， 以及通过受损线粒体的自噬清除或线粒体自噬。破坏 线粒体内稳态与许多获得性和遗传性疾病密切相关 状态，其特征是细胞水平的心肌细胞死亡和 系统层面。因此，清楚地彻底了解的分子调节剂， 心脏中的线粒体稳态对于减少心脏功能障碍相关的 mortality.我们的初步数据表明，线粒体E3泛素连接酶，木兰， 是哺乳动物心脏线粒体动力学和线粒体自噬的一种新型调节剂。木兰 参与维持线粒体的完整性和功能。而帕金， 细胞质E3连接酶，在线粒体自噬中已经被广泛研究，木兰的作用被认为是一种 线粒体损伤传感器、线粒体自噬的介体和细胞死亡的诱导物都是新的 这与该领域目前的理解状态有很大的不同。鉴于 Mulan在Parkin敲除小鼠心脏中上调，我们推测Mulan的上调可能 用于补偿帕金的损失，从而维持心脏的基础功能， Parkin无效小鼠。运用最先进的技术，我们将调查 蛋白质-蛋白质和蛋白质-底物相互作用的木兰，以及如何调节 木兰的表达从根本上改变了线粒体动力学。最终，我们的数据可能 第一次看到木兰作为一个未被承认的，但重要的角色， 心脏中的线粒体损伤传感器。此外，我们打算定义不同的 木兰在线粒体自噬中的贡献，这是独立于帕金，以及木兰在 线粒体功能、动力学和心脏细胞死亡。鉴于新出现的重要性 心脏病理学中线粒体功能障碍的研究，我们提案的发现将有助于 确定木兰作为关键线粒体损伤传感器的作用。此外，拟议的 这些研究将对理解和治疗心脏病产生广泛的影响。