Microprotein Regulation of Mitochondrial Function

项目摘要 心力衰竭是一种复杂的临床综合征，由心肌收缩功能受损引起。 性能。几种代谢变化导致心力衰竭，包括线粒体 心脏底物利用的功能障碍和改变，导致能量缺乏和 降低心肌细胞的收缩能力。目前治疗心力衰竭的方法更多的是治疗症状。 而不是疾病的病因学基础，无法逆转 在患病的心肌细胞中发生的分子变化。开发新的方法来 增强线粒体功能和调节心力衰竭的心脏代谢是一种很有前途的方法 纠正心肌能量学以恢复心功能的方法。尽管中央 线粒体在心脏健康和疾病中的作用，我们仍然缺乏关键的洞察力 有多少基本的线粒体过程是在分子水平上受到调控的。近期 计算和实验数据表明，哺乳动物的基因组包含数千个 以前被忽视的被称为微蛋白的小蛋白，其中数百种已经被 连接到线粒体，在那里它们被认为作为调节分子发挥着重要作用。 线粒体微蛋白(Mitomps)的例子已经被证明可以调节必需的 线粒体过程包括细胞呼吸、底物利用、代谢和应激 发信号。丝裂原蛋白通常通过结合和调节较大的蛋白质来实现其功能。 膜结构域中的伙伴或多蛋白复合体。与此相适应，我们最近 发现了2个新的MitoMPs，命名为Moxi(b-氧化微肽调节剂)和 Mitolamban，每个都与离散的代谢调节复合体相互作用，以执行不同的 功能。Moxi在调节长链脂肪酸氧化方面起着关键作用，可能是通过 与线粒体三功能蛋白(MTP)直接相互作用，而Mitolamban相互作用 具有电子传输链的络合物III，并有助于复杂的组装和功能。 在这里，我们提出了一个全面的研究计划，以剖析其分子作用机制。 利用失功和得失小鼠心脏内莫昔单(目标1)和米托拉班(目标2)的作用 模特们。此外，我们的目标是评估它们作为治疗靶点的潜力。 心力衰竭和缺血性心脏病的模型。此外，为了实现获得一个 为了更全面地了解心脏中的线粒体生物学，我们提出了 3个新发现的MitoMps的分析(目标3)。我们假设这些微蛋白在 在调节线粒体功能和新陈代谢的不同方面的独特作用，以及它们的 功能表征可能为心力衰竭治疗带来新的靶点。

Project Summary Heart failure is a complex clinical syndrome that is driven by impaired myocardial contractile performance. Several metabolic alterations contribute to heart failure, including mitochondrial dysfunction and changes in cardiac substrate utilization, resulting in energy deficiency and reduced cardiomyocyte contractility. Current therapies for heart failure treat the symptoms rather than the mechanisms underlying the etiology of the disease and are unable to reverse the molecular changes that occur in diseased cardiomyocytes. Developing novel approaches to enhance mitochondrial function and modulate cardiac metabolism in heart failure is a promising approach towards correcting myocardial energetics to restore heart function. Despite the central role that mitochondria play in cardiac health and disease, we are still lacking critical insight into how many fundamental mitochondrial processes are regulated at the molecular level. Recent computational and experimental data suggest that the mammalian genome contains thousands of previously overlooked small proteins called microproteins, and hundreds of these have been linked to the mitochondria where they are thought to play important roles as regulatory molecules. Examples of mitochondrial microproteins (MitoMPs) have been shown to regulate essential mitochondrial processes including cellular respiration, substrate utilization, metabolism and stress signaling. MitoMPs typically manifest their functions by binding to and regulating larger protein partners or multiprotein complexes within membrane domains. In line with this, we recently discovered 2 novel MitoMPs named MOXI (micropeptide regulator of b-oxidation) and mitolamban, which each interact with discrete metabolic regulatory complexes to perform distinct functions. MOXI plays a critical role in regulating long chain fatty acid oxidation, likely through a direct interaction with the mitochondrial trifunctional protein (MTP), while mitolamban interacts with complex III of the electron transport chain and contributes to complex assembly and function. Here we propose a comprehensive research plan to dissect the molecular mechanisms of action of MOXI (Aim 1) and mitolamban (Aim 2) in the heart using gain- and loss-of-function mouse models. Additionally, we aim to evaluate their potential as therapeutic targets using experimental models of heart failure and ischemic heart disease. Furthermore, towards the goal of gaining a more complete understanding of mitochondrial biology in the heart, we propose the functional analysis of 3 newly identified MitoMPs (Aim 3). We hypothesize that these microproteins play unique roles in regulating distinct aspects of mitochondrial function and metabolism and that their functional characterization could give rise to novel targets for heart failure therapeutics.