Microprotein Regulation of Mitochondrial Function

线粒体功能的微生物蛋白调节

基本信息

批准号：
10531907
负责人：
Catherine A Makarewich
金额：
$ 39.75万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531907
关键词：
Affect Binding Bioenergetics Biological Assay Biology Calcium Carbohydrates Cardiac Cardiac Myocytes Cardiac health Cardiovascular Diseases Cell Respiration Clinical Code Complex Computer Analysis Data Disease Disease model Electron Transport Electron Transport Complex III Equilibrium Etiology Event Experimental Models Fractionation Gene Deletion Generations Genes Glucose Goals Heart Heart Diseases Heart Mitochondria Heart failure Homeostasis Impairment Inner mitochondrial membrane Knockout Mice Link Measures Membrane Metabolic Metabolism Methods Mitochondria Molecular Molecular Mechanisms of Action Multiprotein Complexes Mus Muscle Cells Myocardial Myocardial Ischemia Names Neonatal Open Reading Frames Outcome Output Oxidation-Reduction Peptides Performance Physiological Play Process Protein Import Proteins Pump Rattus Regulation Research Respiration Role Series Signal Transduction Stress Syndrome Testing Therapeutic Transgenic Mice Translational Repression Vascular blood supply Ventricular Virus candidate identification cardioprotection experimental analysis fatty acid oxidation gain of function glucose metabolism heart function heart metabolism in vitro Assay in vivo insight link protein long chain fatty acid loss of function mammalian genome mitochondrial dysfunction mitochondrial membrane mouse model novel novel strategies overexpression oxidation pressure protein complex recruit reduce symptoms respiratory response small hairpin RNA symptom treatment therapeutic target

项目摘要

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.

项目摘要心力衰竭是一种复杂的临床综合症，受心肌收缩受损驱动表现。几种代谢改变导致心力衰竭，包括线粒体功能障碍和心脏底物利用率的变化，导致能源缺乏和降低心肌细胞收缩力。当前的心力衰竭治疗症状而不是比疾病病因的基础机制，无法扭转患病的心肌细胞发生的分子变化。发展新颖的方法增强线粒体功能并在心力衰竭中调节心脏代谢是一种有希望的纠正心肌能量以恢复心脏功能的方法。尽管有中央线粒体在心脏健康和疾病中发挥的作用，我们仍然缺乏对在分子水平上调节了多少个基本线粒体过程。最近的计算和实验数据表明哺乳动物基因组包含数千个以前被忽视的小蛋白称为微蛋白，其中数百种是与线粒体有关，在那里它们被认为是调节分子的重要作用。线粒体微蛋白（MITOMPS）的实例已被证明可以调节必需品线粒体过程包括细胞呼吸，底物利用率，代谢和应力信号。 MITOMP通常通过结合和调节较大蛋白质来表现其功能膜结构域内的伴侣或多蛋白络合物。因此，我们最近发现了2个名为Moxi的新型MITOMP（B-氧化的微肽调节剂）和 Mitolamban，每种都与离散的代谢调节配合物相互作用以执行不同的功能。 Moxi在调节长链脂肪酸氧化中起着至关重要的作用，可能通过A 与线粒体三官能蛋白（MTP）直接相互作用，而Mitolamban相互作用具有电子传输链的复合物III，并有助于复杂的组装和功能。在这里，我们提出了一项全面的研究计划，以剖析作用的分子机制莫西（AIM 1）和Mitolamban（AIM 2）在心脏中使用功能和功能丧失鼠标型号。此外，我们旨在使用实验评估其作为治疗靶标的潜力心力衰竭和缺血性心脏病的模型。此外，要获得一个目标对心脏中线粒体生物学的更完整理解，我们提出了功能分析3个新鉴定的MITOMP（AIM 3）。我们假设这些微蛋白会发挥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功能表征可能导致心力衰竭治疗的新目标。