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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.