Microprotein Regulation of Mitochondrial Function

点击翻译按钮获取中文摘要

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.