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Loss of mitochondrial NAD+ as a unifying cause of heart failure

线粒体 NAD 丢失是心力衰竭的统一原因

基本信息

批准号：
10708778
负责人：
Caroline Perry
金额：
$ 3.52万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708778
关键词：
Address Adult Ataxia Cardiac Cardiac Myocytes Cardiac Output Cardiovascular Diseases Cause of Death Cell Line Cells Cessation of life Characteristics Citric Acid Cycle Complex Data Depressed mood Development Disease EFRAC Echocardiography Electron Transport Electrons Enzymes Etiology Fibroblasts Friedreich Ataxia Functional disorder Future Generations Glycolysis Pathway Heart Heart Diseases Heart Hypertrophy Heart Mitochondria Heart Transplantation Heart failure Human Hypertrophic Cardiomyopathy Iron Left Ventricular Remodeling Left ventricular structure Literature Maintenance Mediating Mediator Metabolic Metabolism Mitochondria Mitochondrial Diseases Mitochondrial Myopathies Mitochondrial Proteins Modeling Mus Myocardial dysfunction NADH Nicotinamide adenine dinucleotide Organelles Oxygen Pathogenesis Patients Phase Play Pre-Clinical Model Protocols documentation Reporting Research Respiration Role Stress Sulfur Supplementation Testing Therapeutic Therapeutic Effect Therapeutic Intervention Thick Tissues United States associated symptom cell type curative treatments experience experimental study fatty acid oxidation frataxin heart function improved in vivo ischemic injury knock-down loss of function mutation metabolomics mitochondrial dysfunction mitochondrial metabolism mouse model nicotinamide riboside supplementation nicotinamide-beta-riboside pre-clinical preference premature prevent reduce symptoms respiratory

项目摘要

Project Summary Heart disease results in over 650,000 deaths per year in the United States, and nearly half of all adults are currently living with some form of cardiovascular disease. Currently there is no curative treatment option except for a heart transplant. Thus, there is significant need for better therapeutic interventions. Heart failure can take years to develop, but is ultimately characterized by a reduction in cardiac output. There is a considerable body of research demonstrating maladaptive metabolic reprogramming of cardiomyocytes at this stage, which contributes to heart dysfunction and adverse remodeling of the left ventricle. The hypothesis detailed in this application proposes that nicotinamide adenine dinucleotide (NAD+) deficiency in the mitochondria is sufficient to cause heart failure. Recent literature demonstrates tissue-level NAD+ decline during ischemic injury. NAD+ precursors have been found to be therapeutic for heart failure in multiple pre-clinical models. Preliminary data generated in our lab suggests that the NAD+ precursor nicotinamide riboside (NR) prevented heart dysfunction, protected mitochondrial function, and improved survival in a model of Friedreich’s Ataxia (FA), in which mice typically develop progressive hypertrophic cardiomyopathy. This result suggests that NAD+ deficiency may be involved in the pathogenesis of heart failure in FA. Alternatively, it provides preclinical evidence that NR is therapeutic in FA even without NAD+ deficiency, suggesting that boosting NAD+ levels in the heart tissue can be protective of heart function under mitochondrial stress. To address these points, this proposal first aims to determine whether low mitochondrial NAD+ levels are observed with loss of frataxin, and whether increasing mitochondrial NAD+ synthesis with NR ex vivo can directly support mitochondrial respiration (Aim 1). This proposal also aims to define the metabolic consequences of mitochondrial NAD+ deficiency in cardiomyocytes, to determine whether mitochondrial NAD+ loss demonstrates characteristic metabolism of the hypertrophic heart in vivo (Aim 2). Together, this set of experiments will demonstrate whether NAD+ decline is a metabolic consequence of frataxin loss and mitochondrial damage, and define the importance of mitochondrial NAD+ maintenance in supporting the normal metabolism of cardiomyocytes. Further, it will provide mechanistic understanding of the specific action of NAD+ precursors to protect against mitochondrial- dysfunction mediated heart failure, which will inform future therapeutic interventions in progressive heart disease.

项目总结