Investigating the novel role of acetylation in cardiac mitochondrial bioenergetics and function in the aging heart

研究乙酰化在心脏线粒体生物能学和衰老心脏功能中的新作用

• 批准号: 10683270
• 负责人: Dharendra Thapa
• 金额: $ 24.89万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-08 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683270
• 关键词: Acetylation; Acetyltransferase; Age; Aging; Animal Model; Animals; Bioenergetics; Biological Assay; Biological Process; Biology; Cardiac; Cardiac Myocytes; Coenzyme A; Coupled; Data; Deacetylase; Development; Development Plans; Disease; Energy Metabolism; Energy Supply; Environment; Enzymes; Functional disorder; Future; Generations; Genetic; Goals; Health; Heart; Human; In Vitro; Knowledge; Long-Chain-Acyl-CoA Dehydrogenase; Lysine; Mass Spectrum Analysis; Mediating; Mentorship; Metabolic; Mitochondria; Modeling; Molecular; Mus; Myocardial dysfunction; Obese Mice; Oxidoreductase; Pathogenesis; Peptides; Population Growth; Post-Translational Protein Processing; Process; Protein Acetylation; Proteins; Proteomics; Regulation; Research; Research Personnel; Research Proposals; Resolution; Resources; Role; Site; Stress; System; Testing; Tissues; Training and Education; Universities; Work; age related; aged; aging population; biochemical tools; career development; diet-induced obesity; economic impact; enzyme activity; enzyme substrate; fatty acid oxidation; flexibility; healthy aging; heart function; improved; in vivo; insight; long chain fatty acid; middle age; mitochondrial dysfunction; mitochondrial metabolism; new therapeutic target; novel; novel therapeutics; oxidation; prevent; research study; therapy outcome; training opportunity

Cardiac mitochondrial dysfunction is central to the pathogenesis of aging and many age related diseases. Mitochondria supply the bioenergetic capacity for cardiac contractile function through oxidation of fuel substrates and a complete control of this system is indispensable to maintain cardiac efficiency. Specifically, the role of Hydroxyacyl-CoA Dehydrogenase (HADHA) and Long Chain Acyl-CoA Dehydrogenase (LCAD) in catalyzing the oxidation of long chain fatty acids in the heart is well studied and their dysfunction is associated with decreased fatty acid oxidation (FAO) and cardiac energy depletion. However, studies focused on understanding the cellular mechanisms that regulate these key mitochondrial energy substrate enzymes in the aging heart are scarce. In a recent study, we described that increased acetylation increases the activities of LCAD and HADHA in diet induced obesity, which was mediated by changes in the expression of mitochondrial acetyltransferase GCN5L1 and deacetylase SIRT3. In the aging heart, we observe increased GCN5L1 and decreased SIRT3 expression resulting in an increased acetylation status of HADHA and LCAD. Based on these observations, we hypothesize that GCN5L1 and SIRT3 control HADHA and LCAD acetylation, and that dysregulation of this mechanism in aging contributes to reduced mitochondrial bioenergetics and cardiomyocyte energy depletion. To test our central hypothesis, we propose the following aims: 1. We will investigate how acetylation regulates the activity of HADHA and LCAD in young, middle aged and old mouse hearts. Using high resolution mass spectrometry based proteomics; we will identify acetylation sites, relative quantification and assess their impact in key biological processes and enzymatic functions. 2. We will investigate the mechanisms associated with regulation of HADHA and LCAD activity in young, middle aged and old mouse hearts. We will use novel GCN5L1 and SIRT3 cardiac KO animal to delineate the molecular mechanisms underlying changes in HADHA and LCAD acetylation in aging process. 3. We will investigate how changes in fatty acid oxidation protein acetylation impacts mitochondrial bioenergetics and cardiac contractile function in aging heart. The long term goal of this study is to understand the regulatory role of cardiac mitochondrial acetylation in human aging and age related diseases. Our results will improve our understanding of acetylation mediated regulation of FAO enzymes in aging mitochondrial biology and provide novel insights on regulation of fuel substrate usage in the aging heart and their contribution towards improving mitochondrial and cardiac function with age.

心脏线粒体功能障碍是衰老和许多年龄相关疾病的发病机制的核心。

项目成果

Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.

心肌细胞特异性删除 GCN5L1 可减少赖氨酸乙酰化，并通过改善心脏脂肪酸氧化来减轻老年小鼠的舒张功能障碍。

• DOI: 10.1042/bcj20230421
• 发表时间: 2024
• 期刊: The Biochemical journal
• 作者: Stewart,JacksonE;Crawford,JennaM;Mullen,WilliamE;Jacques,Angelica;Stoner,MichaelW;Scott,Iain;Thapa,Dharendra
• 通讯作者: Thapa,Dharendra