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.
The proposed research proposal seeks to provide a better understanding of the role of cardiac mitochondrial mechanisms in human aging and age related diseases. An unprecedented rate of aging population growth (projected to reach 1.6 billion by 2050) has a tremendous health and economic impact, and new strategies to mitigate the development of age-related diseases are of paramount importance which makes the proposed research studies significant as they address novel insights into the regulatory role of protein acetylation on mitochondrial bioenergetics and cardiac contractile function in aging heart. Identification of new mechanisms and targets holds significant promise for the development of novel therapeutic outcomes for healthy aging.