Abstract P3199: Role Of Acetylation In Regulating Mitochondrial Dysfunction In The Aged Heart

Abstract

Cardiac mitochondrial dysfunction is a critical contributor to the pathogenesis of aging. Cardiac muscle is an extremely high energy demanding tissue, necessitating properly functioning mitochondria to meet this demand for contractile function. As such, complete control of mitochondrial function is indispensable to maintain cardiac efficiency. Lysine acetylation is a post-translational modification of proteins that has been shown to regulate several metabolic and biochemical processes in the mitochondria. The goal of this study is to understand the role of mitochondrial lysine acetylation in regulating mitochondrial processes in the aged heart. We observed an increased propensity towards a pro-acetylation profile resulting in increased acetylation of several cardiac mitochondrial proteins involved in metabolism, redox milieu and electron transport chain complexes in aging which was attenuated in our cardiac GCN5L1 knockout old animal. Based upon these findings, we hypothesize that mitochondrial acetyltransferase GCN5L1 has a critical role in regulating the function of mitochondrial proteins in the aged heart. Using immunoprecipitation assay, we observed an age-associated increase in acetylation of several key fatty acid oxidation and glucose oxidation proteins. This increased acetylation correlated with decreased activity of several fatty acid oxidation proteins, including short- and long-chain acyl-CoA dehydrogenase. Several mitochondrial proteins involved in mitochondrial fatty acid import and electron transport chain complexes were hyperacetylated in aging. These proteins largely exhibited increased acetylation levels in response to age that was attenuated by cardiac-specific GCN5L1 knockout. Lastly, we observed an age-associated increase in GCN5L1-mediated acetylation of the antioxidant enzyme manganese superoxide dismutase (SOD2) at lysine site K122. Acetylation of SOD2 at the K122 site has been shown to inhibit SOD2 activity. Based upon our findings, we conclude that age-associated increases in GCN5L1 expression results in derangements in cardiac fuel substrate utilization, electron transport chain complex function, and mediation of reactive oxygen species-associated damage.