Abstract 284: Loss of Cardiomyocyte General Control of Amino-Acid Synthesis 5-like 1 Expression Impairs Mitochondrial Function and Exacerbates Heart Failure Progression

Background: Energy starvation resulting from impaired mitochondrial function is one of the key mechanisms of heart failure development. Emerging evidence shows that lysine acetylation is one of the critical post-translational modifications that modulates mitochondrial bioenergetic output. We have identified General Control of Amino-Acid Synthesis 5-like 1 (GCN5L1) as a key acetyltransferase protein responsible for dynamic mitochondrial protein acetylation, and that this mechanism plays an essential role in regulating fatty acid oxidation. However, the role of GCN5L1 regulation on mitochondrial function in heart failure development is unknown. Methods and results: We examined GCN5L1 expression in cultured neonatal cardiac myocytes (RNCM) challenged with hypertrophy inducer phenylepherine (PE), and in failing hearts. We found that GCN5L1 mRNA and protein expression is markedly decreased in RNCM treated with PE, and in heart failure induced by mouse transaortic constriction (TAC). In addition, total mitochondrial protein acetylation in failing hearts was significantly decreased, corresponding to the decreased levels of GCN5L1. Next, we investigated the impact of decreased level of GCN5L1 on mitochondrial function and cardiac function in response to pathological stress. We found that GCN5L1 knockdown by shRNA in RNCM results in a decrease in basal oxygen consumption rate and ATP-linked respiration upon PE stimulation. More importantly, knocking down GCN5L1 in the presence of PE exacerbates the RNCM hypertrophic response assessed by increased cellular area and elevated ANP and BNP. Consistent with these in vitro studies, cardiac specific GCN5L1 knockout mice subjected to TAC display accelerated cardiac hypertrophy and heart failure, compared to WT littermates (fractional shortening 15.7% vs 26.4%, n=6-7 in each group, P < 0.05). Conclusion: GCN5L1 plays a critical role in mitochondrial function and cardiac bioenergetics in response to stress. Impaired GCN5L1 function might be one of the key mechanisms of metabolic derangement in heart failure development, and could be a promising therapeutic target.