Abstract 476: Cardiac Adaptation to the Oncometabolite D-2-hydroxyglutarate is Driven by Alpha-Ketoglutarate and Acetyl-CoA

Abstract

Metabolic reprogramming is a hallmark in both cancer and heart failure. Mutations of the isocitrate deyhydrogenase (IDH) 1 and 2 cause metabolic dysfunction in cancer cells through overproduction of the oncometabolite D-2-hydroxyglutarate (D2-HG) and are associated with cardiomyopathy. We recently discovered that alpha-Ketoglutarate dehydrogenase inhibition by D2-HG redirects Krebs cycle flux. This implies a central role for IDH and ATP citrate lyase (ACL) in regulating reductive formation of citrate and histone acetylation in response to mitochondrial impairment in heart and skeletal muscle. Elucidating how metabolic rewiring promotes changes in gene expression and remodeling in heart muscle holds the promise for development of metabolic strategies to support the failing heart. We tested whether modulation of ACL activity reverses D2-HG-mediated metabolic changes using adult rat ventricular cardiomyocytes and L6 myocytes. The ACL inhibitor BMS303141 (BMS) decreased ATP provision in cultured myocytes in a concentration-dependent manner. There was an inverse relation between alpha-KG and ACL activities. Conversely, co-culture with both BMS (0.5 μM) and D2-HG (1 mM) increased ATP provision suggesting that ACL inhibition in presence of D2-HG may be beneficial for energy provision. Next, we conducted isolated working rat heart perfusions with BMS (0.5 μM) and/or D2-HG (1 mM). Cardiac power rapidly declined (by 25%) in the presence of BMS or D2-HG. Simultaneous perfusion with D2-HG and BMS improved cardiac power, suggesting that ACL inhibition protects the heart from metabolic dysfunction by D2-HG. Further, D2-HG elevation mediated structural remodeling in the heart by activating authophagy through increased acetylation of p300, increased phosphorylation of AMPK, and a corresponding decrease in activation and phosphorylation of mTOR. Parallel tracer studies using labeled glucose and glutamine allowed us to conduct computational flux rate analysis by applying the metabolic network CardioNet. We identified major metabolic pathways that are up- and downregulated by D2-HG. Our findings suggest an “oncometabolic axis” in the heart and underscore the potential application of ACL inhibitors to protect the heart from failing.