Metabolic Rewiring of the Heart Through Reductive Carboxylation

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Summary The term “cancer and the heart” traditionally refers to the cardiotoxic effects of chemotherapeutic agents. However, independent of any cytostatic treatment, cancer survivors have a five-fold higher risk for developing heart failure. Therefore, new therapeutic strategies must consider tumor biology when aiming at protecting the heart. For example, it has been observed that in isocitrate dehydrogenase (IDH) 1 and 2 mutant tumors, the elevated production of the oncometabolite D-2-hydroxyglutarate (D2-HG) is associated with systemic effects, including dilated cardiomyopathy. About 20% of acute myeloid leukemia cases harbor mutations of the IDH. These mutations lead to significantly reduced patient survival and cause metabolic dysfunction which are associated with high levels of the oncometabolite D2-HG. However, the extent to which D2-HG can directly impair cardiac function and metabolism, and which processes are involved, is still unknown. Recently I discovered that D2-HG mediates cardiac dysfunction by inhibiting α-ketoglutarate dehydrogenase, which leads to redirection of Krebs cycle intermediates, increased ATP citrate lyase activity, and increased histone 3 pan- acetylation. Furthermore, chronic treatment with D2-HG causes heart and skeletal muscle atrophy, suggesting that IDH mutation also stimulates structural remodeling. I now propose that inhibition of α-KG dehydrogenase by the oncometabolite D2-HG induces reductive carboxylation of α-KG in the heart resulting in pathologic structural remodeling. My goal is to determine the role of oncometabolism in the pathogenesis of heart failure. In the K99 phase, Specific Aim 1 will define the role of reductive carboxylation as a mediator for metabolic remodeling of the heart using the oncometabolite D2-HG as a model. Specific Aim 2 will define the role of reductive citrate metabolism as a link between energy substrate metabolism and epigenetic remodeling by lysine acetylation. These experiments will transition into the R00 phase, which in Specific Aim 3 will extend the findings to address the impact of branched chain amino acid metabolism and autophagy on proteomic remodeling in the metabolically deregulated state of D2-HG. Collectively, this project will advance the hypothesis that oncometabolic stress drives development of heart failure. These new insights ultimately change the way cancer and heart failure patients are treated.