Abstract Body (Do not enter title and authors here): Background: Cardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits alpha-ketoglutarate dehydrogenase (alpha-KGDH) and is associated with reduced cardiac contractile function.

Methods: We combined stable isotope tracer studies with computational modeling to study the fundamental role of IDH isoforms for cardiac adaptation during oncometabolic stress.

Results: We uncovered an unexpected cardiac phenotype that expands the role of IDH1 in the heart beyond oxidative metabolism. We quantified the stable isotopomer distributions from glucose and glutamine in perfused working rat hearts and isolated adult ventricular cardiomyocytes using mass spectrometry-based metabolomics. Our analysis revealed that defective mitochondrial metabolism causes the redirection of carbon flux oxidative towards reductive pathways. Reductive carboxylation of α-KGDH increases glutamine uptake and glutamine-derived citrate formation in working rat heart perfusions and cultured adult mouse ventricular cardiomyocytes. To identify which IDH isoform is responsible for redirecting carbon flux, we developed knockout models of IDH1, 2, and 3 in adult mouse ventricular cardiomyocytes. Loss of IDH1 expression impaired the reductive formation of citrate and caused functional defects in cardiomyocytes. Lastly, epigenetic analyses of histone marks revealed that IDH1 causes widespread histone acetylation and tri-methylation alterations.

Conclusion: Our results highlight a novel role for IDH1 in cardiac metabolism and transcriptional control of metabolic adaptation in response to tumor-mediated stress and provide evidence of how reductive-citrate formation may induce epigenetic modifications in the heart.