Abstract 17143: The Oncometabolite D2-hydroxyglutarate Redirects Krebs Cycle Flux and Impairs Contractile Function in Rodent Heart
Introduction: Somatic mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) have been described in a large subset of patients with acute myeloid leukemia (AML) and lead to increased production of the oncometabolite D-2-hydroxyglutarate (D2-HG). Recent reports show that increased amounts of D2-HG are associated with cardiomyopathy. However, the mechanism by which D2-HG affects cardiac function and metabolism remains unknown.
Hypothesis: We propose that D2-HG mediates metabolic stress in the heart causing functional and structural remodeling.
Methods: Sprague Dawley rat hearts were perfused ex vivo in the presence or absence of D2-HG in concentrations similar to those found in the plasma of AML patients. Rats were perfused acutely with the ATP citrate lyase (ACL) inhibitor BMS303141. C57BL/6 mice were treated chronically with D2-HG for 32-days to investigate the chronic effects of D2-HG.
Results: D2-HG caused acute contractile dysfunction in working rat hearts. This contractile dysfunction was associated with impaired oxidative decarboxylation of α-ketoglutarate caused by inhibition of α-ketoglutarate dehydrogenase (α-KGDH). Using labeled glucose and oleate, we found that energy substrate metabolism shifted from fatty acids to increased glucose utilization in the presence of D2-HG. Computational flux rate analysis revealed that D2-HG redirects Krebs cycle intermediates into citrate, oxaloacetate and acetyl-CoA, which are precursors for de-novo lipid synthesis and protein acetylation. In hearts from mice injected for 32 days with D2-HG, levels of succinate and citrate were increased while ACL activity was also increased. These metabolic changes were associated with increased pan-acetylation of histone 3. Lastly, we tested whether pharmacological modulation of ACL activity with BMS303141 would reverse D2-HG mediated metabolic effects in rat hearts and isolated cardiomyocytes. We observed that ACL inhibition was only beneficial when α-KGDH activity was decreased.
Conclusions: We conclude that the oncometabolite D2-HG redirects Krebs cycle flux through inhibition of α-KGDH. Our results suggest a novel role for α-KGDH and ACL in regulating cardiac energy substrate metabolism and contractile function.
Author Disclosures: A. Karlstaedt: None. X. Zhang: None. R. Khanna: None. H. Vitrac: None. R. Hermancey: None. H. Vasquez: None. M. Goodell: None. H. Taegtmeyer: None.
- © 2016 by American Heart Association, Inc.