Abstract 15562: Loss of Mitochondrial Pyruvate Carrier 1 in Cardiomyocytes Leads to Cardiac Dysfunction and Heart Failure via Hif-1 Activation
Glucose and lactate are important fuel substrates for the heart, particularly during acute hemodynamic stresses such as pressure overload or following exercise training. Cytosolic pyruvate that is generated by glycolytic metabolism of glucose or by conversion of lactate is transported into mitochondria via the recently described mitochondrial pyruvate carrier complex, which has two subunits, MPC1 and MPC2. The role of pyruvate uptake in regulating cardiac function and metabolism is incompletely understood. Thus, we generated cardiomyocyte-restricted MPC1 knockout mice (CMPC1-/-). Loss of MPC1 resulted in degradation of MPC2 leading to functional inactivation of the MPC complex in CMPC1-/- mouse hearts. Cardiac function examined by echocardiography revealed that CMPC1-/- mice exhibited normal cardiac function by the age of 8 weeks but overt systolic dysfunction was noted at the age of 18 weeks. Survival analysis showed that only 61% of CMPC1-/- mice remained alive at the age of 1year while 98% of control mice survived. At the age of 8 weeks, heart weight (HW) and the heart weight to tibia ratio (HW/TL) were significantly increased, as were characteristic transcriptional markers of pathological cardiac hypertrophy, NPPA, NPPB and Acta1. Substrate metabolism measured in isolated working hearts, revealed a 58% reduction in glucose oxidation in CMPC1-/- mice relative to control mice while palmitate oxidation was increased by 35%. Metabolomics analyses revealed accumulation of pyruvate, lactate and alanine. In contrast, malate and glutamate levels were decreased, suggesting a compensatory increase in malate and glutamate utilization. 2-hydroxyglutarate (2-HG) was also increased in CMPC1-/- mouse hearts, which may activate Hif-1α signaling. Indeed, downstream transcriptional targets of Hif-1 (LDHA, PDK1 and PKM2) were increased. These data suggest that mitochondrial pyruvate uptake although dispensable for normal cardiac development and function in non-stressed juvenile hearts ultimately precipitates pathological cardiac hypertrophy and heart failure in CMPC1-/- mice via 2-HG-mediated Hif-1 activation.
Author Disclosures: Y. Zhang: None. J. Cox: None. J. Rutter: None. E. Abel: None.
- © 2015 by American Heart Association, Inc.