Abstract 13015: Inhibition of Mitochondrial Calcium Uptake in the Heart Does Not Compromise Cardiac Energetics or Function Due to a Preferential Increase in Fatty Acid Oxidation During Increased Cardiac Work

Abstract

The mitochondrial calcium (Ca 2+ ) uniporter (MCU) is primarily responsible for relaying cytosolic Ca 2+ transients to the mitochondria. Increasing cardiac workload by positive inotropes results in increased mitochondrial Ca 2+ , increasing glucose oxidation in comparison to fatty acid oxidation. This has been attributed to Ca 2+ stimulation of pyruvate dehydrogenase, the rate-limiting enzyme in glucose oxidation. We examined what effect increasing workload has on cardiac energetics and cardiac function if mitochondrial Ca 2+ levels are decreased in hearts from inducible cardio-specific deleted MCU (MCU -/- ) mice. Hearts from MCU -/- and MCU fl/fl control mice were isolated and perfused as working hearts with 5 mM glucose, 0.8 mM palmitate, 3% albumin, ± insulin (100 μU/ml) and isoproterenol (10 nM). Surprisingly, MCU -/- hearts showed increased cardiac work (p<0.05 vs. MCU fl/fl ). MCU -/- hearts were also not energy-starved, displaying basal rates of glucose and fatty acid oxidation comparable to controls, and even higher glucose oxidation in response to insulin (3027±213 vs. 2268±166 nmol . g dry wt -1. min -1 in MCU fl/fl , p <0.05). In response to isoproterenol treatment, MCU -/- hearts showed a similar increase in glucose oxidation, compared to controls. However, palmitate oxidation increased to a larger extent in MCU -/- hearts compared to controls (793±60 vs. 558±55 nmol . g dry wt -1. min -1 , p <0.05, respectively), resulting in a greater reliance on fatty acid oxidation for ATP production (40.1±1.9 % vs. 32.7±2.1% in MCU fl/fl , p <0.05). This high fatty acid oxidation supported the higher energy demand at increased workload and provided a higher energy reserve as evident by higher acetyl-CoA/ CoA ratios (0.36±0.03 vs. 0.26±0.02 in MCU fl/fl , p<0.05). The rise in fatty acid oxidation correlated with lower levels of malonyl CoA, an endogenous fatty acid oxidation inhibitor, (4.50±0.29 vs. 8.66±0.98 nmol . g dry wt -1 in MCU fl/fl , p< 0.05), and to an increase in acetylation of the fatty acid oxidation enzyme 3-hydroxyacyl CoA dehydrogenase (which stimulates activity). These results suggest that low mitochondrial Ca 2+ does not compromise cardiac energetics due to a compensatory stimulation of fatty acid oxidation.