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
The mitochondrial calcium (Ca2+) uniporter (MCU) is primarily responsible for relaying cytosolic Ca2+ transients to the mitochondria. Increasing cardiac workload by positive inotropes results in increased mitochondrial Ca2+, increasing glucose oxidation in comparison to fatty acid oxidation. This has been attributed to Ca2+ 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 Ca2+ levels are decreased in hearts from inducible cardio-specific deleted MCU (MCU-/-) mice. Hearts from MCU-/- and MCUfl/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. MCUfl/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 MCUfl/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 MCUfl/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 MCUfl/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 MCUfl/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 Ca2+ does not compromise cardiac energetics due to a compensatory stimulation of fatty acid oxidation.
Author Disclosures: T.R. Altamimi: None. J. Kwong: None. A. Fukushima: None. J.D. Molkentin: None. G.D. Lopaschuk: None.
- © 2016 by American Heart Association, Inc.