The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition

• DOI: 10.1016/j.celrep.2015.06.017
• Publication Date: 2015-06-25T17:55:11Z
• Authors: Timothy S. Luongo; Jonathan P. Lambert; Ancai Yuan; Xueqian Zhang; Polina Gross; Jianliang Song; Santhanam Shanmug...; Erhe Gao; Mohit Jain; Steven R. Houser; Walter J. Koch; Joseph Y. Cheung; Muniswamy Madesh; John W. Elrod
• Keywords: QH301-705.5; Cells; Physiological; Medical Physiology; 610; Myocardial Reperfusion Injury; 612; Cardiovascular; Inbred C57BL; Stress; Mice; 03 medical and health sciences; Stress, Physiological; 2.1 Biological and endogenous factors; Animals; Myocytes, Cardiac; Aetiology; Biology (General); Cells, Cultured; Myocytes; 0303 health sciences; Cultured; Myocardial Contraction; Mice, Inbred C57BL; Heart Disease; Calcium; Biochemistry and Cell Biology; Calcium Channels; Energy Metabolism; Cardiac

Cardiac contractility is mediated by a variable flux in intracellular calcium (Ca(2+)), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here, we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu(-/-) mice display no overt baseline phenotype and are protected against mCa(2+) overload in an in vivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu(-/-) mice lack contractile responsiveness to acute β-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca(2+)-dependent metabolism during acute stress.