Abstract

© 2015 The Authors.In the heart, augmented Ca 2+ fluxing drives contractility and ATP generation through mitochondrial Ca 2+ loading. Pathologic mitochondrial Ca 2+ overload with ischemic injury triggers mitochondrial permeability transition pore opening and cardiomyocyte death. Mitochondrial Ca 2+ uptake is primarily mediated by the mitochondrial Ca 2+ uniporter. Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca 2+ uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca 2+ challenge. Mice lacking Mcu inthe adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca 2+ levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca 2+ after stress stimulation. Indeed, Mcu-deleted mice were unable to immediately sprint on a treadmill unless warmed up for 30min. Hence, MCU is a dedicated regulator of short-term mitochondrial Ca 2+ loading underlying a"fight-or-flight" response that acutely matches cardiac workload with ATP production.