Abstract 16592: Excessive MCU-Mediated Mitochondrial Calcium Uptake During Chronic Stress Impairs Cardiac Contractility

Calcium (Ca 2+ ) uptake into the mitochondrial matrix occurs via the mitochondrial Ca 2+ uniporter channel (mtCU) and tunes mitochondrial metabolism to meet acute changes in cellular ATP demand. However, the role of mtCU-dependent mitochondrial Ca 2+ ( m Ca 2+ ) uptake in regulating homeostatic heart function and adaptation to chronic increases in workload remain controversial. We subjected mice with tamoxifen-inducible, cardiomyocyte-specific gain (flox-stop-MCU x αMHC-MCM, MCU-Tg) or loss ( Mcu fl/fl x αMHC-MCM , Mcu- cKO) of MCU function to 2wk isoproterenol (iso) infusion to test the hypothesis that m Ca 2+ uptake through MCU contributes to functional adaptation to sustained catecholamine signaling. Neither gain nor loss of MCU function altered baseline cardiac structure or function. Fractional shortening was increased after 2d of iso infusion in MCM control mice, but loss of MCU blocked this effect. In contrast, fractional shortening declined significantly after 7-14d of iso in MCU-Tg mice. MCU-Tg mice also exhibited increased LV dilation, heart mass, and lung edema compared to controls after 14d of iso. Acute treatment of MCU-Tg cardiomyocytes in vitro with the Ca 2+ ionophore ionomycin revealed increased ROS production and a trend towards increased sensitivity to Ca 2+ -induced cell death. In agreement, Evans blue dye exclusion assays revealed increased cardiomyocyte necrosis in MCU-Tg hearts following iso. Therefore, we deleted the mPTP regulator cyclophilin D (CypD) in MCU-Tg mice to test whether cardiomyocyte dropout due to m Ca 2+ overload-induced mPTP contributed to iso-induced contractile dysfunction. Unexpectedly, CypD deletion failed to attenuate contractile dysfunction and hypertrophic remodeling, and increased rather than attenuated iso-induced cardiomyocyte death in MCU-Tg mice. We conclude that while MCU-dependent m Ca 2+ uptake is required for the heart’s initial contractile response to catecholaminergic stress, under prolonged stimulation augmented m Ca 2+ uptake becomes deleterious and predisposes to cardiomyocyte death and heart failure. Our findings support the notion that the detrimental effects of sustained MCU-dependent m Ca 2+ uptake are mediated by mechanisms distinct from mitochondrial permeability transition.