MCU gain-and loss-of-function models define the duality of mitochondrial calcium uptake in heart failure

Abstract

ABSTRACTBackgroundMitochondrial calcium (mCa2+) uptake through the mitochondrial calcium uniporter channel (mtCU) stimulates metabolism to meet acute increases in cardiac energy demand. However, excessivemCa2+uptake during stress, as in ischemia-reperfusion, initiates permeability transition and cell death. Despite these often-reported acute physiological and pathological effects, a major unresolved controversy is whether mtCU-dependentmCa2+uptake and long-term elevation of cardiomyocytemCa2+contributes to the heart’s adaptation during sustained increases in workload.ObjectiveWe tested the hypothesis that mtCU-dependentmCa2+uptake contributes to cardiac adaptation and ventricular remodeling during sustained catecholaminergic stress.MethodsMice with tamoxifen-inducible, cardiomyocyte-specific gain (αMHC-MCM x flox-stop-MCU; MCU-Tg) or loss (αMHC-MCM xMcufl/fl;Mcu-cKO) of mtCU function received 2-wk catecholamine infusion.ResultsCardiac contractility increased after 2d of isoproterenol in control, but notMcu-cKO mice. Contractility declined and cardiac hypertrophy increased after 1-2-wk of isoproterenol in MCU-Tg mice. MCU-Tg cardiomyocytes displayed increased sensitivity to Ca2+- and isoproterenol-induced necrosis. However, loss of the mitochondrial permeability transition pore (mPTP) regulator cyclophilin D failed to attenuate contractile dysfunction and hypertrophic remodeling, and increased isoproterenol-induced cardiomyocyte death in MCU-Tg mice.ConclusionsmtCUmCa2+uptake is required for early contractile responses to adrenergic signaling, even those occurring over several days. Under sustained adrenergic load excessive MCU-dependentmCa2+uptake drives cardiomyocyte dropout, perhaps independent of classical mitochondrial permeability transition pore opening, and compromises contractile function. These findings suggest divergent consequences for acute versus sustainedmCa2+loading, and support distinct functional roles for the mPTP in settings of acutemCa2+overload versus persistentmCa2+stress.