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

Mitochondrial calcium (_mCa²⁺) uptake through the mitochondrial calcium uniporter channel (mtCU) stimulates metabolism to meet acute increases in cardiac energy demand. However, excessive _mCa²⁺ 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-dependent _mCa²⁺ uptake and long-term elevation of cardiomyocyte _mCa²⁺ contributes to the heart's adaptation during sustained increases in workload.

We tested the hypothesis that mtCU-dependent _mCa²⁺ uptake contributes to cardiac adaptation and ventricular remodeling during sustained catecholaminergic stress.

Mice with tamoxifen-inducible, cardiomyocyte-specific gain (αMHC-MCM × flox-stop-MCU; MCU-Tg) or loss (αMHC-MCM × Mcu^fl/fl; Mcu-cKO) of mtCU function received 2-wk catecholamine infusion.

Cardiac contractility increased after 2d of isoproterenol in control, but not Mcu-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.

mtCU _mCa²⁺ uptake is required for early contractile responses to adrenergic signaling, even those occurring over several days. Under sustained adrenergic load excessive MCU-dependent _mCa²⁺ 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 sustained _mCa²⁺ loading, and support distinct functional roles for the mPTP in settings of acute _mCa²⁺ overload versus persistent _mCa²⁺ stress.