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bioRxiv · 10.1101/2023.04.17.537222

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

Garbincius, J. F.·Luongo, T. S.·Lambert, J. P.·Mangold, A. S.·Murray, E. K.·Hildebrand, A. N.·Jadiya, P.·Elrod, J. W.
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Abstract

BackgroundMitochondrial 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 hearts adaptation during sustained increases in workload. ObjectiveWe tested the hypothesis that mtCU-dependent mCa2+ uptake contributes to cardiac adaptation and ventricular remodeling during sustained catecholaminergic stress. MethodsMice with tamoxifen-inducible, cardiomyocyte-specific gain (MHC-MCM x flox-stop-MCU; MCU-Tg) or loss (MHC-MCM x Mcufl/fl; Mcu-cKO) of mtCU function received 2-wk catecholamine infusion. ResultsCardiac 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. ConclusionsmtCU 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.

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Garbincius, J. F., Luongo, T. S., Lambert, J. P., Mangold, A. S., Murray, E. K., Hildebrand, A. N., Jadiya, P., Elrod, J. W.. 2023-04-18. MCU gain- and loss-of-function models define the duality of mitochondrial calcium uptake in heart failure. https://doi.org/10.1101/2023.04.17.537222

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