Enhanced NCLX-dependent mitochondrial Ca2+ efflux attenuates pathological remodeling in heart failure

Abstract

Mitochondrial calcium (_mCa²⁺) uptake couples changes in cardiomyocyte energetic demand to mitochondrial ATP production. However, excessive _mCa²⁺ uptake triggers permeability transition and necrosis. Despite these established roles during acute stress, the involvement of _mCa²⁺ signaling in cardiac adaptations to chronic stress remains poorly defined. Changes in NCLX expression are reported in heart failure (HF) patients and models of cardiac hypertrophy. Therefore, we hypothesized that altered _mCa²⁺ homeostasis contributes to the hypertrophic remodeling of the myocardium that occurs upon a sustained increase in cardiac workload. The impact of _mCa²⁺ flux on cardiac function and remodeling was examined by subjecting mice with cardiomyocyte-specific overexpression (OE) of the mitochondrial Na⁺/Ca²⁺ exchanger (NCLX), the primary mediator of _mCa²⁺ efflux, to several well-established models of hypertrophic and non-ischemic HF. Cardiomyocyte NCLX-OE preserved contractile function, prevented hypertrophy and fibrosis, and attenuated maladaptive gene programs in mice subjected to chronic pressure overload. Hypertrophy was attenuated in NCLX-OE mice, prior to any decline in cardiac contractility. NCLX-OE similarly attenuated deleterious cardiac remodeling in mice subjected to chronic neurohormonal stimulation. However, cardiomyocyte NCLX-OE unexpectedly reduced overall survival in mice subjected to severe neurohormonal stress with angiotensin II + phenylephrine. Adenoviral NCLX expression limited _mCa²⁺ accumulation, oxidative metabolism, and de novo protein synthesis during hypertrophic stimulation of cardiomyocytes in vitro. Our findings provide genetic evidence for the contribution of _mCa²⁺ to early pathological remodeling in non-ischemic heart disease, but also highlight a deleterious consequence of increasing _mCa²⁺ efflux when the heart is subjected to extreme, sustained neurohormonal stress.