Enhanced NCLX-dependent mitochondrial Ca efflux attenuates pathological remodeling in heart failure.

Mitochondrial calcium (Ca) uptake couples changes in cardiomyocyte energetic demand to mitochondrial ATP production. However, excessive Ca uptake triggers permeability transition and necrosis. Despite these established roles during acute stress, the involvement of Ca 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 Ca homeostasis contributes to the hypertrophic remodeling of the myocardium that occurs upon a sustained increase in cardiac workload. The impact of Ca flux on cardiac function and remodeling was examined by subjecting mice with cardiomyocyte-specific overexpression (OE) of the mitochondrial Na/Ca exchanger (NCLX), the primary mediator of Ca 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 Ca accumulation, oxidative metabolism, and de novo protein synthesis during hypertrophic stimulation of cardiomyocytes in vitro. Our findings provide genetic evidence for the contribution of Ca to early pathological remodeling in non-ischemic heart disease, but also highlight a deleterious consequence of increasing Ca efflux when the heart is subjected to extreme, sustained neurohormonal stress.