Heart failure (HF) is a leading cause of disability and death among Americans that currently affects 6 million people at an economic burden of ~$30 billion per year in the United States alone. The flow of calcium (Ca2+) into and out of the mitochondria is a key mechanism regulating cellular energy metabolism and cell death. Since both energetics and cardiomyocyte survival are compromised in the failing heart, altered mitochondrial Ca2+ (mCa2+) handling has been proposed as a contributing factor in HF. However, the specific changes that occur in mCa2+ exchange during the development and progression of HF, and the mechanisms that mediate these effects, remain poorly defined. Therefore, a necessary step before the development of HF therapies aimed at modulating mCa2+ exchange is to determine exactly how mCa2+ handling changes throughout the failure process and to understand the specific consequences of chronically-altered mCa2+ exchange on the function of the failing heart. Recent studies reveal that the mitochondrial sodium-calcium exchanger (NCLX), which mediates extrusion of mCa2+, is transcriptionally upregulated in human HF. NCLX structure and function are also controlled via mechanisms including phosphorylation and alternative splicing, and preliminary data indicate that cardiomyocytes regulate NCLX through these processes during physiological or pathological stress. Initial findings also suggest that transgenic overexpression of NCLX to enhance cardiomyocyte mCa2+ extrusion is sufficient to protect contractile function and attenuate pathological remodeling in mouse models of non-ischemic HF. Based on these data, we hypothesize that cardiomyocytes increase net NCLX activity as an adaptive mechanism to control mCa2+ homeostasis in HF. Here we will pursue Specific Aims employing genetic mouse models with net gain or reduction of cardiac NCLX function to examine the contribution of altered NCLX activity to the development and progression of chronic HF and assess the therapeutic potential of NCLX modulation for this disease. We will also combine robust proteomic and molecular approaches with direct in vitro assessments of NCLX function to determine the endogenous mechanisms that control NCLX activity within the heart. This project will be the first to causatively examine how alterations in NCLX activity protect or predispose the heart to failure when subjected to sustained pathological stress, and will generate fundamental knowledge that can be exploited for therapeutic control of NCLX activity. These findings will have broad translational relevance not only for cardiac disease, but also for other conditions characterized by altered mCa2+ homeostasis such as Alzheimer?s disease and neurodegeneration. A detailed training plan outlining the mentorship to be provided to the Applicant and the resources and technical support available at Temple University?s Center for Translational Medicine has been developed to ensure successful completion of the proposed work and foster the Applicant?s scientific maturation into an independent academic investigator.
Six million Americans live with heart failure, for which there is no cure, so it is critical to uncover the fundamental mechanisms driving this disease. Disrupted mitochondrial calcium homeostasis causes deterioration of heart function via cardiomyocyte death and/or compromised cellular energetics. The determination of how mitochondrial calcium exchange pathways are altered in the development and progression of heart failure, and the discovery of the mechanisms that modulate mitochondrial calcium flux, will generate fundamental insights to enable the development of novel therapies for this disease.
