DESCRIPTION (provided by applicant): The incidence of heart failure (HF) is projected to increase by 25% over the next 20 years with a projected cost of $69.7 billion representing a substantial health and economic burden on the US. In general, HF is characterized by a decrease in contractility and maladaptive ventricular remodeling ultimately leading to impaired cardiac output to the systemic circulation. Immense scientific effort has been focused on unraveling the molecular and cellular mechanisms driving decreased cardiac contractility and while a multitude of changes no doubt contribute, it is generally agreed that much of the contractile deficit is due to a reduction in cytosolic calcium (Ca2+) transients and a decrease in sarcoplasmic reticulum (SR) Ca2+ content. Similarly, recent studies have supported the theory that mitoCa2+ content is actually diminished in HF despite elevations in diastolic Ca2+. To examine the role of mitoCa2+ in the development and progression of HF we have developed mutant mouse models of a proposed mitochondrial Na+/Ca2+ exchanger (mitoNCX). The mitoCa2+ microdomain has been under intense investigation due to its significant influence on energy production and cell death and HF in particular, is characterized by both significant metabolic dysfunction and gradual cell dropout. This project is testing the central hypothesis that reducing mitoCa2+ efflux protects against gradual cell dropout and adverse remodeling in heart failure by enhancing cardiomyocyte metabolic and redox capacity. For the first time, utilizing genetic gain- and loss-of-function approaches we will characterize the biophysical properties of this novel exchanger, assess its contribution to cellular physiology and examine its role in clinically relevant animal models. The ultimate goal of this research endeavor is to define the role of mitoCa2+ signaling in the development and progression of HF and foster therapeutic application.

PUBLIC HEALTH RELEVANCE: This goal of this research project is to further our understanding of the cellular events that promote the development of heart failure. Specifically, we are examining how small channels within the mitochondria might regulate various signaling processes that change both how a heart cell (cardiomyocyte) dies and how it uses energy in the context of heart failure. A more developed understanding of these very important processes we hope will foster new treatments for heart disease.