Cellular heterogeneity in mitochondrial calcium dynamics in heart failure

Project Summary/Abstract Heart failure with preserved ejection fraction (HFpEF) affects nearly 50% of heart failure patients and represents a significant unmet medical need due to a lack of effective treatments and incomplete understanding of its molecular mechanisms. Recent studies suggest mitochondrial dysfunction plays a causal role in HFpEF, with mitochondrial calcium (mCa2+) emerging as a crucial regulator of mitochondrial metabolism and function. While genetic manipulation of mCa2+ flux in cardiomyocytes has shown promise in heart failure with reduced ejection fraction (HFrEF), its role in HFpEF remains unexplored. Furthermore, cellular heterogeneity in mCa2+ signaling and functions in HFpEF, along with the potential therapeutic manipulation of mCa2+ in a heart cell-specific manner, remain undetermined. This study aims to address these gaps by investigating heart cell-specific mCa2+ signaling and function in HFpEF. We hypothesize that disrupted cellular heterogeneity in mCa2+ signaling contributes to HFpEF progression, and therapeutic manipulation of cell type-specific (cardiomyocytes, fibroblasts and endothelial) mCa2+ flux may offer novel treatment strategies. Our approach involves characterizing heart cell- specific mCa2+ signaling and functions in HFpEF mouse models (aim1), evaluating the effects of manipulating mCa2+ flux on HFpEF pathogenesis (aim2), and studying the molecular mechanisms of mitochondrial dysfunction in HFpEF (aim3). This proposal is significant and innovative, offering insights into heart cell-specific mechanisms contributing to mitochondrial dysfunction and identifying new therapeutic targets for HFpEF. It shifts the paradigm by proposing cellular heterogeneity in mCa2+ as a key molecular target for HFpEF. Additionally, it enables the PI to transition into a new research direction and involves a strong team of investigators with expertise in HFpEF and cardiovascular studies to ensure project success.