Heart failure (HF) is a major cause of mortality worldwide. HF is linked to increased cardiac myocyte (CM) death and mitochondrial dysfunction. Mechanisms linking mitochondrial dysfunction and the development or progression of HF are complex and remain unknown, although epigenetic regulation of gene expression plays a role in governing cardiac remodeling and HF pathogenesis. Indeed, epigenetic alterations such as histone methylation, have been causally associated with HF. However, the precise role of enzymes that write and erase epigenetic marks, especially those of histone demethylases, in HF is unknown. We recently demonstrated activation of KDM5A in human HF samples. We also found that KDM5A activity and protein levels are induced, prior to cardiac dysfunction, in mouse models of dilated cardiomyopathy (DCM). Gene function analysis of KDM5A targets revealed that most of them are enriched for OXPHOS (oxidative phosphorylation) and metabolism and are suppressed in failing heart samples. The mechanisms that regulate KDM5A protein levels, as well as the phenotypic consequences of KDM5A activation in HF, are unknown. Preliminary findings show that 1. KDM5A is induced in the hearts of mice with cardiac hypertrophy caused by transverse aortic constriction (TAC) 2. USP38 (ubiquitin-specific peptidase 38), a deubiquitinating enzyme, regulates KDM5A levels in cardiac myocytes. KDM5A steady-state levels are correlated with USP38, both are decreased after birth and induced by HF. SiRNA-mediated USP38 knockdown in CM led to a reduction in KDM5A levels. 3. Gain of function studies in cardiac myocytes show that KDM5A suppress expression of genes involved in OXPHOS. Based on these findings, we propose that in heart failure, the functional effect of KDM5A is reinforced by increased protein levels by USP38. KDM5A activation in adult CM leads to suppression of OXPHOS genes, resulting in mitochondrial dysfunction, cell death, and ensuing phenotypes. Therefore, main goals of this proposal are to determine the mechanism of activation of KDM5A in HF, and to delineate its role in the pathogenesis of HF. The hypothesis will be tested in three specific aims. In aim 1 we will determine the mechanism of KDM5A regulation in HF. In aim 2 we will determine the effect of KDM5A activation on expression of OXPHOS genes and other targets in HF and finally in aim 3 we will determine the pathogenic role of KDM5A activation in HF.