Summary Heart failure is the leading cause of death and a huge burden on health care in the United States. Recently, impaired energy metabolism has emerged as a key contributor to the failure of the heart’s pumping function, and new breakthroughs in metabolic research and mitochondrial biology have been reported. One of the key mechanisms for regulating mitochondrial function in the beating heart is calcium uptake through mitochondrial calcium uniporter (MCU). Surprisingly, MCU knockout mice exhibited normal phenotype, heart performance and mitochondrial function, indicating that MCU is dispensable in the normal heart. Pathological significance of MCU or mitochondrial calcium in the hypertrophic and failing heart is also elusive and highly debated. Finally, how MCU gene expression is regulated in the heart remains unexplored. These gaps in knowledge diminished the initial excitement ignited by the discovery of the molecular identity of MCU. Our promising preliminary results show that MCU expression is high in perinatal heart and in the chronically stressed adult heart via transcriptional regulation by calcium-calmodulin dependent protein kinase II δB (CaMKIIδB). Loss-of-function and gain-of- function approaches reveal that MCU plays a compensatory role in heart hypertrophy and dysfunction through modulating cytosolic calcium and cell death pathways. Unexpectedly, knockout MCU during the perinatal stage worsened pressure overload-induced heart dysfunction in adult mice. Based on these results, we hypothesize that MCU expression is strategically enhanced in the perinatal heart and in the stressed adult heart to ameliorate pathological heart remodeling. We will test this hypothesis in three Specific Aims. We will determine the molecular mechanisms by which CaMKIIδB regulates MCU gene expression. We will answer why cardiac hypertrophy and dysfunction are alleviated by MCU upregulation but aggravated by MCU inhibition. Furthermore, we will investigate the regulation of MCU in perinatal heart and how MCU limits pressure overload-induced dysfunction in the adult heart. Results of this study will depict a full mechanism by which MCU gene expression is fine tuned in the heart. This study also aims to uncover novel roles of MCU in perinatal heart and in the hypertrophic adult heart that counteract cardiac remodeling induced by multiple stresses.