Heart failure (HF) represents one of the leading causes of cardiovascular diseases with high rates of hospitalization,morbidity and mortality worldwide.Ample evidence has consolidated a crucial role for mitochondrial injury in the progression of HF.It is well established that mitochondrial Ca2+ participates in the regulation of a wide variety of biological processes,including oxidative phosphorylation,ATP synthesis,reactive oxygen species (ROS) generation,mitochondrial dynamics and mitophagy.Nonetheless,mitochondrial Ca2+ overload stimulates mitochondrial permeability transition pore (mPTP) opening and mitochondrial swelling,resulting in mitochondrial injury,apoptosis,cardiac remodeling,and ultimately development of HF.Moreover,mitochondria possess a series of Ca2+ transport influx and efflux channels,to buffer Ca2+ in the cytoplasm.Interaction at mitochondria-associated endoplasmic reticulum membranes (MAMs) may also participate in the regulation of mitochondrial Ca2+ homeostasis and plays an essential role in the progression of HF.Here,we provide an overview of regulation of mitochondrial Ca2+ homeostasis in maintenance of cardiac function,in an effort to identify novel therapeutic strategies for the management of HF.