Mitochondrial Ca(2+) regulation in the etiology of heart failure: physiological and pathophysiological implications

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 Ca(2+) 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 Ca(2+) 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 Ca(2+) transport influx and efflux channels, to buffer Ca(2+) in the cytoplasm. Interaction at mitochondria-associated endoplasmic reticulum membranes (MAMs) may also participate in the regulation of mitochondrial Ca(2+) homeostasis and plays an essential role in the progression of HF. Here, we provide an overview of regulation of mitochondrial Ca(2+) homeostasis in maintenance of cardiac function, in an effort to identify novel therapeutic strategies for the management of HF.