Mitochondrial calcium uptake in organ physiology: from molecular mechanism to animal models

Mitochondrial Ca(2+) is involved in heterogeneous functions, ranging from the control of metabolism and ATP production to the regulation of cell death. In addition, mitochondrial Ca(2+) uptake contributes to cytosolic [Ca(2+)] shaping thus impinging on specific Ca(2+)-dependent events. Mitochondrial Ca(2+) concentration is controlled by influx and efflux pathways: the former controlled by the activity of the mitochondrial Ca(2+) uniporter (MCU), the latter by the Na(+)/Ca(2+) exchanger (NCLX) and the H(+)/Ca(2+) (mHCX) exchanger. The molecular identities of MCU and of NCLX have been recently unraveled, thus allowing genetic studies on their physiopathological relevance. After a general framework on the significance of mitochondrial Ca(2+) uptake, this review discusses the structure of the MCU complex and the regulation of its activity, the importance of mitochondrial Ca(2+) signaling in different physiological settings, and the consequences of MCU modulation on organ physiology.