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

Mitochondrial Ca²⁺ is involved in heterogeneous functions, ranging from the control of metabolism and ATP production to the regulation of cell death. In addition, mitochondrial Ca²⁺ uptake contributes to cytosolic [Ca²⁺] shaping thus impinging on specific Ca²⁺-dependent events. Mitochondrial Ca²⁺ concentration is controlled by influx and efflux pathways: the former controlled by the activity of the mitochondrial Ca²⁺ uniporter (MCU), the latter by the Na⁺/Ca²⁺ exchanger (NCLX) and the H⁺/Ca²⁺ (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 Ca²⁺ uptake, this review discusses the structure of the MCU complex and the regulation of its activity, the importance of mitochondrial Ca²⁺ signaling in different physiological settings, and the consequences of MCU modulation on organ physiology.