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

Abstract

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.

Keywords: Animal models; Heart; Mitochondria Ca2+ uptake; Neurons; Pancreatic β cells; Skeletal muscle.

Fig. 1

Mitochondrial Ca²⁺ homeostasis is regulated by influx and efflux mechanism and impinges on oxidative metabolism, mROS generation, and mPTP opening. Physiologically, mitochondrial Ca²⁺ uptake stimulates TCA cycle and ATP production (right-hand side), while in pathological conditions, mitochondrial Ca²⁺ overload causes the opening of the mPTP (left-hand side). mROS play either a signaling role or behave as damaging agents depending on their concentration and on the biological context

Fig. 2

The mitochondrial Ca²⁺ uniporter is a complex composed of pore-forming proteins (comprising the channel subunit MCU, the dominant-negative subunit of the channel MCUb, and the short transmembrane regulator EMRE) and of regulatory proteins (MICU1 and MICU2). Both MICU1 and MICU2 contain EF-hand domains facing the intermembrane space. By sensing IMS [Ca²⁺], MICU1 and MICU2 coordinately regulate both the threshold and the cooperativity of channel opening

Fig. 3

Dominant-negative MCU (DN-MCU) transgenic mice and inducible heart-specific MCU^−/− mice are characterized by impaired “fight or flight” response, due to lack of ATP production required for heart rate increase

Fig. 4

Inducible cardiac-specific MCU deletion confers protection from ischemia-reperfusion (I-R)-induced damage associated to mitochondrial Ca²⁺ overload and mPTP opening

Fig. 5

The importance of proper mitochondrial Ca²⁺ homeostasis in different organs, like the skeletal muscle, endocrine pancreas, and brain, is highlighted by the dysfunctional phenotype of specific animal models, as detailed in the figure