FIGURE 1.

Ca²⁺ influx and efflux pathways of the inner mitochondrial membrane. The mitochondrial calcium uniporter channel (mtCU) exists as a channel composed of a total of 4 MCU subunits and up to 4 EMRE subunits. For simplicity, only a single EMRE subunit is shown here. In some cases, the dominant-negative MCU paralog, MCUB, replaces MCU subunits within the complex. The channel is gated by dimers of MICU1/2 or, in some tissues, dimers of MICU1/3. The accessory subunit MCUR1 also binds to and regulates the channel. Two uniporter channels can dimerize, and the function of these dimers is regulated by interactions between the MICU2 subunit associated with each channel. The driving force for Ca²⁺ entry through the mtCU is the highly negative (approximately −180 mV) potential established across the inner mitochondrial membrane (IMM) by the electron transport chain. Other proposed routes of mitochondrial Ca²⁺ (_mCa²⁺) uptake may include the mitochondrial ryanodine receptor (mRyR) or reverse-mode operation of NCLX and LETM1. The Na⁺/Ca²⁺ exchanger NCLX is a major route for _mCa²⁺ efflux, and the Ca²⁺/H⁺ exchanger LETM1 may contribute to _mCa²⁺ efflux in some tissues. Transient opening of the mitochondrial permeability transition pore (mPTP), termed “flickering,” is proposed as another mechanism by which Ca²⁺ leaves the mitochondrial matrix under physiological conditions. See glossary for abbreviations.