The ins and outs of mitochondrial calcium

Abstract

Calcium is thought to play an important role in regulating mitochondrial function. Evidence suggests that an increase in mitochondrial calcium can augment ATP production by altering the activity of calcium-sensitive mitochondrial matrix enzymes. In contrast, the entry of large amounts of mitochondrial calcium in the setting of ischemia-reperfusion injury is thought to be a critical event in triggering cellular necrosis. For many decades, the details of how calcium entered the mitochondria remained a biological mystery. In the past few years, significant progress has been made in identifying the molecular components of the mitochondrial calcium uniporter complex. Here, we review how calcium enters and leaves the mitochondria, the growing insight into the topology, stoichiometry and function of the uniporter complex, and the early lessons learned from some initial mouse models that genetically perturb mitochondrial calcium homeostasis.

Keywords: calcium signaling; cell death; mitochondria.

Figure 1:

Mitochondrial ion transport mechanisms involved in regulating calcium entry (red arrows) and efflux (green arrows). Calcium enters the mitochondria primarily through the mitochondria calcium uniporter (MCU). Although MCU appears to be the main calcium influx pathway, other influx mechanisms such as RyR1 (not shown) or LETM1 have also been proposed^–. Questions remain however, as others have suggested that LETM1 is, in fact, a mitochondrial K⁺/H⁺ exchanger^, . Calcium efflux is driven by NCLX using the influx of sodium down its electrochemical gradient. The intracellular sodium is set below the cytosolic sodium by the sodium-proton exchanger (NHE), which uses the energy of the inwardly directed proton gradient to maintain mitochondrial sodium below the concentration of sodium in the cytosol.

Figure 2:

Potential model to explain the observed sigmoidal calcium response curve. In this model, at low calcium concentrations (calcium ions are indicated as red circles), MICU1 and MICU2 act as a gatekeeper, preventing calcium entry. At higher calcium levels, calcium binds to the EF hands of MICU1/MICU2, resulting in a conformational change in these proteins, opening the pore and stimulating calcium entry. This is one potential model, however, additional models exist including where MICU1 and MICU2 have independent and opposite functions. See text for details.

Figure 3:

Molecular components of the uniporter complex. Data strongly suggest that MCU is the pore. Most but not all experimental evidence suggests that MICU1 and MICU2 are located within the inner mitochondrial space. EMRE appears to link MCU with MICU1 and to be necessary for MCU to open and allow calcium entry (red circles) into the mitochondrial matrix. Not pictured here is MCUb, the dominant negative form of MCU that exists in various ratios with MCU. See text for further details.