Dual functions of a small regulatory subunit in the mitochondrial calcium uniporter complex.

Like all power plants, mitochondria – the compartments inside our cells that supply energy – must adjust their energy output to match fluctuations in demand. Inside cells, the levels of calcium ions in the cytoplasm often signal such demands. Mitochondria therefore control their calcium ion levels with tightly regulated, membrane-embedded proteins that move calcium ions into and out of the mitochondria. One of these membrane machines, the mitochondrial calcium uniporter (MCU) complex, is a "smart channel" that admits calcium ions into the mitochondria only when their cytoplasmic levels exceed a threshold. The MCU complex contains four essential proteins: MCU, which forms the pore through which the calcium ions enter the mitochondrion; MICU1 and MICU2, which act as “gatekeepers”, opening the pore only when the cell contains high levels of calcium ions; and EMRE, a small, mysterious protein. Why is EMRE required for the channel's operation, and how does it fit into the four-protein complex? By comparing EMRE proteins from different species, constructing mutant forms of EMRE, and recording calcium ion transport in mitochondria from cultured human cells, Tsai, Phillips et al. show that EMRE has two key roles. First, it snuggles up against the MCU protein and forms an essential part of the calcium ion-selective pore. Second, it acts as molecular glue to fix the calcium ion-sensing MICU gatekeepers to the pore. These two linked functions ensure that the MCU complex switches on only when the cell contains high levels of calcium ions, preventing the cell becoming catastrophically overloaded with calcium ions and cell death. Challenges for the future are to purify the MCU complex and reconstitute its ability to transport calcium ions from its component parts. This will help to determine the structure of the channel.