Coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca 2+ uptake.

Ca ²⁺ uptake by mitochondria regulates bioenergetics, apoptosis, and Ca ²⁺ signaling. The primary pathway for mitochondrial Ca ²⁺ uptake is the mitochondrial calcium uniporter (MCU), a Ca ²⁺ -selective ion channel in the inner mitochondrial membrane. MCU-mediated Ca ²⁺ uptake is driven by the sizable inner-membrane potential generated by the electron-transport chain. Despite the large thermodynamic driving force, mitochondrial Ca ²⁺ uptake is tightly regulated to maintain low matrix [Ca ²⁺ ] and prevent opening of the permeability transition pore and cell death, while meeting dynamic cellular energy demands. How this is accomplished is controversial. Here we define a regulatory mechanism of MCU-channel activity in which cytoplasmic Ca ²⁺ regulation of intermembrane space-localized MICU1/2 is controlled by Ca ²⁺ -regulatory mechanisms localized across the membrane in the mitochondrial matrix. Ca ²⁺ that permeates through the channel pore regulates Ca ²⁺ affinities of coupled inhibitory and activating sensors in the matrix. Ca ²⁺ binding to the inhibitory sensor within the MCU amino terminus closes the channel despite Ca ²⁺ binding to MICU1/2. Conversely, disruption of the interaction of MICU1/2 with the MCU complex disables matrix Ca ²⁺ regulation of channel activity. Our results demonstrate how Ca ²⁺ influx into mitochondria is tuned by coupled Ca ²⁺ -regulatory mechanisms on both sides of the inner mitochondrial membrane.
Competing Interests: The authors declare no competing interest.