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

Significance Control of the level of calcium inside mitochondria is important because mitochondrial calcium regulates metabolism, cell death, and cellular signaling. The main pathway for mitochondrial calcium uptake is a calcium-selective ion channel complex in the inner mitochondrial membrane called the mitochondrial calcium uniporter (MCU). How the activity of the MCU ion channel is regulated is controversial. Here we employed electrophysiology of single isolated mitochondria to record MCU calcium and sodium ionic currents. We found that MCU ion channel activity is controlled by distinct Ca 2+ -regulated mechanisms on both sides of the inner mitochondrial membrane that are coupled to each other. These mechanisms allow for enhanced cellular regulation of mitochondrial calcium homeostasis.