The mitochondrial calcium uniporter is a highly selective ion channel

Abstract

During intracellular Ca²⁺ signalling mitochondria accumulate significant amounts of Ca²⁺ from the cytosol^1,2. Mitochondrial Ca²⁺ uptake controls the rate of energy production^1,3,4, shapes the amplitude and spatio-temporal patterns of intracellular Ca²⁺ signals^1,5,6,7,8, and is instrumental to cell death^9,10. This Ca²⁺ uptake is undertaken by the mitochondrial Ca²⁺ uniporter (MCU) located in the organelle's inner membrane^11,12. The uniporter passes Ca²⁺ down the electrochemical gradient maintained across this membrane without direct coupling to ATP hydrolysis or transport of other ions¹¹. Carriers are characterized by turnover numbers that are typically 1,000-fold lower than ion channels, and until now it has been unclear whether the MCU is a carrier or a channel¹³. By patch-clamping the inner mitochondrial membrane, we identified a previously unknown Ca²⁺-selective ion channel sensitive to inhibitors of mitochondrial Ca²⁺ uptake. Our data indicate that this unique channel binds Ca²⁺ with extremely high affinity (dissociation constant ≤2 nM), enabling high Ca²⁺ selectivity despite relatively low cytoplasmic Ca²⁺ concentrations. The channel is inwardly rectifying, making it especially effective for Ca²⁺ uptake into energized mitochondria. Thus, we conclude that the properties of the current mediated by this novel channel are those of the MCU.