1. Howard Hughes Medical Institute, Department of Cardiovascular Research, Children's Hospital, and Department of Neurobiology, Harvard Medical School, 320 Longwood Avenue, Boston, Massachusetts 02115, USA

Correspondence to: David E. Clapham¹ Email: dclapham@enders.tch.harvard.edu

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.

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