Letters to Nature

Nature 427, 360-364 (22 January 2004) | doi:10.1038/nature02246; Received 20 August 2003; Accepted 18 November 2003

The mitochondrial calcium uniporter is a highly selective ion channel

Yuriy Kirichok1, Grigory Krapivinsky1 & David E. Clapham1

  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

During intracellular Ca2+ signalling mitochondria accumulate significant amounts of Ca2+ from the cytosol1, 2. Mitochondrial Ca2+ uptake controls the rate of energy production1, 3, 4, shapes the amplitude and spatio-temporal patterns of intracellular Ca2+ signals1, 5, 6, 7, 8, and is instrumental to cell death9, 10. This Ca2+ uptake is undertaken by the mitochondrial Ca2+ uniporter (MCU) located in the organelle's inner membrane11, 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 less than or equal to2 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.