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The mitochondrial calcium uniporter is a highly selective ion channel

Abstract

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 ≤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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Figure 1: Ca2+ current through the inner mitochondrial membrane.
Figure 2: RuR and Ru360 sensitivity.
Figure 3: IMiCa selectivity.
Figure 4: Single iMiCa Ca2+ channels from inner mitochondrial membrane inside-out patches (105 mM CaCl2 solution at the cytoplasmic surface (pipette)).

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Acknowledgements

We would like to thank J. Borecky for advice on the whole-mitoplast configuration; L. DeFelice, H. Xu, B. Desai, V. Sandler and P. Smith for discussions; and S. Gapon and Y. Manasian for technical assistance.

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Correspondence to David E. Clapham.

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Kirichok, Y., Krapivinsky, G. & Clapham, D. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360–364 (2004). https://doi.org/10.1038/nature02246

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