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The mitochondrial calcium uniporter is a highly selective ion channel

Author

Listed:
  • Yuriy Kirichok

    (Harvard Medical School)

  • Grigory Krapivinsky

    (Harvard Medical School)

  • David E. Clapham

    (Harvard Medical School)

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.

Suggested Citation

  • Yuriy Kirichok & Grigory Krapivinsky & David E. Clapham, 2004. "The mitochondrial calcium uniporter is a highly selective ion channel," Nature, Nature, vol. 427(6972), pages 360-364, January.
  • Handle: RePEc:nat:nature:v:427:y:2004:i:6972:d:10.1038_nature02246
    DOI: 10.1038/nature02246
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    Cited by:

    1. Enrique Balderas & David R. Eberhardt & Sandra Lee & John M. Pleinis & Salah Sommakia & Anthony M. Balynas & Xue Yin & Mitchell C. Parker & Colin T. Maguire & Scott Cho & Marta W. Szulik & Anna Bakhti, 2022. "Mitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Wanbiao Chen & Rongfeng Zou & Yi Mei & Jiawei Li & Yumi Xuan & Bing Cui & Junjie Zou & Juncheng Wang & Shaoquan Lin & Zhe Zhang & Chongyuan Wang, 2024. "Structural insights into drug transport by an aquaglyceroporin," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    3. Jason N Bazil & Ranjan K Dash, 2011. "A Minimal Model for the Mitochondrial Rapid Mode of Ca2+ Uptake Mechanism," PLOS ONE, Public Library of Science, vol. 6(6), pages 1-13, June.
    4. Weier Bao & Ming Liu & Jiaqi Meng & Siyuan Liu & Shuang Wang & Rongrong Jia & Yugang Wang & Guanghui Ma & Wei Wei & Zhiyuan Tian, 2021. "MOFs-based nanoagent enables dual mitochondrial damage in synergistic antitumor therapy via oxidative stress and calcium overload," Nature Communications, Nature, vol. 12(1), pages 1-17, December.

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