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Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex

Author

Listed:
  • Minrui Fan

    (Stanford University School of Medicine)

  • Jinru Zhang

    (Stanford University School of Medicine)

  • Chen-Wei Tsai

    (University of Colorado Anschutz Medical Campus)

  • Benjamin J. Orlando

    (Harvard Medical School)

  • Madison Rodriguez

    (University of Colorado Anschutz Medical Campus)

  • Yan Xu

    (Stanford University School of Medicine)

  • Maofu Liao

    (Harvard Medical School)

  • Ming-Feng Tsai

    (University of Colorado Anschutz Medical Campus)

  • Liang Feng

    (Stanford University School of Medicine)

Abstract

Mitochondria take up Ca2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca2+ signalling and cell death1,2. In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU protein, the gatekeepers MICU1 and MICU2, and an auxiliary subunit, EMRE, essential for Ca2+ transport3–8. To prevent detrimental Ca2+ overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic Ca2+ concentrations to switch MCU on and off9,10. Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca2+-activated states. These structures define the architecture of this multicomponent Ca2+-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated Ca2+ uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial Ca2+ overload.

Suggested Citation

  • Minrui Fan & Jinru Zhang & Chen-Wei Tsai & Benjamin J. Orlando & Madison Rodriguez & Yan Xu & Maofu Liao & Ming-Feng Tsai & Liang Feng, 2020. "Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex," Nature, Nature, vol. 582(7810), pages 129-133, June.
    • Handle: RePEc:nat:nature:v:582:y:2020:i:7810:d:10.1038_s41586-020-2309-6
    DOI: 10.1038/s41586-020-2309-6
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