Abstract

The mitochondrial calcium uniporter is a Ca2+-gated ion channel complex that controls mitochondrial Ca2+ entry and regulates cell metabolism. MCU and EMRE form the channel while Ca2+-dependent regulation is conferred by MICU1 and MICU2 through an enigmatic process. We present a cryo-EM structure of an MCU-EMRE-MICU1-MICU2 holocomplex comprising MCU and EMRE subunits from the beetle Tribolium castaneum in complex with a human MICU1-MICU2 heterodimer at 3.3 Å resolution. With analogy to how neuronal channels are blocked by protein toxins, a uniporter interaction domain on MICU1 binds to a channel receptor site comprising MCU and EMRE subunits to inhibit ion flow under resting Ca2+ conditions. A Ca2+-bound structure of MICU1-MICU2 at 3.1 Å resolution indicates how Ca2+-dependent changes enable dynamic response to cytosolic Ca2+ signals.

Data availability

The atomic coordinates and EM maps have been deposited in the Protein Data Bank (www.rcsb.org) and the EMDB (www.ebi.ac.uk/pdbe/emdb/): PDB ID 6XQN, EMDB ID EMD-22290 (holocomplex in low Ca2+); PDB ID 6XQO, EMDB ID EMD-22291 (Ca2+-bound MICU1-MICU2 heterodimer).

The following data sets were generated

Article and author information

Author details

  1. Chongyuan Wang

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Agata Jacewicz

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bryce D Delgado

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rozbeh Baradaran

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Stephen Barstow Long

    Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    longs@mskcc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8144-1398

Funding

National Institute of General Medical Sciences (R35GM131921)

  • Stephen Barstow Long

National Cancer Institute (P30CA008748)

  • Stephen Barstow Long

National Institute of General Medical Sciences (5T32GM008539)

  • Bryce D Delgado

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Version history

  1. Received: June 13, 2020
  2. Accepted: July 14, 2020
  3. Accepted Manuscript published: July 15, 2020 (version 1)
  4. Accepted Manuscript updated: July 23, 2020 (version 2)
  5. Version of Record published: August 18, 2020 (version 3)

Copyright

© 2020, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Chongyuan Wang
  2. Agata Jacewicz
  3. Bryce D Delgado
  4. Rozbeh Baradaran
  5. Stephen Barstow Long
(2020)
Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2
eLife 9:e59991.
https://doi.org/10.7554/eLife.59991

Share this article

https://doi.org/10.7554/eLife.59991

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    Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown.

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    Funding:

    This work was supported by the Weizmann Krenter Foundation and the Weizmann – Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.