Structure and mechanism of the mitochondrial Ca.sup.2+ uniporter holocomplex

Mitochondria take up Ca.sup.2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca.sup.2+ signalling and cell death.sup.1,2. In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU protein, the gatekeepers MICU1 and...

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Published in:Nature (London) 2020-06, Vol.582 (7810), p.129
Main Authors: Fan, Minrui, Zhang, Jinru, Tsai, Chen-Wei, Orlando, Benjamin J, Rodriguez, Madison, Xu, Yan, Liao, Maofu
Format: Article
Language:English
Subjects:
Calcium ions
Carrier proteins
Mitochondria
Physiological aspects
Structure
Online Access:Get full text
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Summary:Mitochondria take up Ca.sup.2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca.sup.2+ signalling and cell death.sup.1,2. 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 Ca.sup.2+ transport.sup.3-8. To prevent detrimental Ca.sup.2+ overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic Ca.sup.2+ concentrations to switch MCU on and off.sup.9,10. Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca.sup.2+-activated states. These structures define the architecture of this multicomponent Ca.sup.2+-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated Ca.sup.2+ uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial Ca.sup.2+ overload.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-020-2309-6