Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex

Minrui Fan, Jinru Zhang, Chen-Wei Tsai, Benjamin J. Orlando, Madison Rodriguez, Yan Xu, Maofu Liao, Ming-Feng Tsai () and Liang Feng ()
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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

Nature, 2020, vol. 582, issue 7810, 129-133

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2309-6

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