Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex

Fan, Meiqiang; Zhang, Jinru; Tsai, Chen-Wei; Orlando, Benjamin J.; Rodriguez, Madison; Xu, Yan; Liao, Maofu; Tsai, Ming-Feng; Feng, Liang

doi:10.1038/s41586-020-2309-6

Cited by 206 publications

(253 citation statements)

References 54 publications

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“…S2). Compared to a most recent study (Fan et al, 2020), our MEMMS structure showed more accurate information about interactions between MICU1 and EMRE. Based on our structural and functional analysis, we conclude that MEMMS is an integral unit in mammals, EMRE may act as a lever to regulate the matrix gate of the MCU channel, and MICU1/2 enhance the Ca 2+ uptake by interactions with the C-termini of EMRE in high [Ca 2+ ] condition.…”

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confidence: 62%

Structure of intact human MCU supercomplex with the auxiliary MICU subunits

et al. 2020

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Structure of intact human MCU supercomplex with the auxiliary MICU subunits Dear Editor, Mitochondrial Ca 2+ homeostasis regulates energy production, cell division, and cell death. The basic properties of mitochondrial Ca 2+ uptake have been firmly established. The Ca 2+ influx is mediated by MCU, driven by membrane potential and using a uniporter mechanism (Vasington and Murphy, 1962). Patch-clamp analysis of MCU currents demonstrated that MCU is a channel with exceptionally high Ca 2+ selectivity (Kirichok et al., 2004). Even in the absence of structural data on the MCU complex, mitochondrial Ca 2+ uptake and its regulation in mammals has been assumed to rely on a complex comprising MCU, EMRE, MICU1, and MICU2 (De Stefani et al., 2016). Previous models generally believe that MICU1 and MICU2 form a cap to occlude the MCU channel in low [Ca 2+ ] condition, and when [Ca 2+ ] is elevated, through conformational changes of the EF hands in these two regulators, they will depart from the MCU/EMRE pore to allow Ca 2+ permeation (Phillips et al., 2019).

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confidence: 62%

Structure of intact human MCU supercomplex with the auxiliary MICU subunits

et al. 2020

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“…The channel (MCU/EMRE) densities were removed for the projection. MICU2:MICU2 interfaces mediate a dimerization of MICU1-MICU2 heterodimers in that structure ( Fan et al, 2020 ). The projection resembles the 2D class from (B) with two MICU1-MICU2 heterodimers (asterisk), which suggests, but does not prove, that a MICU2:MICU2 interface mediates the dimerization of MICU1-MICU2 heterodimers in a fraction of our cryo-EM data.…”

Section: Resultsmentioning

confidence: 99%

“…During the preparation of this manuscript, cryo-EM structures of a holocomplex comprising human MCU, EMRE, MICU1 and MICU2 subunits in resting and activated [Ca 2+ ] conditions were reported ( Fan et al, 2020 ). The conclusions of that work are congruous with the present study and validate the proposed mechanism of Ca 2+ -dependent regulation of the uniporter by MICU1-MICU2.…”

Section: Discussionmentioning

confidence: 99%

Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2

Wang

Jacewicz

Delgado

et al. 2020

eLife

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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.

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“…However, to understand the molecular mechanisms of the uniplex assembly and its Ca 2+ -dependent gating necessitates the structural determination of the four-component MCU holocomplex. To this end, several groups have recently reported the structures of the MCU holocomplex in various states, including the structures of the human MCU holocomplex in low and high [Ca 2+ ] ( Fan et al, 2020 ), the structure of human MCU holocomplex in the absence of Ca 2+ ( Zhuo et al, 2020 ), and the structure of a holocomplex formed by the beetle MCU-EMRE and the human MICU1-MICU2 under resting [Ca 2+ ] conditions ( Wang et al, 2020 ). Here, we also present the cryo-EM structures of the human MCU holocomplex in the apo and Ca 2+ -bound states.…”

Section: Introductionmentioning

confidence: 99%

Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter

Wang

Han

She

et al. 2020

eLife

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Mitochondrial Ca2+ uptake is mediated by an inner mitochondrial membrane protein called the mitochondrial calcium uniporter. In humans, the uniporter functions as a holocomplex consisting of MCU, EMRE, MICU1 and MICU2, among which MCU and EMRE form a subcomplex and function as the conductive channel while MICU1 and MICU2 are EF-hand proteins that regulate the channel activity in a Ca2+ dependent manner. Here we present the EM structures of the human mitochondrial calcium uniporter holocomplex (uniplex) in the presence and absence of Ca2+, revealing distinct Ca2+ dependent assembly of the uniplex. Our structural observations suggest that Ca2+ changes the dimerization interaction between MICU1 and MICU2, which in turn determines how the MICU1-MICU2 subcomplex interacts with the MCU-EMRE channel and, consequently, changes the distribution of the uniplex assemblies between the blocked and unblocked states.

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Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex

Cited by 206 publications

References 54 publications

Structure of intact human MCU supercomplex with the auxiliary MICU subunits

Structure of intact human MCU supercomplex with the auxiliary MICU subunits

Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2

Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter

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