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 175 publications

(193 citation statements)

References 54 publications

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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%

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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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Section: Resultsmentioning

confidence: 99%

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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“…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.…”

mentioning

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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“…They proposed that a MICU1-MICU2 heterodimer covers MCU pores at rest using a five-residue K/R ring. When Ca 2+ concentration increases (over 1uM), the conformational change of the complex weakens the interaction between MICU1-MCU and opens the MCU pore [ 82 ]. This finding suggested an alternative regulation mechanism from a previous study.…”

Section: The Molecular Basis and Regulation Of The Mitochondrial Cmentioning

confidence: 99%

The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart

Lai

Qiu

2020

IJMS

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Calcium ion (Ca2+) plays a critical role in the cardiac mitochondria function. Ca2+ entering the mitochondria is necessary for ATP production and the contractile activity of cardiomyocytes. However, excessive Ca2+ in the mitochondria results in mitochondrial dysfunction and cell death. Mitochondria maintain Ca2+ homeostasis in normal cardiomyocytes through a comprehensive regulatory mechanism by controlling the uptake and release of Ca2+ in response to the cellular demand. Understanding the mechanism of modulating mitochondrial Ca2+ homeostasis in the cardiomyocyte could bring new insights into the pathogenesis of cardiac disease and help developing the strategy to prevent the heart from damage at an early stage. In this review, we summarized the latest findings in the studies on the cardiac mitochondrial Ca2+ homeostasis, focusing on the regulation of mitochondrial calcium uptake, which acts as a double-edged sword in the cardiac function. Specifically, we discussed the dual roles of mitochondrial Ca2+ in mitochondrial activity and the impact on cardiac function, the molecular basis and regulatory mechanisms, and the potential future research interest.

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Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex

Cited by 175 publications

References 54 publications

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

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

Structure of intact human MCU supercomplex with the auxiliary MICU subunits

The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart

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