MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca2+ Flux and Sensitivity to Ru360

Paillard, Mélanie; Csordás, György; Huang, Kai-Ting; Várnai, Péter; Joseph, Suresh K.; Hajnóczky, György

doi:10.1016/j.molcel.2018.09.008

Cited by 106 publications

(113 citation statements)

References 32 publications

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“…Working model for the heterodimer of MICU1-MICU2 regulates Ca 2+ uptake Previous work indicated that the association between the MICU1-MICU2 complex and MCU is Ca 2+ -dependent. At low Ca 2+ concentrations, the MICU1-MICU2 complex binds to the D-ring of MCU [24,25]. Increasing Ca 2+ concentrations induce a conformational change in the MICU1-MICU2 heterodimer and its release from MCU [23].…”

Section: Of 13mentioning

confidence: 99%

The crystal structure of MICU 2 provides insight into Ca ²⁺ binding and MICU 1‐ MICU 2 heterodimer formation

Shen

Lei

et al. 2019

EMBO Reports

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The mitochondrial calcium uniporter (MCU) complex mediates the uptake of Ca2+ into mitochondria. Its activity is regulated by a heterodimer of MICU1 and MICU2, two EF‐hand‐containing proteins that act as the main gatekeeper of the uniporter. Herein we report the crystal structure of human MICU2 at 1.96 Å resolution. Our structure reveals a dimeric architecture of MICU2, in which each monomer adopts the canonical two‐lobe structure with a pair of EF‐hands in each lobe. Both Ca2+‐bound and Ca2+‐free EF‐hands are observed in our structure. Moreover, we characterize the interaction sites within the MICU2 homodimer, as well as the MICU1–MICU2 heterodimer in both Ca2+‐free and Ca2+‐bound conditions. Glu242 in MICU1 and Arg352 in MICU2 are crucial for apo heterodimer formation, while Phe383 in MICU1 and Glu196 in MICU2 significantly contribute to the interaction in the Ca2+‐bound state. Based on our structural and biochemical analyses, we propose a model for MICU1–MICU2 heterodimer formation and its conformational transition from apo to a more compact Ca2+‐bound state, which expands our understanding of this co‐regulatory mechanism critical for MCU's mitochondrial calcium uptake function.

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Section: Of 13mentioning

confidence: 99%

The crystal structure of MICU 2 provides insight into Ca ²⁺ binding and MICU 1‐ MICU 2 heterodimer formation

Shen

Lei

et al. 2019

EMBO Reports

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“…Thus, mitochondrial Ca 2+ uptake must be tightly controlled, but how mitochondrial Ca 2+ uptake through MCU is regulated is controversial (2,3). The MCU channel in metazoans exists as a protein complex comprised of MCU as the tetrameric channel pore-forming subunit (4,5), EMRE, a single-pass transmembrane protein that is essential for channel activity (6)(7)(8), and IMS-localized (but see (9)) Ca 2+ -binding EF hand domain-containing MICU1/2 heterodimers (10-13) that associate with the channel complex by interactions with the carboxyl-terminus of EMRE (14) and with MCU (15,16). In a current model of MCU regulation (but see (2)), MICU1/2 promotes cooperative channel activation in response to Ca 2+ binding by their EF hands, whereas apo-MICU1/2 imposes a threshold [Ca 2+ ]i below which MCU channel activity is inhibited, so-called channel gatekeeping (13,(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

“…Ca 2+ ] and buffering capacity, allowing for enhanced cellular regulation of mitochondrial Ca 2+ homeostasis. Recent studies have demonstrated a direct biochemical interaction of MICU1/2 with the MCU selectivity filter(15, 16). Because mutations in either MCU or MICU1 that disrupt this interaction lead to a constitutively open channel, it has been suggested that MICU1/2 functions as a classic pore blocker (16).…”

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confidence: 99%

Strongly coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca²⁺uptake

Vais

Payne

et al. 2020

Preprint

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Ca 2+ uptake by mitochondria regulates bioenergetics, apoptosis, and Ca 2+ signaling. The primary pathway for mitochondrial Ca 2+ uptake is the mitochondrial calcium uniporter (MCU), a Ca 2+ -selective ion channel in the inner mitochondrial membrane. MCU-mediated Ca 2+ uptake is driven by the sizable inner-membrane potential generated by the electrontransport chain. Despite the large thermodynamic driving force, mitochondrial Ca 2+ uptake is tightly regulated to maintain low matrix [Ca 2+ ] and prevent opening of the permeability transition pore and cell death, while meeting dynamic cellular energy demands. How this is accomplished is controversial. Here we define a regulatory mechanism of MCU-channel activity in which cytoplasmic Ca 2+ regulation of intermembrane space-localized MICU1/2 is controlled by strongly-coupled Ca 2+ -regulatory mechanisms localized across the membrane in the mitochondrial matrix. Ca 2+ that permeates through the channel pore regulates Ca 2+ affinities of coupled inhibitory and activating sensors in the matrix. Ca 2+ binding to the inhibitory sensor within the MCU amino-terminus closes the channel despite Ca 2+ binding to MICU1/2. Conversely, disruption of the interaction of MICU1/2 with the MCU complex abolishes matrix Ca 2+ regulation of channel activity. Our results demonstrate how Ca 2+ influx into mitochondria is tuned by coupled Ca 2+ -regulatory mechanisms on both sides of the inner mitochondrial membrane.The mitochondrial Ca 2+ uniporter (MCU) is a Ca 2+ -selective ion channel in the inner mitochondrial membrane (1) that represents the major mechanism by which mitochondria take up Ca 2+ into the matrix to regulate bioenergetics, cell death pathways and cytoplasmic Ca 2+ signaling. MCU-mediated Ca 2+ uptake is driven by the large (-150 --180 mV) inner-membrane

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“…However, only partial restoration to WT levels can be achieved in the MCU OE model by pharmacologically inhibiting MCU. This could be due to factors other than mitochondrial Ca 2+ uptake being affected in the MCU OE model (such as ER Ca 2+ levels), insufficient permeability of Ru360 into cells, or an abundance of MICU1/MICU3 which can block Ru360 binding to MCU (Paillard et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Ca²⁺influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

Hutto

Bisbach

Abbas

et al. 2019

Preprint

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9Mitochondrial Ca 2+ regulates key cellular processes including cytosolic Ca 2+ signals, 10 energy production, and susceptibility to apoptosis. Photoreceptors are specialized 11 neurons that have extraordinarily high energy demands and rely on cytosolic Ca 2+ 12 signals for light adaptation and neurotransmission. Here we show that unlike other 13 neurons zebrafish cone photoreceptors express low levels of the mitochondrial Ca 2+ 14 uniporter (MCU), the channel that allows mitochondrial Ca 2+ entry. To determine why 15 MCU expression is kept low, we overexpressed MCU specifically in cones. This 16 increases mitochondrial [Ca 2+ ], causes faster cytosolic Ca 2+ clearance, and accelerates 17 photoresponse recovery. Moreover, flux through the citric acid cycle increases despite 18 dramatic changes in mitochondrial ultrastructure and localization. Remarkably, cones 19 survive this ongoing stress until late adulthood. Our findings demonstrate the 20 importance of tuning mitochondrial Ca 2+ influx to modulate physiological and metabolic 21 processes and reveal a novel directed movement of abnormal mitochondria in 22 photoreceptors. 23Mitochondrial Ca 2+ uptake is also involved in energetic output (Glancy and Balaban, 57 2012). Ca 2+ can regulate the activity of mitochondrial enzymes including pyruvate 58 dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase 59

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MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca2+ Flux and Sensitivity to Ru360

Cited by 106 publications

References 32 publications

The crystal structure of MICU 2 provides insight into Ca ²⁺ binding and MICU 1‐ MICU 2 heterodimer formation

The crystal structure of MICU 2 provides insight into Ca ²⁺ binding and MICU 1‐ MICU 2 heterodimer formation

Strongly coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca²⁺uptake

Mitochondrial Ca²⁺influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

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MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca2+ Flux and Sensitivity to Ru360

Cited by 106 publications

References 32 publications

The crystal structure of MICU 2 provides insight into Ca 2+ binding and MICU 1‐ MICU 2 heterodimer formation

The crystal structure of MICU 2 provides insight into Ca 2+ binding and MICU 1‐ MICU 2 heterodimer formation

Strongly coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca2+uptake

Mitochondrial Ca2+influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors

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The crystal structure of MICU 2 provides insight into Ca ²⁺ binding and MICU 1‐ MICU 2 heterodimer formation

The crystal structure of MICU 2 provides insight into Ca ²⁺ binding and MICU 1‐ MICU 2 heterodimer formation

Strongly coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca²⁺uptake

Mitochondrial Ca²⁺influences photoresponse recovery, metabolism, and mitochondrial localization in cone photoreceptors