Affinage

MICU1

Calcium uptake protein 1, mitochondrial · UniProt Q9BPX6

Length
476 aa
Mass
54.4 kDa
Annotated
2026-04-28
91 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MICU1 is an EF-hand Ca²⁺-sensing protein that gates the mitochondrial calcium uniporter (MCU), setting both the cytosolic Ca²⁺ threshold for channel activation and the cooperative gain of mitochondrial Ca²⁺ uptake. At resting cytosolic [Ca²⁺], MICU1 physically occludes the MCU pore by engaging the DIME selectivity filter via its N-terminal polybasic/DID domain, blocking Ca²⁺ and other divalent cation flux; upon Ca²⁺ binding to its EF hands (EC₅₀ ~4.4 µM), MICU1 undergoes conformational rearrangement within a Mia40-dependent disulfide-linked MICU1–MICU2 heterodimer, relieving pore block and cooperatively activating the channel (PMID:23747253, PMID:30454562, PMID:32667285, PMID:37036971, PMID:26387864). Loss of MICU1 causes constitutive mitochondrial Ca²⁺ loading, permeability transition pore sensitization, and tissue-specific pathology including perinatal lethality, neurodegeneration, skeletal myopathy, and impaired liver regeneration in mouse models (PMID:27477272, PMID:35302860, PMID:31665639, PMID:26956930). Independent of MCU gating, MICU1 localizes to the MICOS complex through direct interactions with MIC60 and CHCHD2, where it maintains cristae junction architecture and modulates cytochrome c retention (PMID:37098122, PMID:37290367).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2010 High

    The identity of the Ca²⁺-sensing regulator of mitochondrial Ca²⁺ uptake was unknown; RNAi screening identified MICU1 as an EF-hand protein essential for mitochondrial Ca²⁺ entry, establishing the first molecular handle on the uniporter.

    Evidence RNAi knockdown in intact and permeabilized cells with mitochondrial Ca²⁺ imaging and metabolic assays

    PMID:20693986

    Open questions at the time
    • Pore-forming subunit not yet identified
    • Whether MICU1 is part of the channel or a regulator was unresolved
    • Mechanism of Ca²⁺ sensing not defined
  2. 2012 High

    Whether MICU1 forms the pore or regulates it was unclear; co-immunoprecipitation showed MICU1 interacts with the newly identified MCU pore subunit and functions as a gatekeeper that sets a [Ca²⁺] threshold, preventing constitutive Ca²⁺ loading and ROS-driven apoptosis.

    Evidence Reciprocal Co-IP of MICU1–MCU, MICU1 knockdown with mitochondrial Ca²⁺, ROS, and apoptosis measurements

    PMID:23101630

    Open questions at the time
    • Sidedness of MICU1 (matrix vs. IMS) unresolved
    • Molecular basis of threshold-setting unknown
    • Role of EF hands in gating not yet tested
  3. 2013 High

    The topological orientation and Ca²⁺-sensing mechanism of MICU1 were debated; protease protection and EF-hand mutagenesis established that MICU1 resides in the intermembrane space and uses its EF hands to sense cytosolic [Ca²⁺], providing both threshold gating and cooperative activation of MCU.

    Evidence Submitochondrial localization by protease protection, EF-hand mutagenesis, mitochondrial Ca²⁺ imaging in mouse liver and cultured cells; domain mapping, Co-IP, and mitoplast patch-clamp for polybasic domain–MCU interaction

    PMID:23409044 PMID:23747253 PMID:24332854

    Open questions at the time
    • Structural basis of MICU1–MCU contact undefined
    • MICU2 contribution to gating unclear
    • Disulfide-linked heterodimer not yet identified
  4. 2014 High

    Whether MICU1 and MICU2 are functionally redundant was unknown; CRISPR knockouts showed both are nonredundant gatekeepers, and MICU2's physical association with MCU requires MICU1, positioning MICU1 as the obligate scaffold.

    Evidence CRISPR/Cas9 KO of MICU1 or MICU2 in HEK-293T, EF-hand mutagenesis, Co-IP, mitochondrial Ca²⁺ measurements

    PMID:24503055

    Open questions at the time
    • Physical linkage between MICU1 and MICU2 (homo- vs. heterodimer) not characterized
    • In vivo consequences of combined loss unknown
  5. 2015 High

    How MICU1 and MICU2 are assembled was unresolved; identification of a Mia40-dependent intermolecular disulfide bond linking MICU1–MICU2 into a heterodimer showed this bond is required for Ca²⁺-dependent association/dissociation from MCU, and FRET imaging revealed MICU1 multimer rearrangement with an EC₅₀ of ~4.4 µM Ca²⁺.

    Evidence Mia40 interactome screen, non-reducing SDS-PAGE, Co-IP, mitochondrial Ca²⁺ measurements; live-cell FRET monitoring MICU1 multimers

    PMID:26387864 PMID:26489515

    Open questions at the time
    • Atomic structure of the heterodimer lacking
    • In vivo relevance of disulfide bond not tested
    • Whether homodimers function physiologically unclear
  6. 2016 High

    In vivo consequences of MICU1 loss were unclear; MICU1 knockout mice exhibited perinatal lethality rescued by heterozygous EMRE deletion, establishing that MICU1 counterbalances EMRE-enabled MCU activity, while hepatocyte studies showed MICU1 loss accelerates permeability transition pore opening and prevents liver regeneration.

    Evidence MICU1 KO mouse with EMRE genetic rescue, hepatectomy model with PTP inhibitor rescue, behavioral and metabolic phenotyping

    PMID:26956930 PMID:27477272

    Open questions at the time
    • Tissue-specific roles in brain and heart not yet examined
    • Post-translational regulation in vivo unexplored
  7. 2016 Medium

    Post-translational tuning of MICU1 was unknown; PRMT1 was identified as an arginine methyltransferase that reduces MICU1 Ca²⁺ sensitivity, with UCP2/3 counteracting this inhibition to restore mitochondrial Ca²⁺ uptake.

    Evidence PRMT1 overexpression/knockdown, methylation assays, UCP2/3 knockdown, mitochondrial Ca²⁺ measurements

    PMID:27642082

    Open questions at the time
    • Methylation sites on MICU1 not fully mapped
    • In vivo relevance of PRMT1–MICU1 axis not tested
    • Whether other PTMs regulate MICU1 Ca²⁺ sensitivity unknown
  8. 2017 High

    How tissue-specific uniporter behavior arises was unexplained; quantitative stoichiometry measurements showed the MICU1:MCU ratio varies across tissues and directly determines the Ca²⁺ threshold and cooperativity of uptake, with electrophysiology confirming MICU1 alone mediates both gatekeeping and cooperative activation while MICU2 tunes these parameters.

    Evidence Quantitative Western blot of tissue ratios, MICU1 overexpression in heart with cardiac phenotype, mitoplast patch-clamp with controlled [Ca²⁺]

    PMID:28273446 PMID:29241542

    Open questions at the time
    • Whether MICU1:MCU ratio is dynamically regulated in disease unknown
    • Structural basis for stoichiometry-dependent gating not defined
  9. 2018 High

    The precise molecular interface between MICU1 and the MCU pore was unmapped; identification of the DIME-interacting domain (DID) in MICU1 and its contact with the D-ring of MCU's DIME selectivity filter established the structural basis for pore occlusion, while reconstitution studies showed MICU1 also protects against MCU-mediated toxic Mn²⁺ uptake.

    Evidence DID mutagenesis, Ru360 inhibition assays, Co-IP, yeast reconstitution of MCU/EMRE ± MICU1 under Mn²⁺ stress, human MICU1 KO cells

    PMID:30403999 PMID:30454562

    Open questions at the time
    • Atomic-resolution structure of the MICU1–MCU interface not yet available
    • Whether DID mutation affects MICU2 heterodimer function untested
  10. 2018 Medium

    Degradation pathways controlling MICU1 abundance were uncharacterized; Parkin was shown to interact with MICU1 via its Ubl domain and promote MICU1 proteasomal degradation, with secondary loss of MICU2 stability.

    Evidence Co-IP of Parkin–MICU1, Parkin overexpression/KD, proteasome inhibitor treatment, Ubl-domain mutagenesis

    PMID:30242232

    Open questions at the time
    • Ubiquitination sites on MICU1 not identified
    • Whether Parkin-dependent MICU1 degradation occurs during mitophagy unknown
    • Independent confirmation lacking
  11. 2019 High

    The electrostatic mechanism of MICU1 pore block was unresolved; mutagenesis of both MCU DIME-aspartate and conserved MICU1 Arg residues demonstrated a Ca²⁺-modulated electrostatic interaction at the cytoplasmic pore entrance, and structural studies of MICU2 revealed a conserved dimer interface enabling homo-/heterodimer exchange.

    Evidence Mutagenesis screen of MICU1 and MCU DIME motif with Ca²⁺ flux assays; X-ray crystallography of MICU2 at 2.5 Å with functional mutagenesis

    PMID:30638448 PMID:30755530

    Open questions at the time
    • Full holocomplex structure not yet available
    • Whether dimer exchange is regulated in vivo unknown
  12. 2019 High

    Physiological consequences of MICU1 loss in skeletal muscle were undefined; muscle-specific MICU1 KO mice revealed that MICU1 is required for proper excitation–contraction Ca²⁺ coupling, aerobic metabolism, and sarcolemmal membrane repair.

    Evidence Skeletal muscle-specific MICU1 KO mice, patient cells, mitochondrial Ca²⁺ imaging during excitation-contraction, membrane repair assay

    PMID:31665639

    Open questions at the time
    • Mechanism linking mitochondrial Ca²⁺ to membrane repair unclear
    • Whether MICU1 splice variants contribute differentially unknown
  13. 2020 High

    The structural basis of MICU1 gating was unresolved at atomic resolution; cryo-EM structures of the MCU–EMRE–MICU1–MICU2 holocomplex revealed that MICU1 blocks ion flow through a toxin-like occlusion mechanism, with Ca²⁺-dependent conformational changes in the MICU1–MICU2 heterodimer enabling dynamic gating.

    Evidence Cryo-EM at 3.3 Å (holocomplex) and 3.1 Å (Ca²⁺-bound MICU1–MICU2)

    PMID:32667285

    Open questions at the time
    • Transition-state structures during gating unavailable
    • Whether EMRE stoichiometry modulates MICU1 docking in vivo untested
  14. 2022 High

    Neuron-specific consequences were unknown; neuron-specific MICU1 KO caused progressive neurodegeneration rescued by PTP inhibition, establishing dysregulated mitochondrial Ca²⁺ as causative for excitotoxic neuronal death.

    Evidence Neuron-specific MICU1 KO mouse, excitotoxicity assays, mPTP inhibitor rescue, behavioral phenotyping

    PMID:35302860

    Open questions at the time
    • Which neuronal populations are most vulnerable not defined
    • Whether MICU1 loss contributes to human neurodegenerative disease unknown
  15. 2023 High

    Whether MICU1 has functions independent of MCU gating was unknown; proteomics and imaging revealed MICU1 localizes to the MICOS complex via direct interactions with MIC60 and CHCHD2, where it maintains cristae junction architecture and modulates cytochrome c retention independently of Ca²⁺ transport.

    Evidence Proteomics, super-resolution imaging, Co-IP with MIC60/CHCHD2, MICU1 KO mice/cells, electron microscopy; corroborated by independent study

    PMID:37098122 PMID:37290367

    Open questions at the time
    • Structural basis of MICU1–MIC60 interaction unknown
    • Whether Ca²⁺ sensing regulates the MICOS function of MICU1 untested
    • Relative contribution of MICOS vs. MCU functions to MICU1 KO phenotypes not disentangled
  16. 2023 High

    Direct electrophysiological proof that purified MICU1 blocks the MCU pore was lacking; patch-clamp with purified MICU1 demonstrated strong suppression of MCU currents dependent on K126, and intact-mitochondria assays confirmed MICU1 prevents MCU-mediated Na⁺ leak in the absence of Ca²⁺, resolving long-standing debate about the occlusion mechanism.

    Evidence Mitoplast patch-clamp with purified MICU1, K126 mutagenesis, Na⁺ flux assay, Ru265 pharmacology; complemented by independent Na⁺ influx study in MICU1 KO cells

    PMID:37036971 PMID:37126688

    Open questions at the time
    • Whether pore occlusion involves additional accessory subunits in vivo is unresolved
    • Kinetics of MICU1 dissociation from the pore during physiological Ca²⁺ transients not measured
  17. 2024 High

    MICU1 function in the beating heart was uncharacterized; cardiac MICU1 KO showed altered mitochondrial Ca²⁺ signaling and energy metabolism with compensatory downregulation of EMRE and MCU, demonstrating homeostatic subunit remodeling that limits Ca²⁺ uptake and permits cardiomyocyte survival.

    Evidence Murine cardiac MICU1 KO, Co-IP from human heart, mitochondrial Ca²⁺ imaging, EMRE/MCU protein time-course

    PMID:39163336

    Open questions at the time
    • Whether compensatory EMRE reduction is transcriptional or post-translational unknown
    • Long-term cardiac consequences of MICU1 loss under stress not studied

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the MICU1–MICOS interaction, whether Ca²⁺ sensing by MICU1 regulates its cristae-organizing function, and how MICU1 splice variants and post-translational modifications are integrated to tune tissue-specific uniporter behavior in vivo.
  • No structure of MICU1–MIC60 complex
  • Functional significance of MICU1 splice variants in vivo unknown
  • Integration of PRMT1 methylation and Parkin degradation with physiological Ca²⁺ gating not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0140299 molecular sensor activity 4
Localization
GO:0005739 mitochondrion 7 GO:0043226 organelle 2
Pathway
R-HSA-382551 Transport of small molecules 8 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CHCHD2CHCHD4EMREMCUMIC60MICU2PARK2TOMM70
Complex memberships
MCU complex (mitochondrial calcium uniporter)MICOS complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 MICU1 (CBARA1) is a mitochondrial inner membrane-associated protein with two canonical EF hands required for mitochondrial Ca2+ uptake; RNAi silencing abolishes mitochondrial Ca2+ entry in intact and permeabilized cells without disrupting mitochondrial respiration or membrane potential, and attenuates metabolic coupling between cytosolic Ca2+ transients and matrix dehydrogenase activation. RNAi knockdown in intact and permeabilized cells, mitochondrial Ca2+ imaging, metabolic assays, subcellular fractionation Nature High 20693986
2012 MICU1 interacts with the pore-forming MCU subunit and acts as a gatekeeper that sets a Ca2+ threshold for mitochondrial Ca2+ uptake without altering MCU kinetics; loss of MICU1 causes constitutive mitochondrial Ca2+ loading, excessive ROS generation, and sensitization to apoptotic stress. Co-immunoprecipitation (MICU1–MCU interaction), MICU1 knockdown, mitochondrial Ca2+ measurement, ROS assays, apoptosis assays Cell High 23101630
2013 MICU1 faces the intermembrane space, establishes both the Ca2+ threshold and positive cooperativity (gain) of uniporter activation by sensing cytoplasmic [Ca2+] through its EF hands; loss of MICU1 causes mitochondrial Ca2+ accumulation at low [Ca2+]c but attenuated response to agonist-induced pulses. MICU1 loss-of-function in mouse liver and cultured cells, submitochondrial localization by protease protection/fractionation, mitochondrial Ca2+ imaging, EF-hand mutagenesis Cell Metabolism High 23747253
2013 MICU1 and its paralog MICU2 reside within the same uniporter complex with MCU and cross-stabilize each other's protein expression; in vivo RNAi silencing of MICU1, MICU2, or both causes additive impairment of mitochondrial Ca2+ handling without affecting respiration or membrane potential. Co-immunoprecipitation, in vivo RNAi in mouse liver, Western blot, mitochondrial Ca2+ measurements PLoS One High 23409044
2013 MICU1 localizes to the matrix side of the inner mitochondrial membrane; its N-terminal polybasic domain binds two coiled-coil domains of MCU; MICU1 forms homo-oligomers independently of the polybasic region, but the polybasic region confers oligomeric binding to MCU and controls mitochondrial Ca2+ current; EF hands regulate MCU channel activity but not MCU binding; loss of MICU1 increases oxidative burden and halts cell migration. Domain mapping by deletion/mutagenesis, Co-IP, mitoplast patch-clamp (IMCU), submitochondrial localization, cell migration assay Cell Reports High 24332854
2014 MICU1 and MICU2 are nonredundant gatekeepers: knockout of either abolishes the normal [Ca2+] threshold for uniporter activity; MICU1/2 EF-hand mutants lacking Ca2+-binding cause striking loss of Ca2+ uptake (dominant negative), indicating they disinhibit the channel above threshold; MICU2's activity and physical association with MCU require MICU1, but not vice versa. CRISPR/Cas9 knockout of MICU1 or MICU2 in HEK-293T cells, EF-hand mutagenesis, Co-IP, mitochondrial Ca2+ measurements EMBO Reports High 24503055
2015 Mia40/CHCHD4 oxidoreductase introduces an intermolecular disulfide bond linking MICU1 and MICU2 in a heterodimer; this disulfide bond is required for the MICU1-MICU2 dimer to associate with MCU at low Ca2+ and dissociate upon high Ca2+; absence of the disulfide bond results in increased receptor-induced mitochondrial Ca2+ uptake. Mia40 interactome screen, non-reducing SDS-PAGE to detect disulfide-linked heterodimer, Co-IP, mitochondrial Ca2+ measurements, Mia40 knockdown/overexpression Cell Metabolism High 26387864
2015 Elevations of cytosolic Ca2+ rearrange MICU1 multimers with an EC50 of ~4.4 μM, resulting in MCU/EMRE activation; MICU1 rearrangement requires the EF-hand motifs and is strictly correlated with the shape of cytosolic Ca2+ rises, but is independent of matrix Ca2+ concentration, mitochondrial membrane potential, or MCU/EMRE expression levels. Live-cell FRET approach monitoring MICU1 multimer rearrangement, mitochondrial Ca2+ imaging Scientific Reports Medium 26489515
2016 MICU1 deletion in mice causes perinatal lethality, ataxia, and muscle weakness with increased resting mitochondrial Ca2+, altered mitochondrial morphology, and reduced ATP; deleting one allele of EMRE in MICU1-/- mice normalizes Ca2+ uptake and rescues perinatal mortality, demonstrating that MICU1 counterbalances EMRE-enabled MCU activity in vivo. MICU1 knockout mouse model, EMRE heterozygous genetic rescue, mitochondrial Ca2+ measurements, ATP assays, behavioral phenotyping Cell Reports High 27477272
2016 PRMT1 asymmetrically methylates MICU1, reducing its Ca2+ sensitivity; UCP2/3 normalize the Ca2+ sensitivity of methylated MICU1 to re-establish mitochondrial Ca2+ uptake activity, defining a post-translational regulatory axis that determines UCP2/3 dependency of mitochondrial Ca2+ uptake. PRMT1 overexpression/knockdown, methylation assays, UCP2/3 knockdown, mitochondrial Ca2+ measurements Nature Communications Medium 27642082
2016 MICU1 knockout mice show accelerated Ca2+ overload-induced mitochondrial permeability transition pore opening in hepatocytes; MICU1 loss causes pro-inflammatory phase failure to resolve after partial hepatectomy, preventing liver regeneration via necrosis; PTP inhibition rescues regeneration. MICU1 KO mice, partial hepatectomy model, mitochondrial Ca2+ measurements, PTP inhibitor pharmacology, histology Nature Communications High 26956930
2017 The MICU1:MCU protein stoichiometry directly controls tissue-specific uniporter phenotypes: low MICU1:MCU ratio (heart, skeletal muscle) lowers threshold and reduces cooperativity; overexpressing MICU1 in heart increases MICU1:MCU ratio, converts cardiac mitochondrial Ca2+ uptake to a liver-like phenotype, and causes cardiac contractile dysfunction. Quantitative Western blot of tissue MICU1:MCU ratios, MICU1 overexpression in heart, Co-IP demonstrating proportional MCU association, mitochondrial Ca2+ imaging, cardiac contractile function assays Cell Reports High 28273446
2017 MICU1 overexpression activates pyruvate dehydrogenase (PDH) through the PDH phosphatase–phosphoPDH–PDH axis; in ovarian cancer cells, silencing MICU1 shifts metabolism from glycolysis to oxidative phosphorylation, inhibiting clonal growth, migration, and invasion, and increasing cisplatin efficacy in vivo. MICU1 siRNA knockdown and overexpression, PDH activity assay, lactate/oxygen consumption measurements, xenograft mouse model Nature Communications Medium 28530221
2017 MICU2 regulates the threshold and gain of MICU1-mediated inhibition and activation of MCU; MICU1 alone mediates gatekeeping and cooperative MCU activation, while MICU2 tunes these parameters to spatially restrict Ca2+ crosstalk between single InsP3R and MCU channels. Whole-cell and mitoplast patch-clamp with quantitatively controlled [Ca2+]c, MICU1/MICU2 knockdown Cell Reports High 29241542
2018 The mitochondrial import receptor Tom70 governs the mitochondrial translocation of MICU1; Tom70 deficiency reduces mitochondrial MICU1 levels, worsens Ca2+ overload and ischemia/reperfusion injury; Tom70 supplementation restores mitochondrial MICU1 and is cardioprotective only when MICU1 is present. siRNA knockdown and lentiviral overexpression of Tom70 and MICU1 in vivo, subcellular fractionation, mitochondrial Ca2+ measurement, MI/R mouse model Cell Death & Disease Medium 28703803
2018 Parkin (PARK2) E3 ubiquitin ligase interacts with MICU1 and promotes its proteasomal degradation; Parkin's Ubl domain (not its E3 ligase activity) is required for MICU1 degradation; MICU1 is selectively degraded by the ubiquitin-proteasome system among MCU complex components; MICU2 stability is secondarily affected through loss of MICU1. Co-IP (Parkin–MICU1 interaction), Parkin overexpression/KD, proteasome inhibitor treatment, Parkin Ubl-domain mutagenesis, Western blot time-course Scientific Reports Medium 30242232
2018 MICU1 interacts with the D-ring formed by the DIME selectivity filter motifs of MCU; a putative DIME-interacting domain (DID) in MICU1 is required for both gatekeeping and cooperative activation, and for cell survival; MICU1 suppresses inhibition of MCU by ruthenium red/Ru360 that bind the DIME motif. Mutagenesis of MICU1 DID, Ru360 inhibition assays, mitochondrial Ca2+ measurements, cell survival assays, Co-IP Molecular Cell High 30454562
2019 The DIME-aspartate of MCU mediates a Ca2+-modulated electrostatic interaction with two conserved Arg residues of MICU1 and a nearby Ser at the cytoplasmic entrance of the MCU pore; perturbing these MCU-MICU1 interactions elicits constitutive, unregulated Ca2+ flux into mitochondria, indicating MICU1 gates the uniporter by blocking/unblocking the MCU pore. Mutagenesis screen of MICU1 and MCU DIME motif, mitochondrial Ca2+ flux assays, electrostatic interaction analysis eLife High 30638448
2019 MICU1 is required for low [Ca2+]c gatekeeping in HEK cells but not in Trypanosoma cruzi; TcMICU1 knockout reduces mitochondrial Ca2+ uptake and impairs growth and host cell invasion, revealing lineage-specific adaptations of the MICU1 regulatory mechanism. CRISPR/Cas9 knockout of TcMICU1, mitochondrial Ca2+ uptake assays in permeabilized cells, growth and invasion assays mBio Medium 31064825
2019 Crystal structure of MICU2 (apo form) at 2.5 Å reveals a core structure highly similar to MICU1 with two canonical Ca2+-binding and two structural EF-hands; a symmetrical dimer interface (EF1–EF3) is conserved between MICU1 and MICU2 homodimers, enabling exchange between homo- and heterodimers; MICU2's extended C-terminal helix is dispensable for MICU1 binding in vitro but required for MICU2 function in cells. X-ray crystallography (2.5 Å), in vitro binding assays, C-terminal helix deletion mutagenesis, cellular Ca2+ uptake assays PNAS High 30755530
2019 MICU1 loss causes dysregulation of mitochondrial Ca2+ uptake during excitation-contraction coupling, aerobic metabolism impairment, muscle weakness, fatigue, and myofiber damage; additionally, MICU1 deficit compromises mitochondrial Ca2+ uptake during sarcolemmal injury, causing ineffective myofiber membrane repair. Skeletal muscle-specific MICU1 KO mice, patient cells, mitochondrial Ca2+ imaging during excitation-contraction, membrane repair assay, metabolic assays Cell Reports High 31665639
2020 Cryo-EM structure of the MCU-EMRE-MICU1-MICU2 holocomplex at 3.3 Å shows that a uniporter interaction domain on MICU1 binds a channel receptor site comprising MCU and EMRE subunits, analogous to toxin block, to inhibit ion flow at resting Ca2+; a Ca2+-bound MICU1-MICU2 structure at 3.1 Å reveals how Ca2+-dependent conformational changes enable dynamic response to cytosolic Ca2+ signals. Cryo-EM structure determination (3.3 Å holocomplex; 3.1 Å Ca2+-bound MICU1-MICU2) eLife High 32667285
2020 Inhibition of mitochondrial pyruvate or fatty acid transport increases MICU1 protein abundance (but not MCU) via transcription factor EGR1, thereby suppressing MCU-mediated matrix Ca2+ uptake and reducing resting matrix Ca2+; this defines a metabolic homeostatic circuit protecting cells from Ca2+ overload during nutrient stress. MPC isoform knockdown, dominant-negative MPC1R97W expression, MPC1 KO in hepatocytes and MEFs, EGR1 loss-of-function, mitochondrial Ca2+ measurements, MICU1 protein quantification Science Signaling Medium 32317369
2022 Neuron-specific MICU1 KO mice show progressive motor and cognitive neurodegeneration caused by increased susceptibility to mitochondrial Ca2+ overload-induced excitotoxic insults and cell death; inhibiting the mitochondrial permeability transition pore blunts this neuronal death, establishing dysregulated neuronal mitochondrial Ca2+ homeostasis as causative. Neuron-specific MICU1 KO mouse, excitotoxicity assays, mPTP inhibitor pharmacological rescue, Ca2+ imaging, behavioral phenotyping Science Advances High 35302860
2023 MICU1 localizes to the mitochondrial contact site and cristae organizing system (MICOS) independently of the MCU pore complex; MICU1 directly interacts with MICOS components MIC60 and CHCHD2; MICU1 ablation disrupts MICOS complex formation, alters cristae organization, mitochondrial ultrastructure, membrane dynamics, and cell death signaling—effects distinct from those seen with other mtCU subunit deficiencies. Proteomics, super-resolution imaging, Co-IP of MICU1 with MIC60 and CHCHD2, MICU1 KO mice and cells, electron microscopy Science Signaling High 37098122
2023 Patch-clamp directly demonstrates that purified MICU1 strongly suppresses MCU Ca2+ currents; this inhibition is abolished by mutating MICU1's MCU-interacting K126 residue; a membrane-depolarization assay shows MICU1 prevents MCU-mediated Na+ flux into intact mitochondria in the absence of Ca2+, firmly establishing an occlusion/pore-blocking mechanism for MICU1 gating. Mitoplast patch-clamp with purified MICU1, K126 mutagenesis, membrane depolarization assay for Na+ flux, Ru265-sensitive current measurements PNAS High 37036971
2023 MICU1 physically occludes the mtCU pore in divalent-free conditions: MICU1 KO cells show increased Ru265-sensitive Na+ influx and ensuing mitochondrial depolarization/swelling; excess acute MICU1 overexpression prevents this Na+ flux; some mtCU lack MICU1-dependent gating even in high-MICU1 cells, explaining prior conflicting results from mitoplast preparations. Fluorescence-based mitochondrial matrix [Na+] measurement, mitochondrial swelling/depolarization assay, MICU1 KO and rescue in HEK cells, Ru265 pharmacology PNAS High 37126688
2023 MICU1 deficiency alters mitochondrial cristae junction structure through its interactions with MIC60 and CHCHD2 at the inner boundary membrane, leading to increased cytochrome c release, altered membrane potential, and changes in mitochondrial Ca2+ uptake dynamics. MICU1 KO cells, electron microscopy, Co-IP with MICOS components, cytochrome c release assay, Ca2+ imaging Cell Calcium Medium 37290367
2024 MICU1 and MICU2 gate MCU in the beating mammalian heart; MICU1 is present in complex with MCU in nonfailing human hearts; MICU1 deletion alters cardiomyocyte mitochondrial Ca2+ signaling and energy metabolism; loss of MICU1 causes compensatory reduction in EMRE and later MCU abundance that limits Ca2+ uptake and permits cell survival. Murine cardiac MICU1 KO, Co-IP from human heart tissue, mitochondrial Ca2+ imaging, EMRE/MCU Western blot time-course, metabolic assays PNAS High 39163336
2018 MICU1 confers selectivity of the uniporter by protecting against MCU-dependent Mn2+ uptake; MICU1 deletion sensitizes human cells to Mn2+-dependent cell death by disinhibiting MCU-mediated Mn2+ uptake and increasing oxidative stress, demonstrating MICU1's role in uniporter ion selectivity beyond Ca2+. Evolutionary co-occurrence analysis across 247 eukaryotes, yeast reconstitution of MCU/EMRE with/without MICU1 under Mn2+ stress, MICU1 KO in human cells, ROS assay, cell viability assay Cell Reports High 30403999
2022 MICU1 deficiency in MICU1-/- cells activates SGPL1 (sphingosine phosphate lyase), which stimulates VPS39 recruitment to mitochondria, enhancing mitochondria-lysosome contacts; VPS39 downregulation compromises mitochondrial network maintenance and basal autophagic flux in MICU1-deficient cells. C. elegans micu-1 null mutant transcriptomics/proteomics, biochemical and imaging analysis in mammalian cells and mouse-derived tissues, VPS39 KD Molecular Metabolism Medium 35452878
2022 RBFOX2 splicing factor drives alternative splicing of MICU1 pre-mRNA during myogenic differentiation, generating splice variants (including MICU1.1) with distinct mitochondrial Ca2+ uptake regulatory properties; human tissues express at least two additional MICU1 splice variants beyond the canonical form. RT-PCR characterization of splice variants in human tissues, RBFOX2 knockdown during myogenesis, mitochondrial Ca2+ uptake assays for each variant International Journal of Molecular Sciences Medium 35269658
2018 FOXD1 transcription factor directly represses MICU1 expression in human embryonic stem cells and induced pluripotent stem cells; low MICU1 expression in hESCs/hiPSCs is due to Foxd1-mediated repression; restoration of MICU1 establishes periodic cytosolic Ca2+ oscillations and promotes cellular differentiation and maturation. MICU1 expression analysis in hESCs/hiPSCs, Foxd1 ChIP or reporter assays, MICU1 rescue experiments, Ca2+ imaging Nature Communications Medium 30158529
2025 SIRT1 directly interacts with MICU1; SIRT1 inhibition reduces MICU1 expression, leading to mitochondrial Ca2+ overload and mitochondrial structural fragmentation, indicating SIRT1 regulates mitochondrial Ca2+ uptake at least partly through maintaining MICU1 levels. Co-IP (SIRT1–MICU1 interaction), SIRT1 pharmacological inhibition (EX527), shSIRT1 knockdown, mitochondrial Ca2+ imaging, mitochondrial morphology assessment Life (Basel) Low 40003583

Source papers

Stage 0 corpus · 91 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature 729 20693986
2012 MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 569 23101630
2013 MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²⁺ uniporter. Cell metabolism 413 23747253
2013 MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PloS one 391 23409044
2013 Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nature genetics 310 24336167
2016 MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload. Cell reports 197 27477272
2014 MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO reports 188 24503055
2016 MICU1 regulation of mitochondrial Ca(2+) uptake dictates survival and tissue regeneration. Nature communications 175 26956930
2017 Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca2+ Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU. Cell reports 164 28273446
2015 The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake. Cell metabolism 164 26387864
2017 MICU1 drives glycolysis and chemoresistance in ovarian cancer. Nature communications 141 28530221
2009 emPAI Calc--for the estimation of protein abundance from large-scale identification data by liquid chromatography-tandem mass spectrometry. Bioinformatics (Oxford, England) 133 20031975
2013 MICU1 motifs define mitochondrial calcium uniporter binding and activity. Cell reports 118 24332854
2012 Mitochondrial Ca2+ uptake 1 (MICU1) and mitochondrial ca2+ uniporter (MCU) contribute to metabolism-secretion coupling in clonal pancreatic β-cells. The Journal of biological chemistry 117 22904319
2018 MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca2+ Flux and Sensitivity to Ru360. Molecular cell 101 30454562
2017 MICU1 Alleviates Diabetic Cardiomyopathy Through Mitochondrial Ca2+-Dependent Antioxidant Response. Diabetes 93 28292968
2019 Dysregulation of Mitochondrial Ca2+ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1. Cell reports 84 31665639
2016 Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood. Neurology. Genetics 84 27123478
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2022 MICU1-dependent mitochondrial calcium uptake regulates lung alveolar type 2 cell plasticity and lung regeneration. JCI insight 22 35050901
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