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Showing MICU1 — CALC is a alias.

MICU1

Calcium uptake protein 1, mitochondrial · UniProt Q9BPX6

Length
476 aa
Mass
54.4 kDa
Annotated
2026-06-10
94 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MICU1 is an EF-hand Ca2+-sensing subunit of the mitochondrial Ca2+ uniporter (MCU) complex that establishes the cytoplasmic Ca2+ threshold for mitochondrial Ca2+ uptake and is essential for normal mitochondrial Ca2+ signaling (PMID:20693986, PMID:23101630, PMID:24336167). Facing the intermembrane space, MICU1 binds the pore-forming MCU subunit and acts as a gatekeeper: at resting [Ca2+] it physically occludes the channel pore — a mechanism resolved by reconstituted patch-clamp showing purified MICU1 suppresses MCU currents and restricts cation flux even in divalent-free conditions, with the K126 residue required for inhibition (PMID:23101630, PMID:37036971, PMID:37126688). Cryo-EM of the MCU-EMRE-MICU1-MICU2 holocomplex shows a MICU1 interaction domain binding MCU and EMRE to block ion flow at resting Ca2+, with Ca2+ binding driving conformational rearrangement of MICU1-MICU2 that relieves occlusion (PMID:32667285); the inhibitory interface is built on electrostatic contacts between MICU1 arginine residues and the MCU DIME-aspartate D-ring, disruption of which causes constitutive Ca2+ flux (PMID:30454562, PMID:30638448). Beyond gatekeeping, MICU1 confers the cooperative, sigmoidal activation of the uniporter through its EF-hands, which sense rising cytosolic Ca2+ (rearranging MICU1 multimers with an EC50 near 4.4 µM) without changing MCU binding (PMID:23747253, PMID:24332854, PMID:26489515). MICU1 functions within a heterodimer with MICU2 — cross-linked by a Mia40/CHCHD4-dependent disulfide bond — in which MICU1 is the dominant partner required for MICU2's pore association and activity (PMID:23409044, PMID:24503055, PMID:26387864, PMID:30755530). The MICU1:MCU stoichiometry tunes tissue-specific Ca2+ thresholds, with EMRE acting as a downstream effector of MICU1 gating (PMID:27477272, PMID:28273446). By limiting matrix Ca2+ loading, MICU1 protects against Ca2+ overload-driven permeability transition pore opening and cell death in liver, neurons, and skeletal muscle, and its loss-of-function mutations cause a human disease of disrupted mitochondrial Ca2+ signaling with mitochondrial network fragmentation (PMID:24336167, PMID:26956930, PMID:31665639, PMID:35302860). Independently of Ca2+ gating, MICU1 associates with the MICOS complex through MIC60 and CHCHD2 to organize cristae architecture and restrain cytochrome c release (PMID:37098122, PMID:37290367). MICU1 is further regulated post-translationally by PRMT1 methylation and Parkin-dependent proteasomal degradation, transcriptionally by EGR1, FOXD1 and metabolic state, and by RBFOX2-driven alternative splicing producing a skeletal-muscle variant (PMID:27642082, PMID:30242232, PMID:32317369, PMID:30158529, PMID:35269658).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2010 High

    Established MICU1 as an EF-hand protein required for mitochondrial Ca2+ uptake, answering whether a dedicated Ca2+-sensing component governs uniporter activity.

    Evidence RNAi knockdown with mitochondrial Ca2+ measurement, EF-hand mutagenesis and subcellular fractionation

    PMID:20693986

    Open questions at the time
    • Did not define whether MICU1 is the pore or a regulatory subunit
    • Mechanism of Ca2+ sensing not structurally resolved
  2. 2012 High

    Defined MICU1 as a gatekeeper setting a Ca2+ threshold via interaction with the pore-forming MCU subunit, answering why mitochondria do not load Ca2+ at rest.

    Evidence Co-IP, RNAi knockdown with Ca2+, ROS and apoptosis assays

    PMID:23101630

    Open questions at the time
    • Did not establish the structural basis of gating
    • Did not resolve whether MICU1 occludes the pore or allosterically regulates it
  3. 2013 High

    Showed MICU1 faces the intermembrane space, controls cooperative activation through its EF-hands, maps to MCU coiled-coil/N-terminal contacts, and forms a complex with MICU2, building the architecture of the regulatory module.

    Evidence In vivo mouse-liver RNAi, protease protection, domain mutagenesis, Co-IP and Ca2+ current measurement

    PMID:23409044 PMID:23747253 PMID:24313810 PMID:24332854

    Open questions at the time
    • Topology assignment differed between matrix-side and IMS-facing claims
    • EF-hand-driven conformational change not directly visualized
    • Stoichiometry of MICU1:MCU not quantified
  4. 2013 High

    Linked MICU1 to human disease by showing patient loss-of-function mutations disrupt Ca2+ signaling and fragment the mitochondrial network, establishing physiological relevance.

    Evidence Patient fibroblast Ca2+ imaging, membrane potential measurement and microscopy

    PMID:24336167

    Open questions at the time
    • Did not define the full clinical spectrum mechanistically
    • Did not separate Ca2+-gating from morphological phenotypes
  5. 2014 High

    Dissected the non-redundant MICU1/MICU2 relationship, showing MICU1 is the dominant subunit required for MICU2's pore association, answering how the heterodimer is organized.

    Evidence CRISPR/Cas9 knockout, EF-hand mutagenesis, Co-IP and Ca2+ uptake assays

    PMID:24503055

    Open questions at the time
    • Did not resolve the disulfide-linked dimer chemistry
    • Did not provide structural detail of the heterodimer
  6. 2015 High

    Identified the Mia40/CHCHD4-introduced disulfide linking MICU1-MICU2 and FRET evidence of Ca2+-driven multimer rearrangement (EC50 ~4.4 µM), defining the chemical and dynamic basis of Ca2+-dependent uniporter remodeling.

    Evidence Mia40 interactome MS, disulfide analysis, Co-IP, live-cell FRET and EF-hand mutagenesis

    PMID:26387864 PMID:26489515

    Open questions at the time
    • Single-lab structural inference of the rearrangement
    • Did not capture atomic-resolution conformational states
  7. 2016 High

    Demonstrated in vivo that MICU1 gatekeeping protects against Ca2+ overload, with EMRE as a downstream effector and PTP as the death pathway, establishing the physiological consequence of lost gating.

    Evidence Genetic mouse KO, EMRE heterozygous epistasis cross, partial hepatectomy and PTP inhibitor rescue

    PMID:26956930 PMID:27477272

    Open questions at the time
    • Did not resolve tissue-specific threshold differences mechanistically
    • Did not address non-Ca2+ functions of MICU1
  8. 2016 Medium

    Revealed post-translational control of MICU1 by PRMT1 methylation (modulated by UCP2/3), answering how uniporter Ca2+ sensitivity is tuned beyond protein levels.

    Evidence In vitro methylation assay, UCP2/3 co-expression, Ca2+ uptake and mutagenesis

    PMID:27642082

    Open questions at the time
    • Single lab; physiological context of methylation not established in vivo
    • Methylation site stoichiometry not quantified
  9. 2017 High

    Showed the MICU1:MCU stoichiometry sets tissue-specific Ca2+ thresholds and that Tom70 controls MICU1 import, connecting expression ratios and biogenesis to organ-level uniporter phenotypes.

    Evidence Tissue protein quantification, MICU1 overexpression, Co-IP stoichiometry, cardiac function and in vivo Tom70 knockdown

    PMID:28273446 PMID:28703803

    Open questions at the time
    • Did not define how stoichiometry is set developmentally
    • Tom70 link is Medium-confidence single-lab in vivo knockdown
  10. 2017 Medium

    Connected MICU1 to cellular metabolism by linking its expression to PDH activity and the glycolysis-OXPHOS balance, and refined MICU2's role in modulating MICU1 gating and InsP3R-MCU crosstalk.

    Evidence siRNA knockdown, PDH/oxygen consumption/lactate assays, xenografts and quantitative Ca2+-clamp patch-clamp

    PMID:28530221 PMID:29241542

    Open questions at the time
    • Metabolic axis established in single lab
    • Causal chain from MICU1 to PDH phosphatase not fully resolved
  11. 2018 High

    Mapped the MICU1 DIME-interacting domain (DID) and Parkin-dependent degradation, and showed MICU1 controls uniporter selectivity (manganese), defining both the structural contact with MCU and additional regulatory and selectivity functions.

    Evidence Ru360 assays, DID mutagenesis, Co-IP, yeast reconstitution, manganese toxicity assays and Parkin domain mutants

    PMID:30242232 PMID:30403999 PMID:30454562

    Open questions at the time
    • Parkin and manganese roles are Medium-confidence single-lab
    • Did not capture the DID-DIME contact structurally
  12. 2018 Medium

    Linked MICU1 to development by showing FOXD1 represses it in stem cells and that restoring MICU1 establishes Ca2+ oscillations driving differentiation.

    Evidence ChIP, MICU1 overexpression in hESCs/iPSCs, Ca2+ imaging and differentiation markers

    PMID:30158529

    Open questions at the time
    • Single lab; direct FOXD1 repression mechanism limited to ChIP correlation
    • Generality across lineages not established
  13. 2019 High

    Resolved the molecular contact interface (MICU1 arginines to MCU DIME-aspartate) and solved the MICU2 crystal structure with a conserved dimer interface, providing atomic detail of how MICU1 docks and how homo/heterodimers exchange.

    Evidence Mutagenesis screen, Co-IP, electrophysiology, X-ray crystallography and binding assays

    PMID:30638448 PMID:30755530

    Open questions at the time
    • MICU1's own high-resolution structure within the holocomplex not yet defined here
    • Dynamic Ca2+-driven interface changes inferred not visualized
  14. 2019 High

    Extended MICU1 physiology to skeletal muscle, showing loss lowers the uptake threshold and impairs excitation-contraction metabolism and sarcolemmal repair, defining tissue-specific consequences.

    Evidence Muscle-specific conditional KO, patient cells, Ca2+ imaging, respiration and sarcolemmal repair assays

    PMID:31665639

    Open questions at the time
    • Did not address splice-variant contribution to muscle phenotype
    • Repair mechanism at injury sites not fully resolved
  15. 2020 High

    Captured the apo and Ca2+-bound cryo-EM structures of the MCU-EMRE-MICU1-MICU2 holocomplex, directly visualizing MICU1's toxin-like pore block and Ca2+-dependent conformational switch, the structural culmination of the gating model.

    Evidence Cryo-EM at 3.3 Å (apo) and 3.1 Å (Ca2+-bound) with structural comparison

    PMID:32667285

    Open questions at the time
    • Did not resolve transient intermediate gating states
    • Did not address MICOS-bound pool of MICU1
  16. 2020 Medium

    Showed metabolic signals upregulate MICU1 via EGR1 to inhibit Ca2+ uptake, defining a transcriptional feedback linking fuel availability to uniporter activity.

    Evidence MPC knockdown/KO, dominant-negative MPC1, MICU1 quantification and EGR1 transcription assay

    PMID:32317369

    Open questions at the time
    • Single lab; EGR1-MICU1 promoter regulation not fully mapped
    • Physiological generality across tissues unclear
  17. 2022 High

    Demonstrated MICU1 sits upstream of mPTP in neurodegeneration and that RBFOX2-driven splicing generates a muscle-specific variant, extending its role to neuronal survival and tissue-specific isoform function.

    Evidence Neuron-specific KO with mPTP inhibitor rescue and patient cells; RT-PCR splice analysis with RBFOX2 knockdown

    PMID:35269658 PMID:35302860

    Open questions at the time
    • Splice-variant functional details are Medium-confidence single-lab
    • Did not define neuronal-subtype-specific thresholds
  18. 2023 High

    Resolved a long-standing controversy by directly demonstrating physical pore occlusion (purified MICU1 suppresses MCU currents, K126-dependent; restricts cation flux in divalent-free conditions) and uncovered a Ca2+-independent MICOS function organizing cristae and restraining cytochrome c release.

    Evidence Patch-clamp of purified MCU, Na+ flux assays, K126 mutagenesis, proteomics, Co-IP (MIC60/CHCHD2), EM imaging and cytochrome c release assays

    PMID:37036971 PMID:37098122 PMID:37126688 PMID:37290367

    Open questions at the time
    • MICOS role mechanistically separate but partner recruitment not fully defined
    • Heterogeneity of MICU1-gated vs ungated channels not explained
  19. 2024 High

    Confirmed the MICU1-MCU complex in human heart and showed cardiac MICU1 loss triggers compensatory EMRE/MCU turnover, linking subunit dynamics to cardiac metabolism and survival.

    Evidence Co-IP in human heart tissue, cardiac-specific KO mouse, Ca2+ imaging, metabolic and protein turnover analysis

    PMID:39163336

    Open questions at the time
    • Mechanism of compensatory turnover not molecularly defined
    • Did not separate MICOS from Ca2+ contributions in heart
  20. 2025 Medium

    Identified additional MICU1 interactors (TMBIM5, SIRT1) with functional interplay affecting submitochondrial localization and morphology, expanding the regulatory network.

    Evidence Co-IP, Drosophila genetics, MICU1 rescue in TMBIM5 KO, SIRT1 inhibition and Ca2+/morphology assays

    PMID:40003583 PMID:40973741

    Open questions at the time
    • SIRT1 link is Low-confidence single Co-IP without mechanism of regulation
    • TMBIM5-MICU1 functional interplay direction not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the Ca2+-gating and MICOS-organizing functions of MICU1 are coordinated within a single cell, and what determines the existence of MICU1-gated versus ungated uniporter populations, remains unresolved.
  • No structural model integrating MICU1's MCU-bound and MICOS-bound pools
  • Regulatory inputs (methylation, splicing, degradation) not unified into a quantitative model
  • Mechanism partitioning MICU1 between channel gating and cristae organization unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140299 molecular sensor activity 3
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1430728 Metabolism 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CHCHD2EMREMCUMIC60MICU2PARK2PRMT1TMBIM5
Complex memberships
MICOS complexMICU1-MICU2 heterodimerMitochondrial calcium uniporter (MCU) complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 MICU1 is a mitochondrial inner membrane-associated protein with two canonical EF-hand domains that is required for mitochondrial Ca2+ uptake; RNAi silencing abolishes mitochondrial Ca2+ entry in intact and permeabilized cells without disrupting respiration or membrane potential, and EF-hand mutations abolish its activity, indicating a Ca2+-sensing role. RNAi knockdown, mitochondrial Ca2+ measurement, EF-hand mutagenesis, 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; loss of MICU1 causes constitutive mitochondrial Ca2+ loading, excessive ROS generation, and increased apoptotic sensitivity, without altering MCU kinetic properties. Co-immunoprecipitation, RNAi knockdown, mitochondrial Ca2+ measurement, ROS assay, apoptosis assay Cell High 23101630
2013 MICU1 faces the intermembrane space and controls both the threshold and cooperative (sigmoidal) activation of the mitochondrial Ca2+ uniporter; loss of MICU1 in mouse liver and cultured cells causes Ca2+ accumulation at low cytoplasmic [Ca2+] but an attenuated response to agonist-induced Ca2+ pulses, reflecting loss of positive cooperativity mediated by EF-hands. In vivo RNAi (mouse liver), live-cell Ca2+ imaging, submitochondrial fractionation/protease protection, genetic knockout Cell metabolism High 23747253
2013 MICU1 (CBARA1) and MICU2 reside within the same uniporter complex with MCU; biochemical evidence shows MCU, MICU1, and MICU2 cross-stabilize each other's protein expression in a cell-type-dependent manner, and in vivo silencing of both MICU1 and MICU2 additively impairs Ca2+ handling. Co-immunoprecipitation, Western blot, in vivo RNAi (mouse liver), mitochondrial Ca2+ measurement PloS one High 23409044
2013 MICU1 localizes to the mitochondrial matrix side of the inner membrane; its N-terminal polybasic domain binds to two coiled-coil domains of MCU, and this interaction is required for MICU1 oligomeric binding to MCU and control of mitochondrial Ca2+ current. MICU1 EF-hands regulate MCU channel activity but do not determine MCU binding. Loss of MICU1 promotes MCU activation, oxidative burden, and halts cell migration. Submitochondrial fractionation, domain mutagenesis, Co-IP, Ca2+ current (IMCU) measurement, cell migration assay Cell reports Medium 24332854
2013 Loss-of-function mutations in MICU1 in human patients increase agonist-induced mitochondrial Ca2+ uptake at low cytoplasmic [Ca2+], reduce cytoplasmic Ca2+ signals, and cause severe mitochondrial network fragmentation, establishing that MICU1 is required for normal mitochondrial Ca2+ signaling in humans. Patient fibroblast analysis, mitochondrial Ca2+ imaging, mitochondrial membrane potential measurement, microscopy Nature genetics High 24336167
2014 MICU1 and MICU2 play non-redundant roles: both set the [Ca2+] threshold for uniporter activation. MICU1 or MICU2 KO each eliminate normal Ca2+ uptake threshold. MICU2's activity and physical association with the pore require MICU1 presence, but MICU1 does not require MICU2. EF-hand-dead mutants of either cause striking loss of Ca2+ uptake. CRISPR/Cas9 knockout, Ca2+ uptake assay, Co-immunoprecipitation, EF-hand mutagenesis EMBO reports High 24503055
2014 In MICU1-knockdown cells, mitochondrial Ca2+ uptake rate is increased at low [Ca2+]c (<2 µM) but decreased at high [Ca2+]c (>4 µM), and Ca2+ uptake becomes subject to a slow-developing inhibition at prolonged low micromolar [Ca2+]c. MICU1 thus acts both as a gatekeeper at low [Ca2+]c and as a cofactor needed to reach maximum uptake rate at high [Ca2+]c. shRNA knockdown, real-time mitochondrial Ca2+ measurement with targeted aequorin, Ruthenium Red/Ru360 sensitivity assay The Biochemical journal Medium 24313810
2015 The mitochondrial oxidoreductase Mia40/CHCHD4 introduces an intermolecular disulfide bond linking MICU1 and MICU2 in a heterodimer; absence of this disulfide increases mitochondrial Ca2+ uptake. The MICU1-MICU2 heterodimer associates with MCU at low Ca2+ and dissociates at high Ca2+, providing a Ca2+-dependent remodeling mechanism for uniporter regulation. Mia40 interactome (MS), disulfide bond analysis, Co-IP, Ca2+ uptake assay, mutagenesis Cell metabolism High 26387864
2015 Live-cell FRET experiments show that cytosolic Ca2+ elevation rearranges MICU1 multimers with an EC50 of ~4.4 µM, activating mitochondrial Ca2+ uptake. This rearrangement requires EF-hand motifs and is independent of matrix Ca2+ concentration, mitochondrial membrane potential, and MCU/EMRE expression levels. Live-cell FRET, Ca2+ imaging, EF-hand mutagenesis Scientific reports Medium 26489515
2016 MICU1 deficiency in mice results in altered mitochondrial Ca2+ uptake, increased resting matrix Ca2+, altered mitochondrial morphology, and reduced ATP early in life. Deleting one allele of EMRE in MICU1-/- mice normalizes Ca2+ uptake and rescues perinatal mortality, establishing EMRE as a downstream effector of MICU1-dependent gating. Genetic mouse knockout, EMRE heterozygous cross (epistasis), mitochondrial Ca2+ measurement, ATP assay, electron microscopy Cell reports High 27477272
2016 PRMT1 asymmetrically methylates MICU1, decreasing its Ca2+ sensitivity. UCP2/3 normalize Ca2+ sensitivity of methylated MICU1, re-establishing mitochondrial Ca2+ uptake activity. This defines a post-translational modification pathway controlling uniporter activity. PRMT1 methylation assay, Ca2+ uptake measurement, UCP2/3 co-expression, mutagenesis Nature communications Medium 27642082
2016 MICU1 KO in mice causes perinatally lethal Ca2+ overload-induced mitochondrial permeability transition pore (PTP) opening in hepatocytes; PTP inhibition prevents necrosis and rescues liver regeneration after hepatectomy, establishing that MICU1 gatekeeping of MCU is essential for controlling PTP-dependent cell death under stress. Conditional knockout mouse, partial hepatectomy model, PTP inhibitor treatment, mitochondrial Ca2+ measurement, cell death assays Nature communications High 26956930
2017 The MICU1:MCU protein stoichiometry directly determines tissue-specific uniporter phenotypes: low MICU1:MCU lowers the Ca2+ threshold and activation cooperativity (as in heart/skeletal muscle); overexpressing MICU1 in heart shifts it to a liver-like phenotype with higher threshold and causes cardiac contractile dysfunction. Tissue protein quantification, MICU1 overexpression (adenovirus), Co-IP stoichiometry, mitochondrial Ca2+ uptake, cardiac function measurement Cell reports High 28273446
2017 MICU1 silencing in ovarian cancer activates pyruvate dehydrogenase (PDH) by stimulating the PDH phosphatase–phosphoPDH–PDH axis, increasing oxygen consumption and decreasing aerobic glycolysis; forced MICU1 expression in normal cells phenocopies the metabolic shift to glycolysis seen in cancer cells. siRNA knockdown, PDH activity assay, oxygen consumption measurement, lactate production assay, xenograft tumor model Nature communications Medium 28530221
2017 MICU2 regulates the threshold and gain of MICU1-mediated inhibition and activation of MCU; MICU1 alone can mediate gatekeeping and cooperative activation, while MICU2's fundamental role is to modulate these MICU1 functions, spatially restricting Ca2+ crosstalk between InsP3R and MCU channels. Quantitative cytoplasmic Ca2+ clamping with patch clamp, MICU1/MICU2 knockdown, Ca2+ uptake measurement over wide [Ca2+] range Cell reports Medium 29241542
2018 Parkin (PARK2) E3 ubiquitin ligase interacts with MICU1 and promotes its selective degradation via the ubiquitin proteasome system (UPS); Parkin's Ubl-domain (not its E3 ligase activity) is required for this degradation, reducing MICU1 basal levels and indirectly affecting MICU2 stability. Co-immunoprecipitation, proteasome inhibitor treatment, Parkin domain mutants, Western blot for protein stability Scientific reports Medium 30242232
2018 MICU1 suppresses inhibition of MCU by ruthenium red/Ru360 at MCU's DIME motif. A DIME-interacting domain (DID) in MICU1 is identified that is required for both gatekeeping and cooperative activation of MCU and for cell survival, indicating MICU1 must interact with the D-ring formed by MCU's DIME domains to control the uniporter. Ru360 inhibition assay, MICU1 DID mutagenesis, Co-IP, mitochondrial Ca2+ uptake measurement, cell survival assay Molecular cell High 30454562
2017 Tom70 (mitochondrial import receptor) governs the mitochondrial localization of MICU1; Tom70 deficiency reduces mitochondrial MICU1 levels and worsens Ca2+ overload and myocardial ischemia-reperfusion injury, while MICU1 supplementation rescues Tom70-mediated cardioprotection. siRNA knockdown in vivo (intramyocardial injection), Western blot of mitochondrial fractions, Ca2+ measurement, cardiac function assay Cell death & disease Medium 28703803
2019 The DIME-aspartate of MCU mediates a Ca2+-modulated electrostatic interaction with MICU1, forming a contact interface with a nearby Ser residue; mutagenesis screen identifies two conserved Arg residues in MICU1 that contact DIME-Asp. Disrupting MCU-MICU1 interactions causes unregulated, constitutive Ca2+ flux into mitochondria. Mutagenesis screen, Co-IP, electrophysiology (Ca2+ flux), structural-functional analysis eLife High 30638448
2019 Crystal structure of MICU2 at 2.5 Å resolution reveals a core structure similar to MICU1 with two EF-hand lobes; a symmetric homodimer interface (EF1-EF3) is conserved in both MICU1 and MICU2, enabling exchange between homo- and heterodimers. MICU2's C-terminal helix is dispensable for MICU1 interaction in vitro but required for MICU2 function in cells. X-ray crystallography, in vitro binding assay, C-terminal deletion mutagenesis, cell-based Ca2+ uptake assay PNAS High 30755530
2019 Loss of MICU1 in skeletal muscle (patient cells and muscle-specific KO mice) lowers the MCU-mediated Ca2+ uptake threshold, impairs mitochondrial Ca2+ uptake during excitation-contraction, causes aerobic metabolism impairment, muscle weakness, fatigue, and compromises sarcolemmal repair by reducing mitochondrial Ca2+ uptake at injury sites. Skeletal muscle-specific conditional KO, patient cell analysis, Ca2+ imaging, mitochondrial respiration, sarcolemmal repair assay, grip strength Cell reports High 31665639
2020 Cryo-EM structure of MCU-EMRE-MICU1-MICU2 holocomplex at 3.3 Å shows that a uniporter interaction domain on MICU1 binds a receptor site on MCU and EMRE subunits (analogous to channel block by protein toxins) to inhibit ion flow at resting Ca2+; Ca2+-bound structure at 3.1 Å shows Ca2+-dependent changes in MICU1-MICU2 enabling dynamic response to cytosolic Ca2+ signals. Cryo-EM structure determination (3.3 Å and 3.1 Å), structural comparison of Ca2+-free and Ca2+-bound states eLife High 32667285
2020 Inhibition of glycolysis, mitochondrial pyruvate transport (MPC), or mitochondrial fatty acid transport triggers upregulation of MICU1 protein (but not MCU) via the transcription factor EGR1, resulting in inhibition of MCU-mediated matrix Ca2+ uptake; MPC1 genetic ablation reduces resting matrix Ca2+ through this MICU1-dependent mechanism. MPC isoform knockdown/KO, dominant-negative MPC1 mutant, MICU1 protein quantification, EGR1 transcription factor assay, mitochondrial Ca2+ measurement Science signaling Medium 32317369
2022 Neuron-specific MICU1 KO mice show progressive neurodegeneration with degeneration of motor neurons; MICU1-KO neurons show increased susceptibility to mitochondrial Ca2+ overload-induced excitotoxic cell death, which is prevented by inhibiting the mitochondrial permeability transition pore (mPTP), placing MICU1 upstream of mPTP in neurodegeneration. Neuron-specific conditional KO mouse, electrophysiology, Ca2+ imaging, cell death assay, mPTP inhibitor rescue, patient-derived cell analysis Science advances High 35302860
2023 MICU1 localizes to the mitochondrial contact site and cristae organizing system (MICOS) and directly interacts with MICOS components MIC60 and CHCHD2 independently of the mtCU complex; MICU1 is essential for MICOS complex formation, and its ablation causes altered cristae organization, mitochondrial ultrastructure, membrane dynamics, and cell death signaling independently of matrix Ca2+ uptake. Proteomics (co-fractionation), Co-IP, confocal/EM imaging, MICU1 KO with MICOS component analysis, cell death assay Science signaling High 37098122
2023 MICU1 physically occludes the MCU pore: purified MICU1 strongly suppresses MCU Ca2+ currents in patch-clamp; a K126 mutation in MICU1's MCU-interacting residue abolishes inhibition. MICU1 also prevents MCU-mediated Na+ flux into intact mitochondria under Ca2+-free conditions. MICU1 dissociates from the uniporter complex during mitoplast preparation, explaining why prior patch-clamp studies failed to detect pore blockade. Patch-clamp of purified MCU, membrane depolarization Na+ flux assay, K126 mutagenesis, EMRE quantification, MICU1 KO rescue PNAS High 37036971
2023 MICU1 restricts cation flux through the mtCU in the absence of Ca2+ (divalent-free conditions), as shown by increased Ru265-sensitive Na+ influx in MICU1 KO cells; however, even in WT cells with high MICU1 expression some mtCU lack MICU1-dependent gating, and MICU1 KO causes rearrangement of mtCU and altered number of functional channels. Fluorescence-based mitochondrial matrix [Na+] measurement, mitochondrial swelling/depolarization assay, Ru265 inhibitor, MICU1 KO and stable rescue HEK cells PNAS High 37126688
2023 MICU1 deficiency alters mitochondrial cristae junction structure (through MICOS interaction with Mic60 and CHCHD2), leading to increased cytochrome c release, mitochondrial membrane potential rearrangement, and altered mitochondrial Ca2+ uptake dynamics. MICU1 KO cell analysis, Co-IP (MICU1-Mic60-CHCHD2), cytochrome c release assay, membrane potential measurement, Ca2+ uptake assay Cell calcium Medium 37290367
2018 MICU1 deletion sensitizes human cells to manganese-dependent cell death by disinhibiting MCU-mediated manganese uptake, demonstrating that MICU1's gating function controls uniporter selectivity beyond Ca2+; co-expression of MICU1 with MCU and EMRE in yeast prevents manganese stress, while MICU1 deletion worsens it. Synthetic biology reconstitution in yeast, MICU1 KO human cells, manganese toxicity assay, oxidative stress measurement, evolutionary co-occurrence analysis Cell reports Medium 30403999
2018 FOXD1 directly represses MICU1 expression in human embryonic stem cells (hESCs) and iPSCs; experimentally restoring MICU1 establishes periodic cytoplasmic Ca2+ oscillations and promotes cellular differentiation and maturation, linking MICU1-mediated mitochondrial Ca2+ dynamics to developmental cell differentiation. ChIP, MICU1 overexpression in hESCs/iPSCs, Ca2+ imaging, differentiation marker analysis Nature communications Medium 30158529
2024 MICU1 is present in a complex with MCU in non-failing human hearts; MICU1 deletion in murine cardiomyocytes alters mitochondrial Ca2+ signaling and energy metabolism, and causes compensatory increase in EMRE turnover (early) and MCU turnover (later) that limits mitochondrial Ca2+ uptake and supports cell survival. Co-immunoprecipitation (human heart tissue), cardiac-specific KO mouse, Ca2+ imaging, metabolic measurement, protein turnover analysis PNAS High 39163336
2025 TMBIM5 (mitochondrial Ca2+/proton exchanger) and MICU1 physically coexist in the same macromolecular complex and have opposing effects on submitochondrial localization; partial MICU1 depletion ameliorates Tmbim5-deficiency phenotype in Drosophila, and MICU1 rescues morphological defects in TMBIM5-KO human mitochondria, establishing a functional interplay between TMBIM5 and MICU1. Co-immunoprecipitation, Drosophila genetics (epistasis), MICU1 rescue in TMBIM5 KO cells, mitochondrial morphology imaging Communications biology Medium 40973741
2022 The splicing factor RBFOX2 drives alternative splicing of MICU1 during myogenesis; human skeletal muscle expresses MICU1 splice variants with distinct abilities to regulate mitochondrial Ca2+ uptake. A muscle-specific splice variant (MICU1.1) confers unique properties ensuring sufficient ATP for muscle contraction. RT-PCR splice variant analysis, RBFOX2 knockdown during myogenic differentiation, mitochondrial Ca2+ uptake assay with splice variants International journal of molecular sciences Medium 35269658
2025 SIRT1 directly interacts with MICU1; SIRT1 inhibition reduces MICU1 expression, leading to mitochondrial Ca2+ overload and mitochondrial structural fragmentation. Co-immunoprecipitation, SIRT1 pharmacological inhibition (EX527) and shRNA knockdown, mitochondrial Ca2+ measurement, mitochondrial morphology imaging Life (Basel) Low 40003583

Source papers

Stage 0 corpus · 94 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 733 20693986
2012 MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell 575 23101630
2013 MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²⁺ uniporter. Cell metabolism 415 23747253
2013 MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling. PloS one 394 23409044
2013 Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nature genetics 315 24336167
2016 MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload. Cell reports 198 27477272
2014 MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO reports 189 24503055
2016 MICU1 regulation of mitochondrial Ca(2+) uptake dictates survival and tissue regeneration. Nature communications 177 26956930
2015 The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake. Cell metabolism 169 26387864
2017 Tissue-Specific Mitochondrial Decoding of Cytoplasmic Ca2+ Signals Is Controlled by the Stoichiometry of MICU1/2 and MCU. Cell reports 165 28273446
2017 MICU1 drives glycolysis and chemoresistance in ovarian cancer. Nature communications 143 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 94 28292968
2019 Dysregulation of Mitochondrial Ca2+ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1. Cell reports 86 31665639
2016 Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood. Neurology. Genetics 84 27123478
2017 MICU2 Restricts Spatial Crosstalk between InsP3R and MCU Channels by Regulating Threshold and Gain of MICU1-Mediated Inhibition and Activation of MCU. Cell reports 79 29241542
2016 PRMT1-mediated methylation of MICU1 determines the UCP2/3 dependency of mitochondrial Ca(2+) uptake in immortalized cells. Nature communications 68 27642082
2020 Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity. Science signaling 63 32317369
2019 The conserved aspartate ring of MCU mediates MICU1 binding and regulation in the mitochondrial calcium uniporter complex. eLife 60 30638448
2003 Resistance to enediyne antitumor antibiotics by CalC self-sacrifice. Science (New York, N.Y.) 58 12970566
2020 Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2. eLife 56 32667285
2023 MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca2+ uniporter channel. Science signaling 55 37098122
2017 MICU1 protects against myocardial ischemia/reperfusion injury and its control by the importer receptor Tom70. Cell death & disease 52 28703803
2018 A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients. JIMD reports 49 29721912
2017 Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics. Biochimica et biophysica acta. Molecular cell research 49 28132899
2015 Rearrangement of MICU1 multimers for activation of MCU is solely controlled by cytosolic Ca(2.). Scientific reports 48 26489515
2022 Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients. Science advances 44 35302860
2019 Crystal structure of MICU2 and comparison with MICU1 reveal insights into the uniporter gating mechanism. Proceedings of the National Academy of Sciences of the United States of America 43 30755530
2018 Parkin-dependent regulation of the MCU complex component MICU1. Scientific reports 43 30242232
2020 MicroRNA-195 controls MICU1 expression and tumor growth in ovarian cancer. EMBO reports 40 32851774
2019 MICU1 and MICU2 Play an Essential Role in Mitochondrial Ca2+ Uptake, Growth, and Infectivity of the Human Pathogen Trypanosoma cruzi. mBio 38 31064825
2019 miR-181c Activates Mitochondrial Calcium Uptake by Regulating MICU1 in the Heart. Journal of the American Heart Association 36 31801413
2018 FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation. Nature communications 35 30158529
2015 RPS3 regulates melanoma cell growth and apoptosis by targeting Cyto C/Ca2+/MICU1 dependent mitochondrial signaling. Oncotarget 35 26336993
2022 Perfluorooctane sulfonate induces mitochondrial calcium overload and early hepatic insulin resistance via autophagy/detyrosinated alpha-tubulin-regulated IP3R2-VDAC1-MICU1 interaction. The Science of the total environment 34 35192817
2023 Endothelial MICU1 alleviates diabetic cardiomyopathy by attenuating nitrative stress-mediated cardiac microvascular injury. Cardiovascular diabetology 32 37592255
2014 Dynamics of mitochondrial Ca2+ uptake in MICU1-knockdown cells. The Biochemical journal 32 24313810
2020 Melatonin alleviates angiotensin-II-induced cardiac hypertrophy via activating MICU1 pathway. Aging 31 33259334
2018 MICU1 Confers Protection from MCU-Dependent Manganese Toxicity. Cell reports 30 30403999
2014 The gatekeepers of mitochondrial calcium influx: MICU1 and MICU2. EMBO reports 30 24531720
2021 Molecular pathophysiology of human MICU1 deficiency. Neuropathology and applied neurobiology 28 33428302
2020 Developmental brain abnormalities and acute encephalopathy in a patient with myopathy with extrapyramidal signs secondary to pathogenic variants in MICU1. JIMD reports 27 32395406
2022 MICU1-dependent mitochondrial calcium uptake regulates lung alveolar type 2 cell plasticity and lung regeneration. JCI insight 23 35050901
1988 A third human CALC (pseudo)gene on chromosome 11. FEBS letters 22 2898385
2010 Evaluation of CALC-I gene (CALCA) expression in tissues of dogs with signs of the systemic inflammatory response syndrome. Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001) 21 20955304
2024 MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart. Proceedings of the National Academy of Sciences of the United States of America 19 39163336
2025 Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake. The Journal of clinical investigation 18 40166941
2023 Evidence supporting the MICU1 occlusion mechanism and against the potentiation model in the mitochondrial calcium uniporter complex. Proceedings of the National Academy of Sciences of the United States of America 18 37036971
2023 MICU1 occludes the mitochondrial calcium uniporter in divalent-free conditions. Proceedings of the National Academy of Sciences of the United States of America 16 37126688
2021 Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family. Molecular and cellular pediatrics 16 33969448
2022 Long Noncoding RNA RMRP Contributes to Paclitaxel Sensitivity of Ovarian Cancer by Regulating miR-580-3p/MICU1 Signaling. Journal of oncology 14 35132320
2024 MICU1's calcium sensing beyond mitochondrial calcium uptake. Biochimica et biophysica acta. Molecular cell research 10 38555977
2022 The Splicing of the Mitochondrial Calcium Uniporter Genuine Activator MICU1 Is Driven by RBFOX2 Splicing Factor during Myogenic Differentiation. International journal of molecular sciences 10 35269658
2022 SGPL1 stimulates VPS39 recruitment to the mitochondria in MICU1 deficient cells. Molecular metabolism 10 35452878
2022 Effects of MICU1-Mediated Mitochondrial Calcium Uptake on Energy Metabolism and Quality of Vitrified-Thawed Mouse Metaphase II Oocytes. International journal of molecular sciences 10 35955764
2023 Tianhuang formula regulates adipocyte mitochondrial function by AMPK/MICU1 pathway in HFD/STZ-induced T2DM mice. BMC complementary medicine and therapies 9 37337224
2023 SEPSIS LEADS TO IMPAIRED MITOCHONDRIAL CALCIUM UPTAKE AND SKELETAL MUSCLE WEAKNESS BY REDUCING THE MICU1:MCU PROTEIN RATIO. Shock (Augusta, Ga.) 9 37695737
2023 Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India. Annals of Indian Academy of Neurology 8 37034047
2023 Arvanil induces ferroptosis of hepatocellular carcinoma by binding to MICU1. Cancer gene therapy 7 37985721
2020 The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells. Cells 7 32580385
2018 Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882. Applied and environmental microbiology 7 29654174
2023 MICU1 deficiency alters mitochondrial morphology and cytochrome C release. Cell calcium 6 37290367
2013 CBARA1 plays a role in stemness and proliferation of human embryonic stem cells. PloS one 6 23667653
2024 Compound heterozygous mutation of AFG3L2 causes autosomal recessive spinocerebellar ataxia through mitochondrial impairment and MICU1 mediated Ca2+ overload. Science China. Life sciences 5 39428429
2024 MICU1 alleviates hypobaric hypoxia-induced myocardial injury through regulating Ca2+ uptake to inhibit mitochondria-dependent apoptosis. Cellular signalling 5 39586522
2022 MICU1 and MICU2 potentiation of Ca2+ uptake by the mitochondrial Ca2+ uniporter of Trypanosoma cruzi and its inhibition by Mg2. Cell calcium 5 36166935
2022 Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene. Frontiers in neurology 5 36425804
2025 A novel super-resolution STED microscopy analysis approach to observe spatial MCU and MICU1 distribution dynamics in cells. Biochimica et biophysica acta. Molecular cell research 4 39765273
2016 MICU1 may be a promising intervention target for gut-derived sepsis induced by intra-abdominal hypertension. Cell death discovery 4 27924224
1993 A distal region of the CALC-1 gene is necessary for regulated alternative splicing. FEBS letters 4 8508914
2025 Targeting the HDAC6/Hint2/MICU1 axis to ameliorate acute liver failure via inhibiting NETosis. Life sciences 3 39983829
2025 Sirtuin-1 Regulates Mitochondrial Calcium Uptake Through Mitochondrial Calcium Uptake 1 (MICU1). Life (Basel, Switzerland) 3 40003583
1991 Hybridohistochemical demonstration of alternative splicing of the CALC-I gene. The American journal of pathology 3 1704187
1989 Evolutionary pathways of the calcitonin (CALC) genes. Henry Ford Hospital medical journal 3 2639135
2025 MICU1 is the nexus for CaV3.3 regulation of mitochondrial calcium, redox balance and chondrocyte viability. International journal of biological macromolecules 2 40354861
2025 MICU1 attenuates neuronal apoptosis after subarachnoid hemorrhage by inhibiting mitochondrial calcium overload and damage. Cell calcium 2 40974956
2000 Molecular analysis and chromosomal assignment of the canine CALC-I/alpha-CGRP gene. Mammalian genome : official journal of the International Mammalian Genome Society 2 10967131
2025 Interaction of the mitochondrial calcium/proton exchanger TMBIM5 with MICU1. Communications biology 1 40973741
2025 A systemic immunogenic reactor leveraging modified γ-cyclodextrins for photo-controlled cancer Ca2+ interference via modulating MICU1. Acta pharmaceutica Sinica. B 1 41685149
2024 Dolichocephaly, Arachnodactyly, Diplopia, and Distal Myopathy - Novel Phenotype of MICU1 Variant c.553C>T. Cureus 1 38380193
2024 MICU1 related myopathy - a rare report from India. Journal of neuromuscular diseases 1 39973469
2026 Functional specialization of Ca2+-binding motifs in human MICU1. International journal of biological macromolecules 0 41638268
2026 Novel strategies for mitigating hepatic ischemia-reperfusion injury: targeting MICU1 and calcium-glycolytic homeostasis with acteoside. International journal of biological sciences 0 42088421
2026 MICU1 deficiency exacerbates cisplatin-induced acute kidney injury by tubular apoptosis and mitochondrial dysfunction. Free radical biology & medicine 0 42155615
2026 Deterioration of Liver Fibrosis by ALR Deficiency is associated with reducing MICU1/2 Heterodimerization and Mitochondrial Ca2+ imbalance in Hepatic Stellate Cell. Free radical biology & medicine 0 42242597
2025 HRP2 regulating MICU1-mediated Ca2+ overload to dictate chemoresistance of multiple myeloma. Neoplasia (New York, N.Y.) 0 40058268
2025 Compound heterozygous mutations in MICU1 cause myopathy with extrapyramidal signs in two Chinese pedigrees. Frontiers in neurology 0 41018190
2025 Mitochondrial calcium uptake 1 (micu1) knockout ameliorates cold-induced cell death and inflammatory response by mediating mitochondrial homeostasis in fish. Journal of thermal biology 0 41205365
2025 MICU1 promotes Ca2+ homeostasis and curbs ferroptosis to attenuate brain tissue damage in rats with postoperative cognitive dysfunction. Brain research 0 41349812
2021 MICU1 opens the gates to cold-induced death. Cell calcium 0 34343855
2019 Identification of a Novel Variant Form of Aspergillus fumigatus CalC and Generation of Anti-CalC Monoclonal Antibodies. Medical mycology journal 0 30814465

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