EF-hand calcium-binding protein of the mitochondrial intermembrane space and the principal regulatory subunit of the mitochondrial calcium uniporter. MICU1 sits on the intermembrane-space face of the inner membrane, peripherally associated with the MCU/EMRE pore, and forms disulfide-linked heterodimers with MICU2 or MICU3 (and, in skeletal muscle and kidney, MICU1-MICU1 homodimers). Binding of Ca2+ to the EF-hands of the dimer, with high affinity and strong cooperativity, switches the uniporter between a closed and an open state: below the threshold MICU1 occludes the pore and prevents constitutive Ca2+ leak into the matrix, and above it MICU1 stimulates flux, so that mitochondria respond to cytosolic Ca2+ transients rather than to resting Ca2+. Loss of MICU1 causes constitutive matrix Ca2+ loading, excess reactive oxygen species and sensitisation to apoptotic stress, and in humans causes a myopathy with learning difficulties and extrapyramidal signs. Whether the low-Ca2+ state reflects physical pore occlusion or allosteric potentiation of MCU was disputed, with recent patch-clamp and divalent-free flux measurements favouring occlusion. MICU1 also has functions that do not require the uniporter: it localises to the inner boundary membrane and cristae junctions, interacts with MIC60 and CHCHD2, and is required for MICOS complex assembly and normal cristae architecture, and Micu1-null lethality is not rescued by removing MCU or EMRE. A further uniporter-independent role has been proposed, in which Ca2+-dependent MICU heterodimers scaffold a metabolon coupling glycerol-3-phosphate dehydrogenase to succinate dehydrogenase/complex II; this is a recent single-laboratory claim and is not yet independently corroborated.
Definition: A molecular function in which a calcium-sensing, non-catalytic protein promotes assembly of a supramolecular complex of FADH2-linked dehydrogenases in response to calcium binding, thereby modulating their coupled activity. Proposed to capture the reported MICU-dependent coupling of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) to succinate dehydrogenase/complex II. Recorded as a candidate only: the underlying claim rests on a single study (PMID:42129466) and should not be implemented in the ontology until it is independently replicated.
Justification: No existing GO term captures calcium-dependent scaffolding of a dehydrogenase metabolon by a non-catalytic EF-hand subunit. If the finding replicates, both a molecular function term of this kind and a cellular component term for the GPD2/succinate dehydrogenase metabolon itself will be needed.
Parent term: molecular_function
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0036444 calcium import into the mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: MICU1 binds Ca2+ through its two canonical EF-hands; this is the sensing event that underlies all of its regulatory activity. Reason: Core molecular function. Directly measured: the Ca2+-free and Ca2+-bound crystal structures were solved and an affinity of ~15-20 uM determined, and the EF-hands are required for activity. |
| GO:0051560 mitochondrial calcium ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: Loss of MICU1 causes constitutive mitochondrial Ca2+ loading; MICU1 maintains resting matrix Ca2+. Reason: Core biological process and the phenotype that defines the gene. Note that this is homeostasis of matrix Ca2+ achieved by gating at the inner membrane, not by MICU1 buffering Ca2+ itself. |
| GO:1990246 uniplex complex | IBA GO_REF:0000033 | ACCEPT | Summary: MICU1 is a constitutive subunit of the mitochondrial calcium uniporter holocomplex (uniplex) together with MCU, EMRE and MICU2/MICU3. Reason: Core complex membership, established by biochemistry and by multiple independent cryo-EM structures of the intact human holocomplex. Still current: work published after the 2026 metabolon proposal continues to describe MICU1 as a gatekeeping subunit of this complex. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: MICU1 binds Ca2+ through its two canonical EF-hands; this is the sensing event that underlies all of its regulatory activity. Reason: Core molecular function. Directly measured: the Ca2+-free and Ca2+-bound crystal structures were solved and an affinity of ~15-20 uM determined, and the EF-hands are required for activity. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000120 | ACCEPT | Summary: The Ca2+-sensing EF-hand domains of MICU1 face the intermembrane space. Reason: Core location and the mechanistically important one: MICU1 reports intermembrane-space (effectively cytosolic) Ca2+, not matrix Ca2+. This topology is what makes MCU-independent MICU1 functions possible at all. |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: MICU1 participates in Ca2+ transport across the inner mitochondrial membrane as the regulatory subunit of the uniporter. Reason: Core biological process. MICU1 does not itself conduct Ca2+ - MCU is the pore - but it is a constitutive part of the transporting complex and sets the conditions under which transport occurs, so involved_in is the right relation. |
| GO:0005515 protein binding | IPI PMID:21685886 Integrative genomics identifies MCU as an essential componen... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:23101630 MICU1 is an essential gatekeeper for MCU-mediated mitochondr... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:23178883 MCUR1 is an essential component of mitochondrial Ca2+ uptake... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:26387864 The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:32494073 Structure and mechanism of the mitochondrial Ca(2+) uniporte... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0042802 identical protein binding | IPI PMID:24514027 Structural and mechanistic insights into MICU1 regulation of... | KEEP AS NON CORE | Summary: MICU1 self-association; MICU1-MICU1 homodimers are a genuine, tissue-restricted species of the uniporter. Reason: Real rather than artefactual - skeletal-muscle and kidney uniporters carry a MICU1-MICU1 homodimer - but "identical protein binding" is a low-information term, and the physiologically dominant and mechanistically characterised species is the MICU1-MICU2 heterodimer covered by GO:0046982. Supporting Evidence: PMID:24514027 Our studies reveal that Ca(2+)-free MICU1 forms a hexamer that binds and inhibits MCU. |
| GO:0034704 calcium channel complex | IEA GO_REF:0000120 | MODIFY | Summary: Generic calcium channel complex membership inferred electronically and by orthology. Reason: Correct in kind but under-specific. The complex MICU1 belongs to is named and has its own term - the uniplex (GO:1990246) - which the gene already carries with six IDA annotations. Proposed replacements: uniplex complex |
| GO:0036444 calcium import into the mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0046982 protein heterodimerization activity | IEA GO_REF:0000120 | ACCEPT | Summary: MICU1 forms disulfide-linked heterodimers with MICU2 and with MICU3; the heterodimer, not the monomer, is the Ca2+-sensing gating unit. Reason: Core molecular function and unusually well characterised for a dimerisation term - the heterodimer has been reconstituted, its cooperative Ca2+ affinity measured, its structure solved by several groups, and the intersubunit disulfide shown to protect it from YME1L1 proteolysis. Unlike bare protein binding, this term is mechanistically informative and is retained as core. |
| GO:0061891 calcium ion sensor activity | IEA GO_REF:0000120 | ACCEPT | Summary: MICU1 is the Ca2+ sensor of the uniporter, converting intermembrane-space Ca2+ binding into a change in channel state. Reason: Core molecular function, and the most informative single MF term on the gene: it names the sensing role rather than just the binding. Supported by reconstitution of cooperative high-affinity Ca2+ binding matching the measured threshold for uniporter disinhibition, and by structures of the holocomplex in Ca2+-free and Ca2+-bound states. The 2026 metabolon work (PMID:42129466) reinforces rather than undermines this term - it argues that MICU1 sensing acts on additional targets beyond MCU. |
| GO:1903852 positive regulation of cristae formation | IEA GO_REF:0000120 | ACCEPT | Summary: MICU1 is required for MICOS complex formation and normal cristae architecture, and does this independently of the uniporter. Reason: Accepted as a genuine second function. Two independent groups converge: MICU1 stabilises cristae junctions from the inner boundary membrane, and MICU1 interacts with MIC60 and CHCHD2 and is essential for MICOS assembly with the authors stating explicitly that this is independent of matrix Ca2+ uptake. This is the best-established MCU-independent role of MICU1 and it long predates the 2026 metabolon proposal. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: MICU1 is a mitochondrial protein. Reason: Correct, but less informative than the mitochondrial intermembrane space (GO:0005758) and mitochondrial inner membrane (GO:0005743) annotations the gene also carries, which locate it on the IMS face of the inner membrane where its EF-hands sense Ca2+. |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005743 mitochondrial inner membrane | EXP PMID:23747253 MICU1 controls both the threshold and cooperative activation... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005743 mitochondrial inner membrane | EXP PMID:24231807 EMRE is an essential component of the mitochondrial calcium ... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005743 mitochondrial inner membrane | EXP PMID:26387864 The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005758 mitochondrial intermembrane space | ISS GO_REF:0000024 | ACCEPT | Summary: The Ca2+-sensing EF-hand domains of MICU1 face the intermembrane space. Reason: Core location and the mechanistically important one: MICU1 reports intermembrane-space (effectively cytosolic) Ca2+, not matrix Ca2+. This topology is what makes MCU-independent MICU1 functions possible at all. |
| GO:0005758 mitochondrial intermembrane space | EXP PMID:23747253 MICU1 controls both the threshold and cooperative activation... | ACCEPT | Summary: The Ca2+-sensing EF-hand domains of MICU1 face the intermembrane space. Reason: Core location and the mechanistically important one: MICU1 reports intermembrane-space (effectively cytosolic) Ca2+, not matrix Ca2+. This topology is what makes MCU-independent MICU1 functions possible at all. |
| GO:0005758 mitochondrial intermembrane space | EXP PMID:26387864 The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU... | ACCEPT | Summary: The Ca2+-sensing EF-hand domains of MICU1 face the intermembrane space. Reason: Core location and the mechanistically important one: MICU1 reports intermembrane-space (effectively cytosolic) Ca2+, not matrix Ca2+. This topology is what makes MCU-independent MICU1 functions possible at all. Supporting Evidence: PMID:26387864 The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake. |
| GO:0005743 mitochondrial inner membrane | NAS PMID:24514027 Structural and mechanistic insights into MICU1 regulation of... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005743 mitochondrial inner membrane | NAS PMID:31533452 MCUB Regulates the Molecular Composition of the Mitochondria... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005743 mitochondrial inner membrane | NAS PMID:31862210 Molecular Tuning of the Axonal Mitochondrial Ca(2+) Uniporte... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:32494073 Structure and mechanism of the mitochondrial Ca(2+) uniporte... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. Supporting Evidence: PMID:32494073 Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca2+-activated states. |
| GO:0036444 calcium import into the mitochondrion | NAS PMID:24514027 Structural and mechanistic insights into MICU1 regulation of... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0036444 calcium import into the mitochondrion | NAS PMID:31533452 MCUB Regulates the Molecular Composition of the Mitochondria... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0036444 calcium import into the mitochondrion | NAS PMID:31862210 Molecular Tuning of the Axonal Mitochondrial Ca(2+) Uniporte... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:32494073 Structure and mechanism of the mitochondrial Ca(2+) uniporte... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. Supporting Evidence: PMID:32494073 These structures define the architecture of this multicomponent Ca2+-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. |
| GO:0051560 mitochondrial calcium ion homeostasis | NAS PMID:24514027 Structural and mechanistic insights into MICU1 regulation of... | ACCEPT | Summary: Loss of MICU1 causes constitutive mitochondrial Ca2+ loading; MICU1 maintains resting matrix Ca2+. Reason: Core biological process and the phenotype that defines the gene. Note that this is homeostasis of matrix Ca2+ achieved by gating at the inner membrane, not by MICU1 buffering Ca2+ itself. |
| GO:0051560 mitochondrial calcium ion homeostasis | NAS PMID:31533452 MCUB Regulates the Molecular Composition of the Mitochondria... | ACCEPT | Summary: Loss of MICU1 causes constitutive mitochondrial Ca2+ loading; MICU1 maintains resting matrix Ca2+. Reason: Core biological process and the phenotype that defines the gene. Note that this is homeostasis of matrix Ca2+ achieved by gating at the inner membrane, not by MICU1 buffering Ca2+ itself. |
| GO:0051560 mitochondrial calcium ion homeostasis | NAS PMID:31862210 Molecular Tuning of the Axonal Mitochondrial Ca(2+) Uniporte... | ACCEPT | Summary: Loss of MICU1 causes constitutive mitochondrial Ca2+ loading; MICU1 maintains resting matrix Ca2+. Reason: Core biological process and the phenotype that defines the gene. Note that this is homeostasis of matrix Ca2+ achieved by gating at the inner membrane, not by MICU1 buffering Ca2+ itself. |
| GO:0051560 mitochondrial calcium ion homeostasis | IDA PMID:32494073 Structure and mechanism of the mitochondrial Ca(2+) uniporte... | ACCEPT | Summary: Loss of MICU1 causes constitutive mitochondrial Ca2+ loading; MICU1 maintains resting matrix Ca2+. Reason: Core biological process and the phenotype that defines the gene. Note that this is homeostasis of matrix Ca2+ achieved by gating at the inner membrane, not by MICU1 buffering Ca2+ itself. |
| GO:1990246 uniplex complex | NAS PMID:31533452 MCUB Regulates the Molecular Composition of the Mitochondria... | ACCEPT | Summary: MICU1 is a constitutive subunit of the mitochondrial calcium uniporter holocomplex (uniplex) together with MCU, EMRE and MICU2/MICU3. Reason: Core complex membership, established by biochemistry and by multiple independent cryo-EM structures of the intact human holocomplex. Still current: work published after the 2026 metabolon proposal continues to describe MICU1 as a gatekeeping subunit of this complex. |
| GO:1990246 uniplex complex | IPI PMID:32494073 Structure and mechanism of the mitochondrial Ca(2+) uniporte... | ACCEPT | Summary: MICU1 is a constitutive subunit of the mitochondrial calcium uniporter holocomplex (uniplex) together with MCU, EMRE and MICU2/MICU3. Reason: Core complex membership, established by biochemistry and by multiple independent cryo-EM structures of the intact human holocomplex. Still current: work published after the 2026 metabolon proposal continues to describe MICU1 as a gatekeeping subunit of this complex. Supporting Evidence: PMID:32494073 Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca2+-activated states. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: MICU1 is a mitochondrial protein. Reason: Correct, but less informative than the mitochondrial intermembrane space (GO:0005758) and mitochondrial inner membrane (GO:0005743) annotations the gene also carries, which locate it on the IMS face of the inner membrane where its EF-hands sense Ca2+. |
| GO:0005515 protein binding | IPI PMID:27642082 PRMT1-mediated methylation of MICU1 determines the UCP2/3 de... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005739 mitochondrion | IDA PMID:27642082 PRMT1-mediated methylation of MICU1 determines the UCP2/3 de... | ACCEPT | Summary: MICU1 is a mitochondrial protein. Reason: Correct, but less informative than the mitochondrial intermembrane space (GO:0005758) and mitochondrial inner membrane (GO:0005743) annotations the gene also carries, which locate it on the IMS face of the inner membrane where its EF-hands sense Ca2+. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:27642082 PRMT1-mediated methylation of MICU1 determines the UCP2/3 de... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0044284 mitochondrial crista junction | IDA PMID:31427612 MICU1 controls cristae junction and spatially anchors mitoch... | ACCEPT | Summary: MICU1 is enriched at the inner boundary membrane and at cristae junctions, where it stabilises junction architecture. Reason: Specific, experimentally determined localisation by structured illumination microscopy, and functionally consequential: this positioning is what spatially anchors the uniporter complex. Supporting Evidence: PMID:31427612 Our data show that MICU1 localizes at the inner boundary membrane (IBM) due to electrostatic interaction of its polybasic domain. PMID:31427612 Eventually, our findings unveil an essential function of MICU1 in CJ stabilization and provide mechanistic insights of how sophistically MICU1 controls the MCU-Complex while maintaining the structural mitochondrial membrane framework. |
| GO:0061891 calcium ion sensor activity | IDA PMID:27642082 PRMT1-mediated methylation of MICU1 determines the UCP2/3 de... | ACCEPT | Summary: MICU1 is the Ca2+ sensor of the uniporter, converting intermembrane-space Ca2+ binding into a change in channel state. Reason: Core molecular function, and the most informative single MF term on the gene: it names the sensing role rather than just the binding. Supported by reconstitution of cooperative high-affinity Ca2+ binding matching the measured threshold for uniporter disinhibition, and by structures of the holocomplex in Ca2+-free and Ca2+-bound states. The 2026 metabolon work (PMID:42129466) reinforces rather than undermines this term - it argues that MICU1 sensing acts on additional targets beyond MCU. |
| GO:1903852 positive regulation of cristae formation | IDA PMID:31427612 MICU1 controls cristae junction and spatially anchors mitoch... | ACCEPT | Summary: MICU1 is required for MICOS complex formation and normal cristae architecture, and does this independently of the uniporter. Reason: Accepted as a genuine second function. Two independent groups converge: MICU1 stabilises cristae junctions from the inner boundary membrane, and MICU1 interacts with MIC60 and CHCHD2 and is essential for MICOS assembly with the authors stating explicitly that this is independent of matrix Ca2+ uptake. This is the best-established MCU-independent role of MICU1 and it long predates the 2026 metabolon proposal. Supporting Evidence: PMID:31427612 Eventually, our findings unveil an essential function of MICU1 in CJ stabilization and provide mechanistic insights of how sophistically MICU1 controls the MCU-Complex while maintaining the structural mitochondrial membrane framework. |
| GO:1903852 positive regulation of cristae formation | IDA PMID:37098122 MICU1 regulates mitochondrial cristae structure and function... | ACCEPT | Summary: MICU1 is required for MICOS complex formation and normal cristae architecture, and does this independently of the uniporter. Reason: Accepted as a genuine second function. Two independent groups converge: MICU1 stabilises cristae junctions from the inner boundary membrane, and MICU1 interacts with MIC60 and CHCHD2 and is essential for MICOS assembly with the authors stating explicitly that this is independent of matrix Ca2+ uptake. This is the best-established MCU-independent role of MICU1 and it long predates the 2026 metabolon proposal. Supporting Evidence: PMID:37098122 We demonstrated that MICU1 was essential for MICOS complex formation and that MICU1 ablation resulted in altered cristae organization, mitochondrial ultrastructure, mitochondrial membrane dynamics, and cell death signaling. PMID:37098122 Together, our results suggest that MICU1 is an intermembrane space Ca2+ sensor that modulates mitochondrial membrane dynamics independently of matrix Ca2+ uptake. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:36206740 Mechanisms and significance of tissue-specific MICU regulati... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. Supporting Evidence: PMID:36206740 Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. |
| GO:0046982 protein heterodimerization activity | IPI PMID:29725115 MICU3 is a tissue-specific enhancer of mitochondrial calcium... | ACCEPT | Summary: MICU1 forms disulfide-linked heterodimers with MICU2 and with MICU3; the heterodimer, not the monomer, is the Ca2+-sensing gating unit. Reason: Core molecular function and unusually well characterised for a dimerisation term - the heterodimer has been reconstituted, its cooperative Ca2+ affinity measured, its structure solved by several groups, and the intersubunit disulfide shown to protect it from YME1L1 proteolysis. Unlike bare protein binding, this term is mechanistically informative and is retained as core. |
| GO:0071277 cellular response to calcium ion | IDA PMID:32494073 Structure and mechanism of the mitochondrial Ca(2+) uniporte... | KEEP AS NON CORE | Summary: Generic cellular response to Ca2+, taken from the holocomplex structural study. Reason: Defensible - MICU1 does change conformation in response to Ca2+ - but so general that it adds nothing beyond the calcium ion sensor activity and calcium ion binding annotations. Retained as contextual. |
| GO:0005743 mitochondrial inner membrane | IDA PMID:28615291 High-affinity cooperative Ca(2+) binding by MICU1-MICU2 serv... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:28615291 High-affinity cooperative Ca(2+) binding by MICU1-MICU2 serv... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. Supporting Evidence: PMID:28615291 We conclude that cooperative, high-affinity interaction of the MICU1-MICU2 complex with Ca2+ serves as an on-off switch, leading to a tightly controlled channel, capable of responding directly to cytosolic Ca2+ signals. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:32148862 Structure of the MICU1-MICU2 heterodimer provides insights i... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:32790952 The structure of the MICU1-MICU2 complex unveils the regulat... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0046982 protein heterodimerization activity | IPI PMID:28615291 High-affinity cooperative Ca(2+) binding by MICU1-MICU2 serv... | ACCEPT | Summary: MICU1 forms disulfide-linked heterodimers with MICU2 and with MICU3; the heterodimer, not the monomer, is the Ca2+-sensing gating unit. Reason: Core molecular function and unusually well characterised for a dimerisation term - the heterodimer has been reconstituted, its cooperative Ca2+ affinity measured, its structure solved by several groups, and the intersubunit disulfide shown to protect it from YME1L1 proteolysis. Unlike bare protein binding, this term is mechanistically informative and is retained as core. Supporting Evidence: PMID:28615291 We reconstitute the MICU1-MICU2 heterodimer and demonstrate that it binds Ca2+ cooperatively with high affinity. PMID:28615291 We conclude that cooperative, high-affinity interaction of the MICU1-MICU2 complex with Ca2+ serves as an on-off switch, leading to a tightly controlled channel, capable of responding directly to cytosolic Ca2+ signals. |
| GO:0046982 protein heterodimerization activity | IPI PMID:30699349 Dimerization of MICU Proteins Controls Ca(2+) Influx through... | ACCEPT | Summary: MICU1 forms disulfide-linked heterodimers with MICU2 and with MICU3; the heterodimer, not the monomer, is the Ca2+-sensing gating unit. Reason: Core molecular function and unusually well characterised for a dimerisation term - the heterodimer has been reconstituted, its cooperative Ca2+ affinity measured, its structure solved by several groups, and the intersubunit disulfide shown to protect it from YME1L1 proteolysis. Unlike bare protein binding, this term is mechanistically informative and is retained as core. |
| GO:0046982 protein heterodimerization activity | IPI PMID:32148862 Structure of the MICU1-MICU2 heterodimer provides insights i... | ACCEPT | Summary: MICU1 forms disulfide-linked heterodimers with MICU2 and with MICU3; the heterodimer, not the monomer, is the Ca2+-sensing gating unit. Reason: Core molecular function and unusually well characterised for a dimerisation term - the heterodimer has been reconstituted, its cooperative Ca2+ affinity measured, its structure solved by several groups, and the intersubunit disulfide shown to protect it from YME1L1 proteolysis. Unlike bare protein binding, this term is mechanistically informative and is retained as core. |
| GO:0046982 protein heterodimerization activity | IPI PMID:32790952 The structure of the MICU1-MICU2 complex unveils the regulat... | ACCEPT | Summary: MICU1 forms disulfide-linked heterodimers with MICU2 and with MICU3; the heterodimer, not the monomer, is the Ca2+-sensing gating unit. Reason: Core molecular function and unusually well characterised for a dimerisation term - the heterodimer has been reconstituted, its cooperative Ca2+ affinity measured, its structure solved by several groups, and the intersubunit disulfide shown to protect it from YME1L1 proteolysis. Unlike bare protein binding, this term is mechanistically informative and is retained as core. |
| GO:0061891 calcium ion sensor activity | IDA PMID:28615291 High-affinity cooperative Ca(2+) binding by MICU1-MICU2 serv... | ACCEPT | Summary: MICU1 is the Ca2+ sensor of the uniporter, converting intermembrane-space Ca2+ binding into a change in channel state. Reason: Core molecular function, and the most informative single MF term on the gene: it names the sensing role rather than just the binding. Supported by reconstitution of cooperative high-affinity Ca2+ binding matching the measured threshold for uniporter disinhibition, and by structures of the holocomplex in Ca2+-free and Ca2+-bound states. The 2026 metabolon work (PMID:42129466) reinforces rather than undermines this term - it argues that MICU1 sensing acts on additional targets beyond MCU. Supporting Evidence: PMID:28615291 We conclude that cooperative, high-affinity interaction of the MICU1-MICU2 complex with Ca2+ serves as an on-off switch, leading to a tightly controlled channel, capable of responding directly to cytosolic Ca2+ signals. |
| GO:0061891 calcium ion sensor activity | IDA PMID:32148862 Structure of the MICU1-MICU2 heterodimer provides insights i... | ACCEPT | Summary: MICU1 is the Ca2+ sensor of the uniporter, converting intermembrane-space Ca2+ binding into a change in channel state. Reason: Core molecular function, and the most informative single MF term on the gene: it names the sensing role rather than just the binding. Supported by reconstitution of cooperative high-affinity Ca2+ binding matching the measured threshold for uniporter disinhibition, and by structures of the holocomplex in Ca2+-free and Ca2+-bound states. The 2026 metabolon work (PMID:42129466) reinforces rather than undermines this term - it argues that MICU1 sensing acts on additional targets beyond MCU. |
| GO:0061891 calcium ion sensor activity | IDA PMID:32790952 The structure of the MICU1-MICU2 complex unveils the regulat... | ACCEPT | Summary: MICU1 is the Ca2+ sensor of the uniporter, converting intermembrane-space Ca2+ binding into a change in channel state. Reason: Core molecular function, and the most informative single MF term on the gene: it names the sensing role rather than just the binding. Supported by reconstitution of cooperative high-affinity Ca2+ binding matching the measured threshold for uniporter disinhibition, and by structures of the holocomplex in Ca2+-free and Ca2+-bound states. The 2026 metabolon work (PMID:42129466) reinforces rather than undermines this term - it argues that MICU1 sensing acts on additional targets beyond MCU. |
| GO:0005515 protein binding | IPI PMID:30454562 MICU1 Interacts with the D-Ring of the MCU Pore to Control I... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:30638448 The conserved aspartate ring of MCU mediates MICU1 binding a... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0019855 calcium channel inhibitor activity | IDA PMID:32494073 Structure and mechanism of the mitochondrial Ca(2+) uniporte... | ACCEPT | Summary: MICU1 inhibits Ca2+ flux through MCU when its EF-hands are unoccupied, physically occluding the pore. Reason: Core molecular function. This term sits at the centre of a genuine, still-live dispute that GOA already carries on both sides: structural and biochemical work says MICU1 blocks the pore, while mitoplast patch-clamp work argued it instead potentiates MCU allosterically. Two independent 2023 studies addressed the clash directly and support occlusion - purified MICU1 suppresses MCU currents in patch-clamp in a K126-dependent manner, and MICU1 restricts cation flux through the mtCU in divalent-free conditions. The second of these also reports that some mtCU in cells appear to lack MICU1-dependent gating, so the inhibition is not absolute. Accepted as core, with the caveat recorded. The 2026 metabolon paper (PMID:42129466) proposes that the physiologically dominant role of MICU proteins is MCU-independent scaffolding of a Ca2+-sensitive GPD2/SDH metabolon. That claim does not retract the gatekeeper function - the same paper states that MICU1 is the primary regulator of mtCU-mediated uptake - and it is a single-laboratory result with no independent replication and no published rebuttal, so it is recorded rather than acted on here. Supporting Evidence: PMID:32494073 These structures define the architecture of this multicomponent Ca2+-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. |
| GO:0019855 calcium channel inhibitor activity | IDA PMID:37036971 Evidence supporting the MICU1 occlusion mechanism and agains... | ACCEPT | Summary: MICU1 inhibits Ca2+ flux through MCU when its EF-hands are unoccupied, physically occluding the pore. Reason: Core molecular function. This term sits at the centre of a genuine, still-live dispute that GOA already carries on both sides: structural and biochemical work says MICU1 blocks the pore, while mitoplast patch-clamp work argued it instead potentiates MCU allosterically. Two independent 2023 studies addressed the clash directly and support occlusion - purified MICU1 suppresses MCU currents in patch-clamp in a K126-dependent manner, and MICU1 restricts cation flux through the mtCU in divalent-free conditions. The second of these also reports that some mtCU in cells appear to lack MICU1-dependent gating, so the inhibition is not absolute. Accepted as core, with the caveat recorded. The 2026 metabolon paper (PMID:42129466) proposes that the physiologically dominant role of MICU proteins is MCU-independent scaffolding of a Ca2+-sensitive GPD2/SDH metabolon. That claim does not retract the gatekeeper function - the same paper states that MICU1 is the primary regulator of mtCU-mediated uptake - and it is a single-laboratory result with no independent replication and no published rebuttal, so it is recorded rather than acted on here. Supporting Evidence: PMID:37036971 Structural and biochemical studies have suggested that MICU1 gates MCU by blocking/unblocking the pore. However, mitoplast patch-clamp experiments argue that MICU1 does not block, but instead potentiates MCU via allosteric mechanisms. PMID:37036971 Supporting the MICU1-occlusion mechanism, patch-clamp demonstrates that purified MICU1 strongly suppresses MCU Ca2+ currents, and this inhibition is abolished by mutating the MCU-interacting K126 residue. |
| GO:0019855 calcium channel inhibitor activity | IDA PMID:37126688 MICU1 occludes the mitochondrial calcium uniporter in divale... | ACCEPT | Summary: MICU1 inhibits Ca2+ flux through MCU when its EF-hands are unoccupied, physically occluding the pore. Reason: Core molecular function. This term sits at the centre of a genuine, still-live dispute that GOA already carries on both sides: structural and biochemical work says MICU1 blocks the pore, while mitoplast patch-clamp work argued it instead potentiates MCU allosterically. Two independent 2023 studies addressed the clash directly and support occlusion - purified MICU1 suppresses MCU currents in patch-clamp in a K126-dependent manner, and MICU1 restricts cation flux through the mtCU in divalent-free conditions. The second of these also reports that some mtCU in cells appear to lack MICU1-dependent gating, so the inhibition is not absolute. Accepted as core, with the caveat recorded. The 2026 metabolon paper (PMID:42129466) proposes that the physiologically dominant role of MICU proteins is MCU-independent scaffolding of a Ca2+-sensitive GPD2/SDH metabolon. That claim does not retract the gatekeeper function - the same paper states that MICU1 is the primary regulator of mtCU-mediated uptake - and it is a single-laboratory result with no independent replication and no published rebuttal, so it is recorded rather than acted on here. Supporting Evidence: PMID:37126688 Thus, MICU1 restricts the cation flux across the mtCU in the absence of Ca2+, but even in cells with high endogenous MICU1 expression such as HEK, some mtCU seem to lack MICU1-dependent gating. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:30638448 The conserved aspartate ring of MCU mediates MICU1 binding a... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:31397067 The crystal structure of MICU2 provides insight into Ca(2+) ... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:32762847 Structural insights into the Ca(2+)-dependent gating of the ... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0061891 calcium ion sensor activity | IDA PMID:32762847 Structural insights into the Ca(2+)-dependent gating of the ... | ACCEPT | Summary: MICU1 is the Ca2+ sensor of the uniporter, converting intermembrane-space Ca2+ binding into a change in channel state. Reason: Core molecular function, and the most informative single MF term on the gene: it names the sensing role rather than just the binding. Supported by reconstitution of cooperative high-affinity Ca2+ binding matching the measured threshold for uniporter disinhibition, and by structures of the holocomplex in Ca2+-free and Ca2+-bound states. The 2026 metabolon work (PMID:42129466) reinforces rather than undermines this term - it argues that MICU1 sensing acts on additional targets beyond MCU. |
| GO:1990246 uniplex complex | IDA PMID:32762847 Structural insights into the Ca(2+)-dependent gating of the ... | ACCEPT | Summary: MICU1 is a constitutive subunit of the mitochondrial calcium uniporter holocomplex (uniplex) together with MCU, EMRE and MICU2/MICU3. Reason: Core complex membership, established by biochemistry and by multiple independent cryo-EM structures of the intact human holocomplex. Still current: work published after the 2026 metabolon proposal continues to describe MICU1 as a gatekeeping subunit of this complex. |
| GO:0036444 calcium import into the mitochondrion | IDA PMID:32667285 Structures reveal gatekeeping of the mitochondrial Ca(2+) un... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0061891 calcium ion sensor activity | IDA PMID:32494073 Structure and mechanism of the mitochondrial Ca(2+) uniporte... | ACCEPT | Summary: MICU1 is the Ca2+ sensor of the uniporter, converting intermembrane-space Ca2+ binding into a change in channel state. Reason: Core molecular function, and the most informative single MF term on the gene: it names the sensing role rather than just the binding. Supported by reconstitution of cooperative high-affinity Ca2+ binding matching the measured threshold for uniporter disinhibition, and by structures of the holocomplex in Ca2+-free and Ca2+-bound states. The 2026 metabolon work (PMID:42129466) reinforces rather than undermines this term - it argues that MICU1 sensing acts on additional targets beyond MCU. Supporting Evidence: PMID:32494073 These structures define the architecture of this multicomponent Ca2+-uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. |
| GO:0061891 calcium ion sensor activity | IDA PMID:32667285 Structures reveal gatekeeping of the mitochondrial Ca(2+) un... | ACCEPT | Summary: MICU1 is the Ca2+ sensor of the uniporter, converting intermembrane-space Ca2+ binding into a change in channel state. Reason: Core molecular function, and the most informative single MF term on the gene: it names the sensing role rather than just the binding. Supported by reconstitution of cooperative high-affinity Ca2+ binding matching the measured threshold for uniporter disinhibition, and by structures of the holocomplex in Ca2+-free and Ca2+-bound states. The 2026 metabolon work (PMID:42129466) reinforces rather than undermines this term - it argues that MICU1 sensing acts on additional targets beyond MCU. Supporting Evidence: PMID:32667285 Structures reveal gatekeeping of the mitochondrial Ca(2+) uniporter by MICU1-MICU2. |
| GO:0072732 cellular response to calcium ion starvation | IDA PMID:32494073 Structure and mechanism of the mitochondrial Ca(2+) uniporte... | MARK AS OVER ANNOTATED | Summary: Cellular response to calcium ion starvation, assigned from the same holocomplex structural study. Reason: This appears to read the Ca2+-free ("inhibited") state of the purified uniporter holocomplex as a cellular response to calcium starvation. A conformational state adopted by a purified complex in a low-Ca2+ buffer is not a cellular response to calcium ion starvation, which implies a deprivation stimulus and a coordinated cellular reaction. The underlying structural observation is sound and is already captured by calcium ion sensor activity and calcium channel inhibitor activity; only the process term over-reaches. Supporting Evidence: PMID:32494073 Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca2+-activated states. |
| GO:1990246 uniplex complex | IDA PMID:32667285 Structures reveal gatekeeping of the mitochondrial Ca(2+) un... | ACCEPT | Summary: MICU1 is a constitutive subunit of the mitochondrial calcium uniporter holocomplex (uniplex) together with MCU, EMRE and MICU2/MICU3. Reason: Core complex membership, established by biochemistry and by multiple independent cryo-EM structures of the intact human holocomplex. Still current: work published after the 2026 metabolon proposal continues to describe MICU1 as a gatekeeping subunit of this complex. Supporting Evidence: PMID:32667285 Structures reveal gatekeeping of the mitochondrial Ca(2+) uniporter by MICU1-MICU2. |
| GO:1990246 uniplex complex | IDA PMID:32862359 Structure of intact human MCU supercomplex with the auxiliar... | ACCEPT | Summary: MICU1 is a constitutive subunit of the mitochondrial calcium uniporter holocomplex (uniplex) together with MCU, EMRE and MICU2/MICU3. Reason: Core complex membership, established by biochemistry and by multiple independent cryo-EM structures of the intact human holocomplex. Still current: work published after the 2026 metabolon proposal continues to describe MICU1 as a gatekeeping subunit of this complex. Supporting Evidence: PMID:32862359 Structure of intact human MCU supercomplex with the auxiliary MICU subunits. |
| GO:0005509 calcium ion binding | TAS PMID:26975899 Identification of EFHD1 as a novel Ca(2+) sensor for mitofla... | ACCEPT | Summary: MICU1 binds Ca2+ through its two canonical EF-hands; this is the sensing event that underlies all of its regulatory activity. Reason: Core molecular function. Directly measured: the Ca2+-free and Ca2+-bound crystal structures were solved and an affinity of ~15-20 uM determined, and the EF-hands are required for activity. |
| GO:0005739 mitochondrion | TAS PMID:26975899 Identification of EFHD1 as a novel Ca(2+) sensor for mitofla... | ACCEPT | Summary: MICU1 is a mitochondrial protein. Reason: Correct, but less informative than the mitochondrial intermembrane space (GO:0005758) and mitochondrial inner membrane (GO:0005743) annotations the gene also carries, which locate it on the IMS face of the inner membrane where its EF-hands sense Ca2+. |
| GO:0051561 positive regulation of mitochondrial calcium ion concentration | IMP PMID:26975899 Identification of EFHD1 as a novel Ca(2+) sensor for mitofla... | ACCEPT | Summary: Above its Ca2+ threshold MICU1 stimulates MCU, raising matrix Ca2+. Reason: Correct for the high-Ca2+ regime. MICU1 is bidirectional - inhibitory below threshold, stimulatory above it - so this term captures only one arm, but that arm is directly demonstrated in purified lipid bilayers and in intact cells. Read together with the calcium channel inhibitor activity annotations it gives the complete picture. |
| GO:1900069 regulation of cellular hyperosmotic salinity response | IMP PMID:26975899 Identification of EFHD1 as a novel Ca(2+) sensor for mitofla... | MARK AS OVER ANNOTATED | Summary: MICU1 emerged as one of five hits in a targeted siRNA screen whose readout was the mitoflash response to hyperosmotic stress. Reason: The experiment is real but the term over-reaches on two counts. The measured phenotype is mitoflash frequency, not an osmotic-stress response programme; and hyperosmotic stress was the stimulus used to evoke mitoflashes rather than a salinity challenge of the kind GO:1900069 describes. The paper is about EFHD1, with MICU1 appearing only as a screen hit. Kept rather than removed because it is an experimental annotation and the underlying observation - that MICU1 modulates a Ca2+-dependent mitochondrial event - is not in doubt. Supporting Evidence: PMID:26975899 In silico analysis and targeted siRNA screening identified four mitoflash activators (MICU1, EFHD1, SLC25A23, SLC25A25) and one mitoflash inhibitor (LETM1) in terms of their ability to modulate mitoflash response to hyperosmotic stress. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-8949178 | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-8953461 | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0005515 protein binding | IPI PMID:24430870 SLC25A23 augments mitochondrial Ca²⁺ uptake, interacts with ... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:27099988 Dual functions of a small regulatory subunit in the mitochon... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005743 mitochondrial inner membrane | IMP PMID:27099988 Dual functions of a small regulatory subunit in the mitochon... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IMP PMID:27099988 Dual functions of a small regulatory subunit in the mitochon... | ACCEPT | Summary: MICU1 participates in Ca2+ transport across the inner mitochondrial membrane as the regulatory subunit of the uniporter. Reason: Core biological process. MICU1 does not itself conduct Ca2+ - MCU is the pore - but it is a constitutive part of the transporting complex and sets the conditions under which transport occurs, so involved_in is the right relation. |
| GO:0036444 calcium import into the mitochondrion | IMP PMID:26903221 Functional roles of MICU1 and MICU2 in mitochondrial Ca(2+) ... | ACCEPT | Summary: MICU1 is required for, and sets the threshold of, Ca2+ import into the mitochondrion. Reason: Core biological process, supported by the original RNAi phenotype and by every subsequent structural and electrophysiological study of the holocomplex. |
| GO:0046982 protein heterodimerization activity | IPI PMID:26387864 The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU... | ACCEPT | Summary: MICU1 forms disulfide-linked heterodimers with MICU2 and with MICU3; the heterodimer, not the monomer, is the Ca2+-sensing gating unit. Reason: Core molecular function and unusually well characterised for a dimerisation term - the heterodimer has been reconstituted, its cooperative Ca2+ affinity measured, its structure solved by several groups, and the intersubunit disulfide shown to protect it from YME1L1 proteolysis. Unlike bare protein binding, this term is mechanistically informative and is retained as core. |
| GO:0051560 mitochondrial calcium ion homeostasis | IMP PMID:26903221 Functional roles of MICU1 and MICU2 in mitochondrial Ca(2+) ... | ACCEPT | Summary: Loss of MICU1 causes constitutive mitochondrial Ca2+ loading; MICU1 maintains resting matrix Ca2+. Reason: Core biological process and the phenotype that defines the gene. Note that this is homeostasis of matrix Ca2+ achieved by gating at the inner membrane, not by MICU1 buffering Ca2+ itself. |
| GO:0051560 mitochondrial calcium ion homeostasis | IMP PMID:27099988 Dual functions of a small regulatory subunit in the mitochon... | ACCEPT | Summary: Loss of MICU1 causes constitutive mitochondrial Ca2+ loading; MICU1 maintains resting matrix Ca2+. Reason: Core biological process and the phenotype that defines the gene. Note that this is homeostasis of matrix Ca2+ achieved by gating at the inner membrane, not by MICU1 buffering Ca2+ itself. |
| GO:0005509 calcium ion binding | IDA PMID:24514027 Structural and mechanistic insights into MICU1 regulation of... | ACCEPT | Summary: MICU1 binds Ca2+ through its two canonical EF-hands; this is the sensing event that underlies all of its regulatory activity. Reason: Core molecular function. Directly measured: the Ca2+-free and Ca2+-bound crystal structures were solved and an affinity of ~15-20 uM determined, and the EF-hands are required for activity. Supporting Evidence: PMID:24514027 In this study, we report the crystal structures of Ca(2+)-free and Ca(2+)-bound human MICU1. PMID:24514027 Furthermore, we demonstrate that the affinity of MICU1 for Ca(2+) is approximately 15-20 |
| GO:0005515 protein binding | IPI PMID:24560927 MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter... | REMOVE | Summary: Bare protein binding recorded from a pairwise interaction experiment. Reason: Carries no functional information. The physiologically meaningful interactions on this gene - with MCU, EMRE, MICU2 and MICU3 - are already captured by the uniplex complex (GO:1990246) and protein heterodimerization activity (GO:0046982) annotations, which say what the binding accomplishes. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:24560927 MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter... | ACCEPT | Summary: The Ca2+-sensing EF-hand domains of MICU1 face the intermembrane space. Reason: Core location and the mechanistically important one: MICU1 reports intermembrane-space (effectively cytosolic) Ca2+, not matrix Ca2+. This topology is what makes MCU-independent MICU1 functions possible at all. |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IDA PMID:24560927 MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter... | ACCEPT | Summary: MICU1 participates in Ca2+ transport across the inner mitochondrial membrane as the regulatory subunit of the uniporter. Reason: Core biological process. MICU1 does not itself conduct Ca2+ - MCU is the pore - but it is a constitutive part of the transporting complex and sets the conditions under which transport occurs, so involved_in is the right relation. Supporting Evidence: PMID:24560927 Here we demonstrate that these properties are ensured by a regulatory heterodimer composed of two proteins with opposite effects, MICU1 and MICU2, which, both in purified lipid bilayers and in intact cells, stimulate and inhibit MCU activity, respectively. |
| GO:0046982 protein heterodimerization activity | IPI PMID:24560927 MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter... | ACCEPT | Summary: MICU1 forms disulfide-linked heterodimers with MICU2 and with MICU3; the heterodimer, not the monomer, is the Ca2+-sensing gating unit. Reason: Core molecular function and unusually well characterised for a dimerisation term - the heterodimer has been reconstituted, its cooperative Ca2+ affinity measured, its structure solved by several groups, and the intersubunit disulfide shown to protect it from YME1L1 proteolysis. Unlike bare protein binding, this term is mechanistically informative and is retained as core. Supporting Evidence: PMID:24560927 At low [Ca(2+)], the dominant effect of MICU2 largely shuts down MCU activity; at higher [Ca(2+)], the stimulatory effect of MICU1 allows the prompt response of mitochondria to Ca(2+) signals generated in the cytoplasm. |
| GO:0051260 protein homooligomerization | IDA PMID:24514027 Structural and mechanistic insights into MICU1 regulation of... | KEEP AS NON CORE | Summary: MICU1 oligomerises; Ca2+-free MICU1 was crystallised as a hexamer and MICU1-MICU1 homodimers occur in some tissues. Reason: Genuine but peripheral relative to the MICU1-MICU2 heterodimer, which is the species that gates the uniporter in most tissues. Supporting Evidence: PMID:24514027 Our studies reveal that Ca(2+)-free MICU1 forms a hexamer that binds and inhibits MCU. |
| GO:0051561 positive regulation of mitochondrial calcium ion concentration | IDA PMID:24560927 MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter... | ACCEPT | Summary: Above its Ca2+ threshold MICU1 stimulates MCU, raising matrix Ca2+. Reason: Correct for the high-Ca2+ regime. MICU1 is bidirectional - inhibitory below threshold, stimulatory above it - so this term captures only one arm, but that arm is directly demonstrated in purified lipid bilayers and in intact cells. Read together with the calcium channel inhibitor activity annotations it gives the complete picture. Supporting Evidence: PMID:24560927 At low [Ca(2+)], the dominant effect of MICU2 largely shuts down MCU activity; at higher [Ca(2+)], the stimulatory effect of MICU1 allows the prompt response of mitochondria to Ca(2+) signals generated in the cytoplasm. |
| GO:1990246 uniplex complex | IDA PMID:24560927 MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter... | ACCEPT | Summary: MICU1 is a constitutive subunit of the mitochondrial calcium uniporter holocomplex (uniplex) together with MCU, EMRE and MICU2/MICU3. Reason: Core complex membership, established by biochemistry and by multiple independent cryo-EM structures of the intact human holocomplex. Still current: work published after the 2026 metabolon proposal continues to describe MICU1 as a gatekeeping subunit of this complex. Supporting Evidence: PMID:24560927 Here we demonstrate that these properties are ensured by a regulatory heterodimer composed of two proteins with opposite effects, MICU1 and MICU2, which, both in purified lipid bilayers and in intact cells, stimulate and inhibit MCU activity, respectively. |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:24231807 EMRE is an essential component of the mitochondrial calcium ... | ACCEPT | Summary: The Ca2+-sensing EF-hand domains of MICU1 face the intermembrane space. Reason: Core location and the mechanistically important one: MICU1 reports intermembrane-space (effectively cytosolic) Ca2+, not matrix Ca2+. This topology is what makes MCU-independent MICU1 functions possible at all. Supporting Evidence: PMID:24231807 EMRE is an essential component of the mitochondrial calcium uniporter complex. |
| GO:1990246 uniplex complex | IDA PMID:24231807 EMRE is an essential component of the mitochondrial calcium ... | ACCEPT | Summary: MICU1 is a constitutive subunit of the mitochondrial calcium uniporter holocomplex (uniplex) together with MCU, EMRE and MICU2/MICU3. Reason: Core complex membership, established by biochemistry and by multiple independent cryo-EM structures of the intact human holocomplex. Still current: work published after the 2026 metabolon proposal continues to describe MICU1 as a gatekeeping subunit of this complex. Supporting Evidence: PMID:24231807 EMRE is an essential component of the mitochondrial calcium uniporter complex. |
| GO:0034704 calcium channel complex | ISS GO_REF:0000024 | MODIFY | Summary: Generic calcium channel complex membership inferred electronically and by orthology. Reason: Correct in kind but under-specific. The complex MICU1 belongs to is named and has its own term - the uniplex (GO:1990246) - which the gene already carries with six IDA annotations. Proposed replacements: uniplex complex |
| GO:0005509 calcium ion binding | IDA PMID:23101630 MICU1 is an essential gatekeeper for MCU-mediated mitochondr... | ACCEPT | Summary: MICU1 binds Ca2+ through its two canonical EF-hands; this is the sensing event that underlies all of its regulatory activity. Reason: Core molecular function. Directly measured: the Ca2+-free and Ca2+-bound crystal structures were solved and an affinity of ~15-20 uM determined, and the EF-hands are required for activity. |
| GO:0006851 mitochondrial calcium ion transmembrane transport | IMP PMID:23101630 MICU1 is an essential gatekeeper for MCU-mediated mitochondr... | ACCEPT | Summary: MICU1 participates in Ca2+ transport across the inner mitochondrial membrane as the regulatory subunit of the uniporter. Reason: Core biological process. MICU1 does not itself conduct Ca2+ - MCU is the pore - but it is a constitutive part of the transporting complex and sets the conditions under which transport occurs, so involved_in is the right relation. Supporting Evidence: PMID:23101630 MICU1 interacts with the uniporter pore-forming subunit MCU and sets a Ca(2+) threshold for Ca(2+)(m) uptake without affecting the kinetic properties of MCU-mediated Ca(2+) uptake. |
| GO:0031966 mitochondrial membrane | IDA PMID:23101630 MICU1 is an essential gatekeeper for MCU-mediated mitochondr... | MODIFY | Summary: General mitochondrial membrane localisation. Reason: Correct but under-specific; the gene already carries the specific mitochondrial inner membrane term, which is what the evidence shows. Proposed replacements: mitochondrial inner membrane |
| GO:0051560 mitochondrial calcium ion homeostasis | IMP PMID:23101630 MICU1 is an essential gatekeeper for MCU-mediated mitochondr... | ACCEPT | Summary: Loss of MICU1 causes constitutive mitochondrial Ca2+ loading; MICU1 maintains resting matrix Ca2+. Reason: Core biological process and the phenotype that defines the gene. Note that this is homeostasis of matrix Ca2+ achieved by gating at the inner membrane, not by MICU1 buffering Ca2+ itself. Supporting Evidence: PMID:23101630 Here, we demonstrate that the mitochondrial protein MICU1 is required to preserve normal [Ca(2+)](m) under basal conditions. PMID:23101630 Thus, MICU1 is a gatekeeper of MCU-mediated Ca(2+)(m) uptake that is essential to prevent [Ca(2+)](m) overload and associated stress. |
| GO:0051560 mitochondrial calcium ion homeostasis | IMP PMID:20693986 MICU1 encodes a mitochondrial EF hand protein required for C... | ACCEPT | Summary: Loss of MICU1 causes constitutive mitochondrial Ca2+ loading; MICU1 maintains resting matrix Ca2+. Reason: Core biological process and the phenotype that defines the gene. Note that this is homeostasis of matrix Ca2+ achieved by gating at the inner membrane, not by MICU1 buffering Ca2+ itself. Supporting Evidence: PMID:20693986 Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells |
| GO:0005743 mitochondrial inner membrane | IDA PMID:20693986 MICU1 encodes a mitochondrial EF hand protein required for C... | ACCEPT | Summary: MICU1 is associated with the mitochondrial inner membrane, where it docks onto the MCU/EMRE pore. Reason: Core location, supported from the founding paper onwards and by every subsequent structure of the holocomplex. Supporting Evidence: PMID:20693986 MICU1 is associated with the mitochondrial inner membrane and has two canonical EF hands that are essential for its activity, indicating a role in calcium sensing. |
| GO:0070509 calcium ion import | IDA PMID:20693986 MICU1 encodes a mitochondrial EF hand protein required for C... | MODIFY | Summary: Generic calcium import from the founding RNAi study. Reason: Correct but under-specific; the compartment matters and the gene already carries the specific term for import into the mitochondrion. Proposed replacements: calcium import into the mitochondrion |
| GO:0006952 defense response | TAS PMID:9806765 Isolation of cDNA clones coding for IgE autoantigens with se... | REMOVE | Summary: Legacy annotation from the 1998 paper that first cloned this cDNA, as one of four IgE autoantigens recovered from an expression library screened with serum from atopic dermatitis patients. Reason: Being bound by autoreactive IgE is a property of the patients' immune systems, not a function of the protein. The paper assays IgE reactivity and skin-test responses; it does not assay any defense response carried out by MICU1, and nothing in the subsequent 25 years of MICU1 literature supports an immune function. This is a name-level artefact of the gene's original designation as calcium-binding atopy-related autoantigen 1 (CBARA1). Removing a TAS, not an experimental annotation. Supporting Evidence: PMID:9806765 The fourth cDNA coded for an IgE autoantigen containing a typical calcium binding motif that occurred in histogenetically different cells and tissues (keratinocytes, muscle, brain). |
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Download this section (compressed HTML)Q: Does the proposed MCU-independent MICU metabolon replicate outside the originating laboratory? The claim that Ca2+-dependent MICU heterodimers scaffold a GPD2/SDH metabolon, and that this rather than matrix Ca2+ is the primary physiological calcium signal regulating homeostatic energetics, currently rests on a single study with no independent confirmation and no published rebuttal.
Suggested experts: Elrod JW, Graier WF
Q: If the metabolon role is confirmed, what is the correct GO representation? There is currently no term for the GPD2/succinate dehydrogenase metabolon, and no molecular function term capturing Ca2+-dependent scaffolding of a dehydrogenase assembly by a non-catalytic subunit.
Q: Is the low-Ca2+ inhibited state physical occlusion of the MCU pore or allosteric inhibition? Two 2023 studies support occlusion, but one of them also reports that a fraction of the uniporter in cells with high endogenous MICU1 appears to lack MICU1-dependent gating. What accounts for that fraction?
Suggested experts: Tsai MF, Hajnoczky G
Q: How are MICU1's uniporter-dependent and MICOS/cristae functions related? Is MICOS assembly a consequence of MICU1 positioning at the inner boundary membrane, or a separate Ca2+-regulated activity, and can the two be separated by mutation?
Suggested experts: Tomar D, Gottschalk B
Q: Does the tissue-specific dimer composition - MICU1-MICU1 homodimers in skeletal muscle and kidney, near-absence of MICUs from cardiac uniporters - extend to the proposed metabolon, and could that explain why MICU1 loss and MCU loss give such different organismal phenotypes?
Experiment: Independent replication of the central metabolon result in a second laboratory and a second cell background: measure GPD2+complex III and complex II activities in MICU1, MICU2 and MICU1/MICU2 null cells, in each case on an Mcu-null and an Smdt1-null background, with Ca2+ clamped in permeabilised preparations. The prediction that distinguishes the models is that the MICU effect on dehydrogenase activity should survive complete loss of uniporter function.
Hypothesis: MICU heterodimers regulate GPD2/SDH activity independently of MCU.
Experiment: Identify MICU1 separation-of-function alleles: the MCU-interacting residue K126 for gating, and MICOS-interface or GPD2-interface mutations for the scaffolding roles. Express each at endogenous level in MICU1-null cells and score, in parallel, uniporter threshold by permeabilised-cell Ca2+ uptake, MICOS assembly by blue-native PAGE, and GPD2/SDH coupling by the activity assay. Clean dissociation would justify separate GO core functions rather than one sensing function with multiple targets.
Hypothesis: Gating of MCU and scaffolding of the metabolon are separable activities of MICU1.
Experiment: Rescue Micu1-null mice with EF-hand-dead MICU1, with K126 gating-dead MICU1, and with a MICOS-interface mutant, on a wild-type and on an Mcu-null background. Which allele rescues lethality identifies which activity is the essential one; this is the cleanest available test of the claim that MICU1's primary physiological role is not uniporter gating.
Hypothesis: MICU1 is required for organismal viability through a function other than uniporter gating.
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