{"gene":"MICU2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2013,"finding":"MICU2 resides within the mitochondrial uniporter complex (together with MCU and MICU1), cross-stabilizes the protein expression of other complex members in a cell-type dependent manner, and its RNAi silencing in mouse liver additively impairs mitochondrial calcium handling when combined with MICU1 knockdown.","method":"Co-immunoprecipitation, biochemical fractionation, in vivo RNAi in mouse liver with mitochondrial Ca2+ uptake assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical evidence for complex membership, in vivo RNAi with quantitative Ca2+ phenotype, replicated across cell types","pmids":["23409044"],"is_preprint":false},{"year":2014,"finding":"MICU2 sets a cytoplasmic Ca2+ concentration threshold for mitochondrial Ca2+ uptake (gatekeeping); MICU2's activity and physical association with the MCU pore require the presence of MICU1, but MICU1 does not require MICU2. Mutation of MICU2 Ca2+-binding EF-hands causes a dominant-negative loss of Ca2+ uptake.","method":"CRISPR/Cas9 knockout in HEK-293T cells, EF-hand point mutagenesis, mitochondrial Ca2+ uptake assays, co-immunoprecipitation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with mutagenesis and functional Ca2+ assays, multiple orthogonal methods in one study","pmids":["24503055"],"is_preprint":false},{"year":2015,"finding":"Mia40/CHCHD4 introduces an intermolecular disulfide bond that links MICU1 and MICU2 into a heterodimer in the mitochondrial intermembrane space. This MICU1-MICU2 heterodimer binds MCU at low Ca2+ concentrations and dissociates upon high Ca2+ to release channel inhibition; absence of the disulfide bond increases receptor-induced mitochondrial Ca2+ uptake.","method":"Mia40 interactome analysis, disulfide bond biochemistry, co-immunoprecipitation, mitochondrial Ca2+ uptake assays with Ca2+ titration","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution of disulfide bond formation, functional validation by Ca2+ uptake assay, multiple orthogonal methods","pmids":["26387864"],"is_preprint":false},{"year":2017,"finding":"MICU2 regulates the threshold and gain of MICU1-mediated inhibition and activation of MCU. MICU1 alone can mediate gatekeeping and cooperative activation; MICU2's fundamental role is to modulate these MICU1 functions, spatially restricting Ca2+ crosstalk between InsP3R and MCU channels.","method":"Patch-clamp electrophysiology of MCU channel activity over quantitatively controlled cytoplasmic Ca2+ concentrations in cells with defined MICU1/MICU2 expression","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct electrophysiological measurement of MCU channel activity with quantitative Ca2+ control, single lab but rigorous biophysical approach","pmids":["29241542"],"is_preprint":false},{"year":2019,"finding":"X-ray crystal structure of apo MICU2 at 2.5 Å reveals two-lobe architecture with canonical (EF1, EF4) and structural (EF2, EF3) EF-hands; MICU2 forms a symmetrical homodimer via hydrophobic contacts between EF1 and EF3 of opposing monomers—the same interface used in MICU1 dimers allowing homo/heterodimer exchange. MICU2's C-terminal helix is dispensable in vitro for MICU1 interaction but required for MICU2 function in cells.","method":"X-ray crystallography (2.5 Å), mutagenesis, in vitro binding assays, cellular functional assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis and cellular functional validation","pmids":["30755530"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure of the MCU-EMRE-MICU1-MICU2 holocomplex at 3.3 Å shows that a uniporter interaction domain on MICU1 binds a channel receptor site formed by MCU and EMRE subunits to inhibit ion flow under resting Ca2+ conditions, analogous to toxin block of neuronal channels. A Ca2+-bound MICU1-MICU2 structure at 3.1 Å reveals the Ca2+-dependent conformational changes that relieve this inhibition.","method":"Cryo-EM structure determination (3.3 Å and 3.1 Å), structural analysis of Ca2+-free and Ca2+-bound states","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic cryo-EM structures of both inhibited and Ca2+-bound states with mechanistic interpretation","pmids":["32667285"],"is_preprint":false},{"year":2016,"finding":"MICU2 exists as a monomer in Ca2+-free conditions and forms a dimer in Ca2+-bound conditions; mutation of the first EF-hand abolishes Ca2+-induced dimerization. In addition to disulfide bonds, salt bridges contribute to MICU1-MICU2 heterodimer formation.","method":"Size exclusion chromatography, multi-angle laser light scattering, EF-hand mutagenesis, pull-down assay, co-immunoprecipitation","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (SEC, MALLS, mutagenesis, Co-IP) from single lab","pmids":["27334695"],"is_preprint":false},{"year":2017,"finding":"MICU2 deficiency in cardiomyocytes causes delayed sarcomere relaxation and cytosolic calcium reuptake kinetics (diastolic dysfunction), and Micu2-knockout mice show cardiovascular pathology including left atrial enlargement and vulnerability to angiotensin II-induced aortic rupture, establishing a functional role for MICU2 in cardiac calcium homeostasis.","method":"Micu2 knockout mice, cardiomyocyte calcium imaging, sarcomere relaxation measurements, angiotensin II infusion challenge, RNA-seq","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined cellular Ca2+ phenotype and physiological challenge, single lab","pmids":["29073106"],"is_preprint":false},{"year":2021,"finding":"MICU2 is required for mitochondrial Ca2+ uptake in pancreatic β cells; MICU2 silencing abrogates glucose-stimulated insulin secretion (GSIS), prevents mitochondrial membrane hyperpolarization, lowers ATP/ADP ratio in response to glucose, and causes Ca2+ accumulation in the submembrane compartment that desensitizes voltage-dependent Ca2+ channels.","method":"siRNA silencing in INS-1 832/13 and EndoC-βH1 cells, Micu2-/- mice, live confocal imaging of mitochondrial Ca2+ and membrane potential, submembrane Ca2+ measurement, insulin secretion assays","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods across two cell lines and mouse model, replicated across systems","pmids":["33932586"],"is_preprint":false},{"year":2025,"finding":"MICU2 is present in the developing mouse brain but disappears upon maturation. MICU2 loss augments mitochondrial matrix Ca2+ rise in primary cortical neurons without affecting cytoplasmic Ca2+, leading to neuronal overmigration in the cortex. MICU2-deficient patient fibroblasts replicate the mitochondria-confined Ca2+ alteration seen in developing neurons.","method":"MICU2 knockout mice, primary cortical neuron Ca2+ imaging, cortical migration analysis (in vivo), patient fibroblast functional assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with compartment-specific Ca2+ measurement and in vivo migration phenotype, replicated in patient cells, single lab","pmids":["41273721"],"is_preprint":false},{"year":2024,"finding":"MICU1 and MICU2 gate MCU in the mammalian heart; MICU1 is present in a complex with MCU in nonfailing human hearts, and MICU1 deletion in mice alters cardiomyocyte mitochondrial Ca2+ signaling and energy metabolism with compensatory upregulation of EMRE and subsequently MCU turnover.","method":"Co-immunoprecipitation from human heart tissue, MICU1 knockout mice, mitochondrial Ca2+ influx measurements, pharmacology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model plus human tissue biochemistry, but MICU2-specific functional conclusions are secondary to MICU1 findings in this paper","pmids":["39163336"],"is_preprint":false}],"current_model":"MICU2 is an EF-hand Ca2+-binding protein that resides in the mitochondrial intermembrane space as part of the MCU holocomplex, where it forms a Mia40-catalyzed disulfide-linked heterodimer with MICU1; under resting (low Ca2+) conditions the MICU1-MICU2 heterodimer docks onto the MCU-EMRE channel via a MICU1 interaction domain to block ion flow, while rising cytoplasmic Ca2+ triggers Ca2+-dependent dissociation and channel activation—with MICU2 specifically tuning the threshold and gain of MICU1-mediated gatekeeping rather than acting redundantly, and this regulation is essential for physiological mitochondrial Ca2+ uptake in heart, pancreatic β cells, and developing neurons."},"narrative":{"mechanistic_narrative":"MICU2 is an EF-hand Ca2+-binding regulatory subunit of the mitochondrial calcium uniporter (MCU) complex that tunes the threshold and gain of Ca2+-dependent channel gatekeeping, thereby controlling physiological mitochondrial Ca2+ uptake [PMID:24503055, PMID:29241542]. It resides in the mitochondrial intermembrane space within the uniporter complex alongside MCU and MICU1, where it cross-stabilizes the expression of other complex members [PMID:23409044]. MICU2 is covalently tethered to MICU1 through a Mia40/CHCHD4-catalyzed intermolecular disulfide bond, forming a heterodimer that binds and inhibits the channel at low Ca2+ and dissociates to release inhibition upon rising Ca2+; loss of this disulfide enhances receptor-induced Ca2+ uptake [PMID:26387864]. Cryo-EM of the MCU-EMRE-MICU1-MICU2 holocomplex shows that a MICU1 interaction domain occludes the channel under resting Ca2+, with Ca2+ binding driving the conformational change that relieves block [PMID:32667285]. MICU2's regulatory role is strictly dependent on MICU1 and is not redundant: it modulates MICU1-mediated inhibition and cooperative activation and spatially restricts InsP3R-MCU Ca2+ crosstalk, and mutation of its Ca2+-binding EF-hands acts dominant-negatively [PMID:24503055, PMID:29241542]. Structurally, MICU2 has a two-lobe architecture with canonical and structural EF-hands and exchanges between homo- and heterodimers through a shared dimerization interface, undergoing Ca2+-dependent dimerization [PMID:30755530, PMID:27334695]. This regulation is physiologically essential: MICU2 loss causes cardiac diastolic dysfunction and cardiovascular pathology [PMID:29073106], abrogates glucose-stimulated insulin secretion in pancreatic β cells [PMID:33932586], and dysregulates matrix Ca2+ in developing cortical neurons leading to cortical overmigration, a phenotype reproduced in patient fibroblasts [PMID:41273721].","teleology":[{"year":2013,"claim":"Established that MICU2 is a bona fide member of the uniporter complex rather than a peripheral factor, and that it contributes non-redundantly to mitochondrial Ca2+ handling alongside MICU1.","evidence":"Co-IP, biochemical fractionation, and in vivo RNAi in mouse liver with Ca2+ uptake assays","pmids":["23409044"],"confidence":"High","gaps":["Did not resolve the molecular mechanism by which MICU2 affects Ca2+ flux","Cell-type dependence of cross-stabilization left unexplained"]},{"year":2014,"claim":"Defined MICU2's specific role as setting a cytoplasmic Ca2+ threshold for uptake and showed its dependence on MICU1, distinguishing MICU2 from a redundant paralog.","evidence":"CRISPR/Cas9 KO in HEK-293T, EF-hand point mutagenesis, Ca2+ uptake assays, and Co-IP","pmids":["24503055"],"confidence":"High","gaps":["Did not establish the structural basis of MICU2-MCU association","Mechanism of the dominant-negative EF-hand effect not resolved"]},{"year":2015,"claim":"Identified the covalent basis of the MICU1-MICU2 heterodimer, showing Mia40-catalyzed disulfide bonding controls Ca2+-dependent channel inhibition.","evidence":"Mia40 interactome, disulfide biochemistry, Co-IP, and Ca2+ uptake titration assays","pmids":["26387864"],"confidence":"High","gaps":["Stoichiometry of heterodimer within the holocomplex not defined here","How disulfide status is regulated dynamically remains open"]},{"year":2016,"claim":"Clarified the oligomeric behavior of MICU2, showing Ca2+-driven monomer-to-dimer transition controlled by the first EF-hand and salt-bridge contributions to heterodimerization.","evidence":"Size exclusion chromatography, MALLS, EF-hand mutagenesis, pull-down, and Co-IP","pmids":["27334695"],"confidence":"Medium","gaps":["Single-lab biochemistry without in-channel structural context","Physiological relevance of homodimer vs heterodimer not addressed"]},{"year":2017,"claim":"Resolved MICU2's biophysical function as modulating the threshold and gain of MICU1-mediated gatekeeping and spatially restricting InsP3R-MCU crosstalk.","evidence":"Patch-clamp electrophysiology of MCU channel activity over controlled cytoplasmic Ca2+ in defined MICU1/MICU2 backgrounds","pmids":["29241542"],"confidence":"High","gaps":["Structural mechanism of gain modulation not visualized","Single-lab biophysical measurement"]},{"year":2017,"claim":"Demonstrated the physiological consequence of MICU2 loss in the heart, linking MICU2-dependent Ca2+ handling to diastolic function and cardiovascular integrity.","evidence":"Micu2 knockout mice, cardiomyocyte Ca2+ imaging, sarcomere relaxation, angiotensin II challenge, RNA-seq","pmids":["29073106"],"confidence":"Medium","gaps":["Causal chain from matrix Ca2+ to relaxation kinetics not fully dissected","Single lab, single tissue"]},{"year":2019,"claim":"Provided the first high-resolution structure of MICU2, revealing its EF-hand architecture and a shared dimerization interface enabling homo/heterodimer exchange.","evidence":"2.5 Å X-ray crystallography of apo MICU2 with mutagenesis and cellular functional assays","pmids":["30755530"],"confidence":"High","gaps":["Apo structure does not show Ca2+-bound conformation","C-terminal helix function in cells mechanistically unexplained"]},{"year":2020,"claim":"Visualized the assembled holocomplex, showing the MICU1 interaction domain occludes the channel at resting Ca2+ and the Ca2+-bound conformational change that relieves inhibition.","evidence":"Cryo-EM of MCU-EMRE-MICU1-MICU2 at 3.3 Å and Ca2+-bound MICU1-MICU2 at 3.1 Å","pmids":["32667285"],"confidence":"High","gaps":["MICU2-specific contacts within the inhibited complex not individually defined","Dynamics of the resting-to-activated transition inferred from static states"]},{"year":2021,"claim":"Extended MICU2's physiological role to glucose-stimulated insulin secretion, connecting its gatekeeping to β-cell metabolic coupling and submembrane Ca2+ control.","evidence":"siRNA in INS-1 832/13 and EndoC-βH1, Micu2-/- mice, live imaging of mitochondrial Ca2+/membrane potential, insulin secretion assays","pmids":["33932586"],"confidence":"High","gaps":["Direct link between submembrane Ca2+ accumulation and channel desensitization mechanistically incomplete","Single lab"]},{"year":2024,"claim":"Confirmed MICU1/MICU2 gating of MCU in mammalian heart using human tissue and showed compensatory remodeling of complex subunits upon MICU1 loss.","evidence":"Co-IP from human heart, MICU1 KO mice, mitochondrial Ca2+ influx measurements, pharmacology","pmids":["39163336"],"confidence":"Medium","gaps":["MICU2-specific conclusions secondary to MICU1 findings","MICU2 compensatory behavior not directly tested"]},{"year":2025,"claim":"Revealed a developmental, compartment-specific role: MICU2 restricts matrix Ca2+ in developing neurons, and its loss causes cortical overmigration, with patient fibroblasts recapitulating the phenotype.","evidence":"MICU2 KO mice, primary cortical neuron Ca2+ imaging, in vivo cortical migration analysis, patient fibroblast assays","pmids":["41273721"],"confidence":"Medium","gaps":["Molecular link between matrix Ca2+ and migration not defined","Disease causality from patient evidence remains correlative","Single lab"]},{"year":null,"claim":"How MICU2-imposed threshold/gain tuning is dynamically regulated across tissues and developmental stages, and the precise causal chain from matrix Ca2+ to tissue-specific phenotypes, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanism linking matrix Ca2+ changes to downstream effectors in neurons or β cells","Tissue-specific regulation of MICU2 abundance and disulfide status not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,3,8]}],"complexes":["MCU uniporter holocomplex (MCU-EMRE-MICU1-MICU2)"],"partners":["MICU1","MCU","EMRE","CHCHD4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYU8","full_name":"Calcium uptake protein 2, mitochondrial","aliases":["EF-hand domain-containing family member A1"],"length_aa":434,"mass_kda":49.7,"function":"Calcium sensor of the mitochondrial calcium uniporter (MCU) channel, which senses calcium level via its EF-hand domains (PubMed:24503055, PubMed:24560927, PubMed:26903221, PubMed:28615291, PubMed:30699349, PubMed:31397067, PubMed:32494073, PubMed:32667285, PubMed:32762847, PubMed:32790952). MICU1 and MICU2 form a disulfide-linked heterodimer that stimulates and inhibits MCU activity, depending on the concentration of calcium (PubMed:24560927, PubMed:26903221, PubMed:28615291, PubMed:30699349, PubMed:31397067, PubMed:32148862, PubMed:32494073, PubMed:32667285, PubMed:32762847, PubMed:32790952). At low calcium levels, MICU1 occludes the pore of the MCU channel, preventing mitochondrial calcium uptake (PubMed:32494073, PubMed:32667285, PubMed:32762847). At higher calcium levels, calcium-binding to MICU1 and MICU2 induces a conformational change that weakens MCU-MICU1 interactions and moves the MICU1-MICU2 heterodimer away from the pore, allowing calcium permeation through the MCU channel (PubMed:32494073, PubMed:32667285, PubMed:32762847)","subcellular_location":"Mitochondrion intermembrane space; Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q8IYU8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MICU2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MICU2","total_profiled":1310},"omim":[{"mim_id":"620702","title":"MITOCHONDRIAL CALCIUM UNIPORTER, DOMINANT-NEGATIVE SUBUNIT BETA; MCUB","url":"https://www.omim.org/entry/620702"},{"mim_id":"615588","title":"SINGLE-PASS MEMBRANE PROTEIN WITH ASPARTATE-RICH TAIL 1; SMDT1","url":"https://www.omim.org/entry/615588"},{"mim_id":"610633","title":"MITOCHONDRIAL CALCIUM UPTAKE PROTEIN 3; MICU3","url":"https://www.omim.org/entry/610633"},{"mim_id":"610632","title":"MITOCHONDRIAL CALCIUM UPTAKE PROTEIN 2; MICU2","url":"https://www.omim.org/entry/610632"},{"mim_id":"605084","title":"MITOCHONDRIAL CALCIUM UPTAKE PROTEIN 1; MICU1","url":"https://www.omim.org/entry/605084"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MICU2"},"hgnc":{"alias_symbol":[],"prev_symbol":["EFHA1"]},"alphafold":{"accession":"Q8IYU8","domains":[{"cath_id":"-","chopping":"84-211_227-258","consensus_level":"medium","plddt":87.8242,"start":84,"end":258},{"cath_id":"-","chopping":"273-395","consensus_level":"high","plddt":90.199,"start":273,"end":395}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYU8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYU8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYU8-F1-predicted_aligned_error_v6.png","plddt_mean":74.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MICU2","jax_strain_url":"https://www.jax.org/strain/search?query=MICU2"},"sequence":{"accession":"Q8IYU8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYU8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYU8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYU8"}},"corpus_meta":[{"pmid":"23409044","id":"PMC_23409044","title":"MICU2, a paralog of MICU1, resides within the mitochondrial uniporter complex to regulate calcium handling.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23409044","citation_count":394,"is_preprint":false},{"pmid":"24503055","id":"PMC_24503055","title":"MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter.","date":"2014","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/24503055","citation_count":189,"is_preprint":false},{"pmid":"26387864","id":"PMC_26387864","title":"The Ca(2+)-Dependent Release of the Mia40-Induced MICU1-MICU2 Dimer from MCU Regulates Mitochondrial Ca(2+) Uptake.","date":"2015","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26387864","citation_count":169,"is_preprint":false},{"pmid":"29241542","id":"PMC_29241542","title":"MICU2 Restricts Spatial Crosstalk between InsP3R and MCU Channels by Regulating Threshold and Gain of MICU1-Mediated Inhibition and Activation of MCU.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29241542","citation_count":79,"is_preprint":false},{"pmid":"29073106","id":"PMC_29073106","title":"Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29073106","citation_count":56,"is_preprint":false},{"pmid":"32667285","id":"PMC_32667285","title":"Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32667285","citation_count":56,"is_preprint":false},{"pmid":"29053821","id":"PMC_29053821","title":"A null mutation in MICU2 causes abnormal mitochondrial calcium homeostasis and a severe neurodevelopmental disorder.","date":"2017","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29053821","citation_count":45,"is_preprint":false},{"pmid":"30755530","id":"PMC_30755530","title":"Crystal structure of MICU2 and comparison with MICU1 reveal insights into the uniporter gating mechanism.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30755530","citation_count":43,"is_preprint":false},{"pmid":"31064825","id":"PMC_31064825","title":"MICU1 and MICU2 Play an Essential Role in Mitochondrial Ca2+ Uptake, Growth, and Infectivity of the Human Pathogen Trypanosoma cruzi.","date":"2019","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/31064825","citation_count":38,"is_preprint":false},{"pmid":"24531720","id":"PMC_24531720","title":"The gatekeepers of mitochondrial calcium influx: MICU1 and MICU2.","date":"2014","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/24531720","citation_count":30,"is_preprint":false},{"pmid":"33932586","id":"PMC_33932586","title":"Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion.","date":"2021","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/33932586","citation_count":21,"is_preprint":false},{"pmid":"39163336","id":"PMC_39163336","title":"MICU1 and MICU2 control mitochondrial calcium signaling in the mammalian heart.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39163336","citation_count":19,"is_preprint":false},{"pmid":"27334695","id":"PMC_27334695","title":"Expression and preliminary characterization of human MICU2.","date":"2016","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/27334695","citation_count":13,"is_preprint":false},{"pmid":"32580385","id":"PMC_32580385","title":"The Function of Mitochondrial Calcium Uniporter at the Whole-Cell and Single Mitochondrion Levels in WT, MICU1 KO, and MICU2 KO Cells.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32580385","citation_count":7,"is_preprint":false},{"pmid":"36166935","id":"PMC_36166935","title":"MICU1 and MICU2 potentiation of Ca2+ uptake by the mitochondrial Ca2+ uniporter of Trypanosoma cruzi and its inhibition by Mg2.","date":"2022","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/36166935","citation_count":5,"is_preprint":false},{"pmid":"39466877","id":"PMC_39466877","title":"MICU2 up-regulation enhances tumor aggressiveness and metabolic reprogramming during colorectal cancer development.","date":"2024","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/39466877","citation_count":2,"is_preprint":false},{"pmid":"41273721","id":"PMC_41273721","title":"MICU2 controls mitochondrial calcium signaling and migration in neurons during 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development","date":"2025-06-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.23.660978","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.13.607857","title":"Mitochondrial calcium uniporter regulates human fibroblast-like synoviocytes invasion via altering mitochondrial dynamics and dictates rheumatoid arthritis pathogenesis","date":"2024-08-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.13.607857","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12252,"output_tokens":2959,"usd":0.040571,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10428,"output_tokens":3732,"usd":0.07272,"stage2_stop_reason":"end_turn"},"total_usd":0.113291,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"MICU2 resides within the mitochondrial uniporter complex (together with MCU and MICU1), cross-stabilizes the protein expression of other complex members in a cell-type dependent manner, and its RNAi silencing in mouse liver additively impairs mitochondrial calcium handling when combined with MICU1 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, biochemical fractionation, in vivo RNAi in mouse liver with mitochondrial Ca2+ uptake assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical evidence for complex membership, in vivo RNAi with quantitative Ca2+ phenotype, replicated across cell types\",\n      \"pmids\": [\"23409044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MICU2 sets a cytoplasmic Ca2+ concentration threshold for mitochondrial Ca2+ uptake (gatekeeping); MICU2's activity and physical association with the MCU pore require the presence of MICU1, but MICU1 does not require MICU2. Mutation of MICU2 Ca2+-binding EF-hands causes a dominant-negative loss of Ca2+ uptake.\",\n      \"method\": \"CRISPR/Cas9 knockout in HEK-293T cells, EF-hand point mutagenesis, mitochondrial Ca2+ uptake assays, co-immunoprecipitation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with mutagenesis and functional Ca2+ assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24503055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mia40/CHCHD4 introduces an intermolecular disulfide bond that links MICU1 and MICU2 into a heterodimer in the mitochondrial intermembrane space. This MICU1-MICU2 heterodimer binds MCU at low Ca2+ concentrations and dissociates upon high Ca2+ to release channel inhibition; absence of the disulfide bond increases receptor-induced mitochondrial Ca2+ uptake.\",\n      \"method\": \"Mia40 interactome analysis, disulfide bond biochemistry, co-immunoprecipitation, mitochondrial Ca2+ uptake assays with Ca2+ titration\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution of disulfide bond formation, functional validation by Ca2+ uptake assay, multiple orthogonal methods\",\n      \"pmids\": [\"26387864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MICU2 regulates the threshold and gain of MICU1-mediated inhibition and activation of MCU. MICU1 alone can mediate gatekeeping and cooperative activation; MICU2's fundamental role is to modulate these MICU1 functions, spatially restricting Ca2+ crosstalk between InsP3R and MCU channels.\",\n      \"method\": \"Patch-clamp electrophysiology of MCU channel activity over quantitatively controlled cytoplasmic Ca2+ concentrations in cells with defined MICU1/MICU2 expression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiological measurement of MCU channel activity with quantitative Ca2+ control, single lab but rigorous biophysical approach\",\n      \"pmids\": [\"29241542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"X-ray crystal structure of apo MICU2 at 2.5 Å reveals two-lobe architecture with canonical (EF1, EF4) and structural (EF2, EF3) EF-hands; MICU2 forms a symmetrical homodimer via hydrophobic contacts between EF1 and EF3 of opposing monomers—the same interface used in MICU1 dimers allowing homo/heterodimer exchange. MICU2's C-terminal helix is dispensable in vitro for MICU1 interaction but required for MICU2 function in cells.\",\n      \"method\": \"X-ray crystallography (2.5 Å), mutagenesis, in vitro binding assays, cellular functional assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure combined with mutagenesis and cellular functional validation\",\n      \"pmids\": [\"30755530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of the MCU-EMRE-MICU1-MICU2 holocomplex at 3.3 Å shows that a uniporter interaction domain on MICU1 binds a channel receptor site formed by MCU and EMRE subunits to inhibit ion flow under resting Ca2+ conditions, analogous to toxin block of neuronal channels. A Ca2+-bound MICU1-MICU2 structure at 3.1 Å reveals the Ca2+-dependent conformational changes that relieve this inhibition.\",\n      \"method\": \"Cryo-EM structure determination (3.3 Å and 3.1 Å), structural analysis of Ca2+-free and Ca2+-bound states\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic cryo-EM structures of both inhibited and Ca2+-bound states with mechanistic interpretation\",\n      \"pmids\": [\"32667285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MICU2 exists as a monomer in Ca2+-free conditions and forms a dimer in Ca2+-bound conditions; mutation of the first EF-hand abolishes Ca2+-induced dimerization. In addition to disulfide bonds, salt bridges contribute to MICU1-MICU2 heterodimer formation.\",\n      \"method\": \"Size exclusion chromatography, multi-angle laser light scattering, EF-hand mutagenesis, pull-down assay, co-immunoprecipitation\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (SEC, MALLS, mutagenesis, Co-IP) from single lab\",\n      \"pmids\": [\"27334695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MICU2 deficiency in cardiomyocytes causes delayed sarcomere relaxation and cytosolic calcium reuptake kinetics (diastolic dysfunction), and Micu2-knockout mice show cardiovascular pathology including left atrial enlargement and vulnerability to angiotensin II-induced aortic rupture, establishing a functional role for MICU2 in cardiac calcium homeostasis.\",\n      \"method\": \"Micu2 knockout mice, cardiomyocyte calcium imaging, sarcomere relaxation measurements, angiotensin II infusion challenge, RNA-seq\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined cellular Ca2+ phenotype and physiological challenge, single lab\",\n      \"pmids\": [\"29073106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MICU2 is required for mitochondrial Ca2+ uptake in pancreatic β cells; MICU2 silencing abrogates glucose-stimulated insulin secretion (GSIS), prevents mitochondrial membrane hyperpolarization, lowers ATP/ADP ratio in response to glucose, and causes Ca2+ accumulation in the submembrane compartment that desensitizes voltage-dependent Ca2+ channels.\",\n      \"method\": \"siRNA silencing in INS-1 832/13 and EndoC-βH1 cells, Micu2-/- mice, live confocal imaging of mitochondrial Ca2+ and membrane potential, submembrane Ca2+ measurement, insulin secretion assays\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods across two cell lines and mouse model, replicated across systems\",\n      \"pmids\": [\"33932586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MICU2 is present in the developing mouse brain but disappears upon maturation. MICU2 loss augments mitochondrial matrix Ca2+ rise in primary cortical neurons without affecting cytoplasmic Ca2+, leading to neuronal overmigration in the cortex. MICU2-deficient patient fibroblasts replicate the mitochondria-confined Ca2+ alteration seen in developing neurons.\",\n      \"method\": \"MICU2 knockout mice, primary cortical neuron Ca2+ imaging, cortical migration analysis (in vivo), patient fibroblast functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with compartment-specific Ca2+ measurement and in vivo migration phenotype, replicated in patient cells, single lab\",\n      \"pmids\": [\"41273721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MICU1 and MICU2 gate MCU in the mammalian heart; MICU1 is present in a complex with MCU in nonfailing human hearts, and MICU1 deletion in mice alters cardiomyocyte mitochondrial Ca2+ signaling and energy metabolism with compensatory upregulation of EMRE and subsequently MCU turnover.\",\n      \"method\": \"Co-immunoprecipitation from human heart tissue, MICU1 knockout mice, mitochondrial Ca2+ influx measurements, pharmacology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model plus human tissue biochemistry, but MICU2-specific functional conclusions are secondary to MICU1 findings in this paper\",\n      \"pmids\": [\"39163336\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MICU2 is an EF-hand Ca2+-binding protein that resides in the mitochondrial intermembrane space as part of the MCU holocomplex, where it forms a Mia40-catalyzed disulfide-linked heterodimer with MICU1; under resting (low Ca2+) conditions the MICU1-MICU2 heterodimer docks onto the MCU-EMRE channel via a MICU1 interaction domain to block ion flow, while rising cytoplasmic Ca2+ triggers Ca2+-dependent dissociation and channel activation—with MICU2 specifically tuning the threshold and gain of MICU1-mediated gatekeeping rather than acting redundantly, and this regulation is essential for physiological mitochondrial Ca2+ uptake in heart, pancreatic β cells, and developing neurons.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MICU2 is an EF-hand Ca2+-binding regulatory subunit of the mitochondrial calcium uniporter (MCU) complex that tunes the threshold and gain of Ca2+-dependent channel gatekeeping, thereby controlling physiological mitochondrial Ca2+ uptake [#1, #3]. It resides in the mitochondrial intermembrane space within the uniporter complex alongside MCU and MICU1, where it cross-stabilizes the expression of other complex members [#0]. MICU2 is covalently tethered to MICU1 through a Mia40/CHCHD4-catalyzed intermolecular disulfide bond, forming a heterodimer that binds and inhibits the channel at low Ca2+ and dissociates to release inhibition upon rising Ca2+; loss of this disulfide enhances receptor-induced Ca2+ uptake [#2]. Cryo-EM of the MCU-EMRE-MICU1-MICU2 holocomplex shows that a MICU1 interaction domain occludes the channel under resting Ca2+, with Ca2+ binding driving the conformational change that relieves block [#5]. MICU2's regulatory role is strictly dependent on MICU1 and is not redundant: it modulates MICU1-mediated inhibition and cooperative activation and spatially restricts InsP3R-MCU Ca2+ crosstalk, and mutation of its Ca2+-binding EF-hands acts dominant-negatively [#1, #3]. Structurally, MICU2 has a two-lobe architecture with canonical and structural EF-hands and exchanges between homo- and heterodimers through a shared dimerization interface, undergoing Ca2+-dependent dimerization [#4, #6]. This regulation is physiologically essential: MICU2 loss causes cardiac diastolic dysfunction and cardiovascular pathology [#7], abrogates glucose-stimulated insulin secretion in pancreatic \\u03b2 cells [#8], and dysregulates matrix Ca2+ in developing cortical neurons leading to cortical overmigration, a phenotype reproduced in patient fibroblasts [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that MICU2 is a bona fide member of the uniporter complex rather than a peripheral factor, and that it contributes non-redundantly to mitochondrial Ca2+ handling alongside MICU1.\",\n      \"evidence\": \"Co-IP, biochemical fractionation, and in vivo RNAi in mouse liver with Ca2+ uptake assays\",\n      \"pmids\": [\"23409044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular mechanism by which MICU2 affects Ca2+ flux\", \"Cell-type dependence of cross-stabilization left unexplained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined MICU2's specific role as setting a cytoplasmic Ca2+ threshold for uptake and showed its dependence on MICU1, distinguishing MICU2 from a redundant paralog.\",\n      \"evidence\": \"CRISPR/Cas9 KO in HEK-293T, EF-hand point mutagenesis, Ca2+ uptake assays, and Co-IP\",\n      \"pmids\": [\"24503055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the structural basis of MICU2-MCU association\", \"Mechanism of the dominant-negative EF-hand effect not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the covalent basis of the MICU1-MICU2 heterodimer, showing Mia40-catalyzed disulfide bonding controls Ca2+-dependent channel inhibition.\",\n      \"evidence\": \"Mia40 interactome, disulfide biochemistry, Co-IP, and Ca2+ uptake titration assays\",\n      \"pmids\": [\"26387864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of heterodimer within the holocomplex not defined here\", \"How disulfide status is regulated dynamically remains open\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Clarified the oligomeric behavior of MICU2, showing Ca2+-driven monomer-to-dimer transition controlled by the first EF-hand and salt-bridge contributions to heterodimerization.\",\n      \"evidence\": \"Size exclusion chromatography, MALLS, EF-hand mutagenesis, pull-down, and Co-IP\",\n      \"pmids\": [\"27334695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab biochemistry without in-channel structural context\", \"Physiological relevance of homodimer vs heterodimer not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved MICU2's biophysical function as modulating the threshold and gain of MICU1-mediated gatekeeping and spatially restricting InsP3R-MCU crosstalk.\",\n      \"evidence\": \"Patch-clamp electrophysiology of MCU channel activity over controlled cytoplasmic Ca2+ in defined MICU1/MICU2 backgrounds\",\n      \"pmids\": [\"29241542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of gain modulation not visualized\", \"Single-lab biophysical measurement\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated the physiological consequence of MICU2 loss in the heart, linking MICU2-dependent Ca2+ handling to diastolic function and cardiovascular integrity.\",\n      \"evidence\": \"Micu2 knockout mice, cardiomyocyte Ca2+ imaging, sarcomere relaxation, angiotensin II challenge, RNA-seq\",\n      \"pmids\": [\"29073106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from matrix Ca2+ to relaxation kinetics not fully dissected\", \"Single lab, single tissue\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the first high-resolution structure of MICU2, revealing its EF-hand architecture and a shared dimerization interface enabling homo/heterodimer exchange.\",\n      \"evidence\": \"2.5 \\u00c5 X-ray crystallography of apo MICU2 with mutagenesis and cellular functional assays\",\n      \"pmids\": [\"30755530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apo structure does not show Ca2+-bound conformation\", \"C-terminal helix function in cells mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Visualized the assembled holocomplex, showing the MICU1 interaction domain occludes the channel at resting Ca2+ and the Ca2+-bound conformational change that relieves inhibition.\",\n      \"evidence\": \"Cryo-EM of MCU-EMRE-MICU1-MICU2 at 3.3 \\u00c5 and Ca2+-bound MICU1-MICU2 at 3.1 \\u00c5\",\n      \"pmids\": [\"32667285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MICU2-specific contacts within the inhibited complex not individually defined\", \"Dynamics of the resting-to-activated transition inferred from static states\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended MICU2's physiological role to glucose-stimulated insulin secretion, connecting its gatekeeping to \\u03b2-cell metabolic coupling and submembrane Ca2+ control.\",\n      \"evidence\": \"siRNA in INS-1 832/13 and EndoC-\\u03b2H1, Micu2-/- mice, live imaging of mitochondrial Ca2+/membrane potential, insulin secretion assays\",\n      \"pmids\": [\"33932586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between submembrane Ca2+ accumulation and channel desensitization mechanistically incomplete\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed MICU1/MICU2 gating of MCU in mammalian heart using human tissue and showed compensatory remodeling of complex subunits upon MICU1 loss.\",\n      \"evidence\": \"Co-IP from human heart, MICU1 KO mice, mitochondrial Ca2+ influx measurements, pharmacology\",\n      \"pmids\": [\"39163336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MICU2-specific conclusions secondary to MICU1 findings\", \"MICU2 compensatory behavior not directly tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a developmental, compartment-specific role: MICU2 restricts matrix Ca2+ in developing neurons, and its loss causes cortical overmigration, with patient fibroblasts recapitulating the phenotype.\",\n      \"evidence\": \"MICU2 KO mice, primary cortical neuron Ca2+ imaging, in vivo cortical migration analysis, patient fibroblast assays\",\n      \"pmids\": [\"41273721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between matrix Ca2+ and migration not defined\", \"Disease causality from patient evidence remains correlative\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MICU2-imposed threshold/gain tuning is dynamically regulated across tissues and developmental stages, and the precise causal chain from matrix Ca2+ to tissue-specific phenotypes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism linking matrix Ca2+ changes to downstream effectors in neurons or \\u03b2 cells\", \"Tissue-specific regulation of MICU2 abundance and disulfide status not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 3, 8]}\n    ],\n    \"complexes\": [\"MCU uniporter holocomplex (MCU-EMRE-MICU1-MICU2)\"],\n    \"partners\": [\"MICU1\", \"MCU\", \"EMRE\", \"CHCHD4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}