{"gene":"SMDT1","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2013,"finding":"EMRE (SMDT1) was identified as an essential component of the mitochondrial calcium uniporter holocomplex (uniplex) via quantitative mass spectrometry of affinity-purified uniplex. EMRE is a 10-kDa, metazoan-specific, single-transmembrane domain protein. In its absence, uniporter channel activity was lost despite intact MCU expression and oligomerization. EMRE was required for the interaction of MCU with MICU1 and MICU2, bridging the calcium-sensing role of MICU1/MICU2 with the calcium-conducting role of MCU.","method":"Quantitative mass spectrometry of affinity-purified complex, loss-of-function (siRNA knockdown), co-immunoprecipitation, electrophysiology","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (MS, Co-IP, electrophysiology, KD) in a single rigorous study identifying the protein and its essential role","pmids":["24231807"],"is_preprint":false},{"year":2016,"finding":"EMRE acts as a matrix Ca2+ sensor that governs gatekeeping of the mitochondrial Ca2+ uniporter. Deletion or charge neutralization of EMRE's matrix-localized acidic C terminus abolished matrix Ca2+ inhibition of MCU Ca2+ currents, resulting in MCU channel activation, enhanced mitochondrial Ca2+ uptake, and constitutively elevated matrix Ca2+ concentration. EMRE-dependent regulation requires IMS-localized MICU1 and MICU2 and cytoplasmic Ca2+, coupling Ca2+ sensors on both sides of the inner mitochondrial membrane.","method":"Patch-clamp electrophysiology of mitoplasts, EMRE deletion and charge-neutralization mutagenesis, mitochondrial Ca2+ uptake assays","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct electrophysiology with mutagenesis of EMRE C-terminus, multiple functional readouts, establishes mechanistic role of EMRE's acidic tail","pmids":["26774479"],"is_preprint":false},{"year":2016,"finding":"EMRE topology was experimentally determined using a yeast expression system: its N-terminus projects into the mitochondrial matrix and its C-terminus projects into the intermembrane space. EMRE closely interacts with MCU on both sides of the inner membrane, and this interaction is essential for Ca2+ uptake. Co-expression of MCU with EMRE was necessary for Ca2+ uptake; EMRE expression alone was insufficient. EMRE was not a protein-stabilizing factor for other MCU complex subunits.","method":"Yeast expression system reconstitution, protease protection/topology assays, Ca2+ uptake assays, co-immunoprecipitation","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstitution in yeast with topology and functional assays, single lab with multiple orthogonal methods","pmids":["27001609"],"is_preprint":false},{"year":2020,"finding":"EMRE deletion in a mouse model confirmed that EMRE is required for mitochondrial calcium uniporter function in vivo. EMRE-/- mice showed loss of rapid mitochondrial Ca2+ uptake. EMRE deletion in a muscular dystrophy model associated with mitochondrial Ca2+ overload was examined for disease modification.","method":"Germline EMRE knockout mouse model, mitochondrial Ca2+ uptake assays in isolated mitochondria, exercise and metabolic phenotyping","journal":"JCI Insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout mouse model with direct functional measurement of mitochondrial Ca2+ uptake, replicates cell-culture findings in a whole-organism context","pmids":["32017711"],"is_preprint":false},{"year":2020,"finding":"EMRE controls MCU activity via its transmembrane helix, while an N-terminal PKP motif strengthens binding with MCU. Opening of MCU requires hydrophobic interactions mediated by MCU residues near the pore's luminal end. A single mutation in human MCU that enhances these hydrophobic interactions allows Ca2+ transport without EMRE. EMRE facilitates MCU opening by stabilizing the open state in a conserved MCU gating mechanism.","method":"Mutagenesis of EMRE transmembrane domain and PKP motif, Ca2+ uptake assays, patch-clamp electrophysiology, chimeric MCU constructs","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic mutagenesis combined with electrophysiology and functional Ca2+ assays, multiple orthogonal methods defining the transmembrane mechanism","pmids":["33296646"],"is_preprint":false},{"year":2020,"finding":"Variable assembly of EMRE and MCU creates functional channels with distinct gatekeeping profiles. Most endogenous channels contain two EMRE subunits per MCU tetramer. MCU-EMRE concatemers enforcing 1EMRE:4MCU restored Ca2+ uptake but not full gatekeeping; 4EMRE:4MCU enhanced gatekeeping; 2EMRE:4MCU recapitulated endogenous channel activity and gatekeeping. Increasing EMRE expression raises the cytoplasmic Ca2+ threshold for channel activation.","method":"MCU-EMRE concatemer expression, electrophysiology of mitoplasts, mitochondrial Ca2+ uptake assays, tagged subunit co-expression at defined ratios","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — concatemer approach with electrophysiology and functional assays in single lab, multiple orthogonal methods defining stoichiometry-function relationship","pmids":["32315830"],"is_preprint":false},{"year":2020,"finding":"A cryo-EM structure of the MCU-EMRE complex from Tribolium castaneum at 3.5 Å resolution showed EMRE located at the periphery of the transmembrane domain, associating primarily with the first transmembrane helix of MCU in a tetrameric channel. Ca2+ uptake into proteoliposomes reconstituted with the purified MCU-EMRE complex was EMRE-dependent and also required the mitochondrial lipid cardiolipin.","method":"Cryo-EM structure determination, functional reconstitution in proteoliposomes, Ca2+ uptake assays","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with functional reconstitution and defined lipid requirement, establishes EMRE's structural position and functional dependence","pmids":["32841658"],"is_preprint":false},{"year":2020,"finding":"Using chimeric proteins between EMRE-independent Dictyostelium discoideum MCU and human MCU, a 10-amino acid region in human MCU (the EMRE dependence domain, EDD) was identified as necessary for EMRE dependence. Crosslinking experiments showed EMRE directly interacts with human MCU at its transmembrane domains as well as the EDD. EMRE stabilizes the EDD of MCU, permitting channel opening and Ca2+ conductance.","method":"Chimeric MCU constructs, crosslinking experiments, Ca2+ uptake assays in cells lacking endogenous MCU/EMRE","journal":"Life Science Alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic chimera mapping plus crosslinking in a single lab, two orthogonal methods identifying the interaction domain","pmids":["32769116"],"is_preprint":false},{"year":2019,"finding":"SMDT1 (EMRE) overexpression in PDAC cells led to increased accumulation of pro-apoptotic protein BAX, decrease in anti-apoptotic proteins Bcl-2 and Bcl-xL, and more cytochrome c release. Mechanistically, SMDT1 overexpression promoted mitochondrial fragmentation by increasing phosphorylation of Drp1 and Fis1 while decreasing MFN1, and increased translocation of Drp1 from cytoplasm to mitochondria.","method":"SMDT1 overexpression, Western blotting for apoptosis markers, mitochondrial morphology analysis, cell viability/apoptosis assays","journal":"Biochemical and Biophysical Research Communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression study with phenotypic readouts but limited mechanistic validation of direct EMRE-Drp1 pathway link","pmids":["30782485"],"is_preprint":false},{"year":2023,"finding":"Two patients with SMDT1 variants were characterized showing absence of EMRE protein, induction of MCU subcomplex formation (without EMRE), and impaired mitochondrial Ca2+ uptake in patient fibroblasts. Complementation experiments demonstrated that the SMDT1 variants caused loss of EMRE function. Oxidative phosphorylation enzyme activities, mitochondrial morphology, membrane potential, and routine respiration were not affected.","method":"Patient fibroblast analysis, complementation experiments, mitochondrial Ca2+ uptake assays, OXPHOS enzyme activity assays, mitochondrial morphology imaging","journal":"Biochimica et Biophysica Acta - Molecular Basis of Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human patient variants with complementation, multiple orthogonal functional assays confirming EMRE's role in MCU-dependent Ca2+ uptake","pmids":["37454773"],"is_preprint":false},{"year":2022,"finding":"Quantitative analysis of MCU and EMRE in mouse tissue mitochondria showed that EMRE molecules are fewer than MCU molecules, with MCU:EMRE ratios significantly different among tissues. Statistical modeling suggested most endogenous MCU tetramers in brain bind 2 EMREs; in liver, kidney, and heart predominantly 1 EMRE; with nearly half of MCU tetramers in kidney and heart binding no EMRE, supporting variable stoichiometry of the MCU-EMRE complex in vivo.","method":"Quantitative Western blotting with characterized antibodies and standard proteins, stoichiometric calculations from mouse tissue mitochondrial fractions","journal":"FEBS Open Bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative protein measurement across multiple tissues with calibrated standards, single lab but systematic approach establishing in vivo stoichiometry","pmids":["35060355"],"is_preprint":false},{"year":2023,"finding":"Cardiac-specific, tamoxifen-inducible EMRE deletion established that short-term EMRE loss abolished mitochondrial Ca2+ uptake, lowered basal mitochondrial Ca2+ levels, attenuated Ca2+-induced ATP production and mPTP opening, blunted cardiac adrenergic response, and improved maintenance of cardiac function in ex vivo ischemia/reperfusion. Long-term EMRE deletion similarly impaired mitochondrial Ca2+ handling but lost the protection from I/R injury, demonstrating time-dependent adaptive consequences.","method":"Conditional cardiac-specific tamoxifen-inducible EMRE knockout mouse, mitochondrial Ca2+ uptake assays, ATP production assays, mPTP opening assays, adrenergic stimulation, ex vivo I/R model","journal":"Journal of Molecular and Cellular Cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible cardiac-specific KO with multiple orthogonal functional assays (Ca2+ uptake, ATP production, mPTP, cardiac function) at two time points","pmids":["37230379"],"is_preprint":false}],"current_model":"SMDT1 (EMRE) is a metazoan-specific, single-pass inner mitochondrial membrane protein (N-terminus in matrix, C-terminus in IMS) that is an essential subunit of the mitochondrial calcium uniporter complex: it physically bridges MCU with the Ca2+-sensing regulators MICU1 and MICU2 via its transmembrane helix and N-terminal PKP motif, gates MCU channel opening by stabilizing the open state, and uses its matrix-localized acidic C-terminus to sense matrix Ca2+ and inhibit MCU, thereby protecting mitochondria from both Ca2+ depletion and overload; in vivo, most endogenous MCU tetramers contain 1–2 EMRE subunits with stoichiometry varying by tissue, and EMRE-dependent uniporter activity is required for Ca2+-stimulated ATP production, mPTP regulation, and cardiac responses to adrenergic stress and ischemia/reperfusion injury."},"narrative":{"mechanistic_narrative":"SMDT1 (EMRE) is a metazoan-specific, single-pass inner mitochondrial membrane protein that serves as an essential subunit of the mitochondrial calcium uniporter holocomplex, bridging the Ca2+-conducting MCU channel with the Ca2+-sensing regulators MICU1 and MICU2 [PMID:24231807]. In its absence, uniporter channel activity is lost despite intact MCU expression and oligomerization, and the interaction of MCU with MICU1/MICU2 fails to form [PMID:24231807]. EMRE adopts an Nin-Cout topology with its N-terminus in the matrix and C-terminus in the intermembrane space, and it contacts MCU on both sides of the membrane [PMID:27001609]. Mechanistically, EMRE drives MCU channel opening through its transmembrane helix, which stabilizes the MCU \"EMRE dependence domain\" and the open conformation, while an N-terminal PKP motif strengthens MCU binding [PMID:33296646, PMID:32769116]; a cryo-EM structure places EMRE at the periphery of the tetrameric transmembrane domain in contact with the first MCU helix, with Ca2+ conduction additionally requiring cardiolipin [PMID:32841658]. EMRE also acts as a matrix Ca2+ sensor: its matrix-localized acidic C-terminus confers matrix Ca2+ inhibition of MCU, and removing or neutralizing it produces constitutive channel activation and Ca2+ overload, coupling Ca2+ sensors on both faces of the inner membrane [PMID:26774479]. The MCU:EMRE assembly is variable, with most endogenous tetramers binding one or two EMRE subunits and stoichiometry differing across tissues, which tunes the cytoplasmic Ca2+ threshold for channel gating [PMID:32315830, PMID:35060355]. In vivo, EMRE is required for rapid mitochondrial Ca2+ uptake [PMID:32017711], and cardiac-specific deletion abolishes uptake while attenuating Ca2+-stimulated ATP production, mPTP opening, the adrenergic response, and ischemia/reperfusion outcomes in a time-dependent manner [PMID:37230379]. Loss-of-function SMDT1 variants in patients abolish EMRE protein and impair mitochondrial Ca2+ uptake, establishing a human disease link to defective uniporter function [PMID:37454773].","teleology":[{"year":2013,"claim":"It was unknown how the calcium-sensing MICU proteins coupled to the calcium-conducting MCU; EMRE was identified as the missing essential subunit that bridges them and is required for uniporter channel activity.","evidence":"Quantitative MS of affinity-purified uniplex with siRNA knockdown, Co-IP, and electrophysiology","pmids":["24231807"],"confidence":"High","gaps":["Topology and which membrane faces EMRE contacts MCU not yet defined","Structural basis of the bridging interaction unknown","No in vivo confirmation at this stage"]},{"year":2016,"claim":"The membrane orientation of EMRE and the side(s) on which it engages MCU were unresolved; a yeast reconstitution established Nin-Cout topology and showed EMRE contacts MCU on both membrane faces and is required for Ca2+ uptake rather than acting as a stabilizing chaperone.","evidence":"Yeast reconstitution with protease-protection topology assays, Ca2+ uptake, and Co-IP","pmids":["27001609"],"confidence":"Medium","gaps":["Reconstitution in heterologous yeast system may not fully recapitulate mammalian complex","Atomic-level contact sites not mapped"]},{"year":2016,"claim":"Whether EMRE only enables channel opening or also restrains it was open; mutagenesis of its matrix acidic C-terminus showed this tail senses matrix Ca2+ and confers inhibitory gatekeeping requiring MICU1/MICU2 and cytoplasmic Ca2+.","evidence":"Mitoplast patch-clamp with C-terminal deletion and charge-neutralization mutants and Ca2+ uptake assays","pmids":["26774479"],"confidence":"High","gaps":["Structural mechanism by which the acidic tail transmits inhibition not resolved","Quantitative Ca2+ affinity of the matrix sensor not defined"]},{"year":2019,"claim":"Whether EMRE levels influence cell-death decisions was untested; overexpression in PDAC cells linked EMRE to pro-apoptotic signaling and mitochondrial fragmentation.","evidence":"SMDT1 overexpression with Western blotting of apoptosis markers and mitochondrial morphology analysis","pmids":["30782485"],"confidence":"Low","gaps":["Overexpression phenotype without loss-of-function validation of the EMRE-Drp1 link","Direct molecular connection between EMRE and Drp1/Fis1 phosphorylation not established","Not shown to depend on uniporter Ca2+ flux"]},{"year":2020,"claim":"How EMRE mechanically opens MCU was unknown; mutagenesis and chimera/crosslinking work showed the EMRE transmembrane helix stabilizes the MCU open state via a discrete EMRE-dependence domain, while the N-terminal PKP motif strengthens binding.","evidence":"Transmembrane and PKP mutagenesis, chimeric MCU constructs, crosslinking, electrophysiology, and Ca2+ uptake assays","pmids":["33296646","32769116"],"confidence":"High","gaps":["Dynamic conformational transition captured only indirectly","How the gating signal couples to matrix C-terminal sensing not integrated"]},{"year":2020,"claim":"The structural placement of EMRE within the channel and its lipid requirements were undefined; a cryo-EM structure positioned EMRE at the periphery contacting the first MCU helix and reconstitution showed Ca2+ conduction requires cardiolipin.","evidence":"Cryo-EM of the Tribolium MCU-EMRE complex at 3.5 Å with proteoliposome reconstitution and Ca2+ uptake assays","pmids":["32841658"],"confidence":"High","gaps":["Structure from insect ortholog; human-specific features not directly resolved","MICU1/MICU2-bound state not captured","Role of cardiolipin in gating versus assembly not separated"]},{"year":2020,"claim":"Whether EMRE stoichiometry shapes channel behavior was unknown; defined concatemer ratios showed 2EMRE:4MCU recapitulates endogenous gatekeeping and that EMRE abundance sets the cytoplasmic Ca2+ activation threshold.","evidence":"MCU-EMRE concatemers at fixed ratios with mitoplast electrophysiology and Ca2+ uptake assays","pmids":["32315830"],"confidence":"Medium","gaps":["Single-lab concatemer constructs may not reflect native assembly dynamics","How cells regulate EMRE stoichiometry not addressed"]},{"year":2020,"claim":"Whether EMRE is required for uniporter function in a whole organism was untested; germline knockout mice lost rapid mitochondrial Ca2+ uptake, confirming the in vivo requirement.","evidence":"Germline EMRE knockout mouse with Ca2+ uptake in isolated mitochondria and metabolic phenotyping","pmids":["32017711"],"confidence":"High","gaps":["Tissue-specific consequences not dissected by germline deletion","Disease-modification outcome in dystrophy model not fully resolved"]},{"year":2022,"claim":"Whether the in vitro variable stoichiometry occurs natively was open; quantitative tissue measurements showed EMRE is substoichiometric to MCU with tissue-specific MCU:EMRE ratios.","evidence":"Calibrated quantitative Western blotting of mouse tissue mitochondrial fractions with stoichiometric modeling","pmids":["35060355"],"confidence":"Medium","gaps":["Functional consequence of tissue-specific ratios not directly measured","Estimates derived from statistical modeling rather than direct counting"]},{"year":2023,"claim":"Whether SMDT1 loss causes human disease was unknown; patient variants abolished EMRE protein and impaired mitochondrial Ca2+ uptake, with complementation confirming loss of function.","evidence":"Patient fibroblast analysis, complementation, Ca2+ uptake, OXPHOS activity, and morphology assays","pmids":["37454773"],"confidence":"Medium","gaps":["Only two patients characterized","Clinical phenotype-genotype relationship not broadly defined","OXPHOS and morphology unaffected, leaving the cellular pathology mechanism open"]},{"year":2023,"claim":"The physiological role of EMRE-dependent Ca2+ uptake in the heart and its therapeutic relevance were unclear; inducible cardiac deletion linked EMRE loss to reduced Ca2+-stimulated ATP, attenuated mPTP and adrenergic responses, and time-dependent effects on ischemia/reperfusion injury.","evidence":"Tamoxifen-inducible cardiac-specific EMRE knockout with Ca2+ uptake, ATP, mPTP, adrenergic, and ex vivo I/R assays at two time points","pmids":["37230379"],"confidence":"High","gaps":["Molecular basis of the long-term adaptive loss of I/R protection not defined","Translation to in vivo I/R and other tissues not addressed"]},{"year":null,"claim":"How EMRE expression and stoichiometry are dynamically regulated to tune uniporter activity across tissues and physiological states, and how its dual matrix-sensing and gating functions are mechanistically coupled, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanism for transcriptional or post-translational control of EMRE levels established","Integration of matrix C-terminal sensing with transmembrane gating not structurally resolved","Human disease spectrum from SMDT1 variants poorly defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,6]}],"pathway":[],"complexes":["mitochondrial calcium uniporter complex (uniplex)"],"partners":["MCU","MICU1","MICU2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H4I9","full_name":"Essential MCU regulator, mitochondrial","aliases":["Single-pass membrane protein with aspartate-rich tail 1, mitochondrial"],"length_aa":107,"mass_kda":11.4,"function":"Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria (PubMed:24231807, PubMed:26774479, PubMed:27099988, PubMed:30454562, PubMed:31080062, PubMed:32315830, PubMed:32494073, PubMed:32762847, PubMed:32790952, PubMed:33296646). Required to bridge the calcium-sensing proteins MICU1 with the calcium-conducting subunit MCU (PubMed:24231807, PubMed:30454562, PubMed:32494073, PubMed:32762847, PubMed:32790952). Acts by mediating activation of MCU and retention of MICU1 to the MCU pore, in order to ensure tight regulation of the uniplex complex and appropriate responses to intracellular calcium signaling (PubMed:27099988, PubMed:31080062, PubMed:32315830, PubMed:33296646)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q9H4I9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMDT1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SMDT1","total_profiled":1310},"omim":[{"mim_id":"617267","title":"MATRIX AAA PEPTIDASE-INTERACTING PROTEIN 1; MAIP1","url":"https://www.omim.org/entry/617267"},{"mim_id":"616952","title":"MITOCHONDRIAL CALCIUM UNIPORTER REGULATOR 1; MCUR1","url":"https://www.omim.org/entry/616952"},{"mim_id":"615588","title":"SINGLE-PASS MEMBRANE PROTEIN WITH ASPARTATE-RICH TAIL 1; SMDT1","url":"https://www.omim.org/entry/615588"},{"mim_id":"614197","title":"MITOCHONDRIAL CALCIUM UNIPORTER; MCU","url":"https://www.omim.org/entry/614197"},{"mim_id":"610632","title":"MITOCHONDRIAL CALCIUM UPTAKE PROTEIN 2; MICU2","url":"https://www.omim.org/entry/610632"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SMDT1"},"hgnc":{"alias_symbol":["dJ186O1.1","DDDD","EMRE"],"prev_symbol":["C22orf32"]},"alphafold":{"accession":"Q9H4I9","domains":[{"cath_id":"1.20.5","chopping":"64-96","consensus_level":"medium","plddt":89.6552,"start":64,"end":96}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H4I9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H4I9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H4I9-F1-predicted_aligned_error_v6.png","plddt_mean":72.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMDT1","jax_strain_url":"https://www.jax.org/strain/search?query=SMDT1"},"sequence":{"accession":"Q9H4I9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H4I9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H4I9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H4I9"}},"corpus_meta":[{"pmid":"24231807","id":"PMC_24231807","title":"EMRE is an essential component of the mitochondrial calcium uniporter complex.","date":"2013","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24231807","citation_count":558,"is_preprint":false},{"pmid":"7896833","id":"PMC_7896833","title":"EmrE, an Escherichia coli 12-kDa multidrug transporter, exchanges toxic cations and H+ and is soluble in organic solvents.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7896833","citation_count":261,"is_preprint":false},{"pmid":"18024586","id":"PMC_18024586","title":"X-ray structure of EmrE supports dual topology model.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18024586","citation_count":222,"is_preprint":false},{"pmid":"10637227","id":"PMC_10637227","title":"A membrane-embedded glutamate is required for ligand binding to the multidrug transporter EmrE.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10637227","citation_count":171,"is_preprint":false},{"pmid":"19167526","id":"PMC_19167526","title":"EmrE, a model for studying evolution and mechanism of ion-coupled transporters.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19167526","citation_count":131,"is_preprint":false},{"pmid":"26774479","id":"PMC_26774479","title":"EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26774479","citation_count":128,"is_preprint":false},{"pmid":"10681497","id":"PMC_10681497","title":"An essential glutamyl residue in EmrE, a multidrug antiporter from Escherichia coli.","date":"2000","source":"The Journal of biological 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/37454773","citation_count":8,"is_preprint":false},{"pmid":"37992165","id":"PMC_37992165","title":"Similar but different: Characterization of dddD gene-mediated DMSP metabolism among coral-associated Endozoicomonas.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37992165","citation_count":8,"is_preprint":false},{"pmid":"35994672","id":"PMC_35994672","title":"Cotranslational folding and assembly of the dimeric Escherichia coli inner membrane protein EmrE.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35994672","citation_count":8,"is_preprint":false},{"pmid":"35060355","id":"PMC_35060355","title":"Quantitative analysis of mitochondrial calcium uniporter (MCU) and essential MCU regulator (EMRE) in mitochondria from mouse tissues and HeLa cells.","date":"2022","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/35060355","citation_count":8,"is_preprint":false},{"pmid":"26014489","id":"PMC_26014489","title":"Structural and dynamic changes adopted by EmrE, multidrug transporter protein--Studies by molecular dynamics simulation.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26014489","citation_count":8,"is_preprint":false},{"pmid":"22326892","id":"PMC_22326892","title":"Spectroscopic analysis of small multidrug resistance protein EmrE in the presence of various quaternary cation compounds.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22326892","citation_count":8,"is_preprint":false},{"pmid":"28432015","id":"PMC_28432015","title":"BLaTM 2.0, a Genetic Tool Revealing Preferred Antiparallel Interaction of Transmembrane Helix 4 of the Dual-Topology Protein EmrE.","date":"2017","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28432015","citation_count":8,"is_preprint":false},{"pmid":"29124131","id":"PMC_29124131","title":"Structural and functional comparison of hexahistidine tagged and untagged forms of small multidrug resistance protein, EmrE.","date":"2015","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/29124131","citation_count":7,"is_preprint":false},{"pmid":"25157436","id":"PMC_25157436","title":"Functional response of the small multidrug resistance protein EmrE to mutations in transmembrane helix 2.","date":"2014","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/25157436","citation_count":7,"is_preprint":false},{"pmid":"15583400","id":"PMC_15583400","title":"Crystallography of the integral membrane protein EmrE from Escherichia coli.","date":"2004","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/15583400","citation_count":5,"is_preprint":false},{"pmid":"18845157","id":"PMC_18845157","title":"Structural insights into the catalytic mechanism of the bacterial class B phosphatase AphA belonging to the DDDD superfamily of phosphohydrolases.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18845157","citation_count":5,"is_preprint":false},{"pmid":"39197021","id":"PMC_39197021","title":"Metadynamics Study of Lipid-Mediated Antibacterial Toxin Binding to the EmrE Multiefflux Protein.","date":"2024","source":"The journal of physical chemistry. B","url":"https://pubmed.ncbi.nlm.nih.gov/39197021","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42209,"output_tokens":3880,"usd":0.092413,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11353,"output_tokens":4204,"usd":0.080933,"stage2_stop_reason":"end_turn"},"total_usd":0.173346,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to distinguish between:\n1. Papers about SMDT1/EMRE (the mitochondrial calcium uniporter component) - the query gene\n2. Papers about EmrE (bacterial multidrug resistance transporter) - a completely different protein that shares the alias \"EMRE\" but is unrelated\n3. Papers about DddD, AphA/DDDD superfamily - clearly different proteins\n\nThe HGNC aliases include \"EMRE\" and \"DDDD\" - but I must check context. The \"EMRE\" in the bacterial context (papers 2-19, 21, 23-27, etc.) is the E. coli multidrug transporter EmrE, which is fundamentally different from human SMDT1/EMRE (mitochondrial calcium uniporter subunit). These are symbol collisions, not orthologs.\n\nPapers 1, 6, 22, 28, 50, 57, 63, 70, 71, 78, 89, 92 are about the mammalian SMDT1/EMRE (mitochondrial calcium uniporter).\n\nThe \"DDDD\" alias refers to the gene C22orf32/SMDT1, but papers 67, 75, 99 describe AphA bacterial phosphatases of the \"DDDD superfamily\" - these are symbol collisions, not the query gene.\n\nPaper 82 describes lncRNA C22orf32-1 - this is a non-protein product, exclude.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"EMRE (SMDT1) was identified as an essential component of the mitochondrial calcium uniporter holocomplex (uniplex) via quantitative mass spectrometry of affinity-purified uniplex. EMRE is a 10-kDa, metazoan-specific, single-transmembrane domain protein. In its absence, uniporter channel activity was lost despite intact MCU expression and oligomerization. EMRE was required for the interaction of MCU with MICU1 and MICU2, bridging the calcium-sensing role of MICU1/MICU2 with the calcium-conducting role of MCU.\",\n      \"method\": \"Quantitative mass spectrometry of affinity-purified complex, loss-of-function (siRNA knockdown), co-immunoprecipitation, electrophysiology\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (MS, Co-IP, electrophysiology, KD) in a single rigorous study identifying the protein and its essential role\",\n      \"pmids\": [\"24231807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EMRE acts as a matrix Ca2+ sensor that governs gatekeeping of the mitochondrial Ca2+ uniporter. Deletion or charge neutralization of EMRE's matrix-localized acidic C terminus abolished matrix Ca2+ inhibition of MCU Ca2+ currents, resulting in MCU channel activation, enhanced mitochondrial Ca2+ uptake, and constitutively elevated matrix Ca2+ concentration. EMRE-dependent regulation requires IMS-localized MICU1 and MICU2 and cytoplasmic Ca2+, coupling Ca2+ sensors on both sides of the inner mitochondrial membrane.\",\n      \"method\": \"Patch-clamp electrophysiology of mitoplasts, EMRE deletion and charge-neutralization mutagenesis, mitochondrial Ca2+ uptake assays\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct electrophysiology with mutagenesis of EMRE C-terminus, multiple functional readouts, establishes mechanistic role of EMRE's acidic tail\",\n      \"pmids\": [\"26774479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EMRE topology was experimentally determined using a yeast expression system: its N-terminus projects into the mitochondrial matrix and its C-terminus projects into the intermembrane space. EMRE closely interacts with MCU on both sides of the inner membrane, and this interaction is essential for Ca2+ uptake. Co-expression of MCU with EMRE was necessary for Ca2+ uptake; EMRE expression alone was insufficient. EMRE was not a protein-stabilizing factor for other MCU complex subunits.\",\n      \"method\": \"Yeast expression system reconstitution, protease protection/topology assays, Ca2+ uptake assays, co-immunoprecipitation\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution in yeast with topology and functional assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27001609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EMRE deletion in a mouse model confirmed that EMRE is required for mitochondrial calcium uniporter function in vivo. EMRE-/- mice showed loss of rapid mitochondrial Ca2+ uptake. EMRE deletion in a muscular dystrophy model associated with mitochondrial Ca2+ overload was examined for disease modification.\",\n      \"method\": \"Germline EMRE knockout mouse model, mitochondrial Ca2+ uptake assays in isolated mitochondria, exercise and metabolic phenotyping\",\n      \"journal\": \"JCI Insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout mouse model with direct functional measurement of mitochondrial Ca2+ uptake, replicates cell-culture findings in a whole-organism context\",\n      \"pmids\": [\"32017711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EMRE controls MCU activity via its transmembrane helix, while an N-terminal PKP motif strengthens binding with MCU. Opening of MCU requires hydrophobic interactions mediated by MCU residues near the pore's luminal end. A single mutation in human MCU that enhances these hydrophobic interactions allows Ca2+ transport without EMRE. EMRE facilitates MCU opening by stabilizing the open state in a conserved MCU gating mechanism.\",\n      \"method\": \"Mutagenesis of EMRE transmembrane domain and PKP motif, Ca2+ uptake assays, patch-clamp electrophysiology, chimeric MCU constructs\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic mutagenesis combined with electrophysiology and functional Ca2+ assays, multiple orthogonal methods defining the transmembrane mechanism\",\n      \"pmids\": [\"33296646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Variable assembly of EMRE and MCU creates functional channels with distinct gatekeeping profiles. Most endogenous channels contain two EMRE subunits per MCU tetramer. MCU-EMRE concatemers enforcing 1EMRE:4MCU restored Ca2+ uptake but not full gatekeeping; 4EMRE:4MCU enhanced gatekeeping; 2EMRE:4MCU recapitulated endogenous channel activity and gatekeeping. Increasing EMRE expression raises the cytoplasmic Ca2+ threshold for channel activation.\",\n      \"method\": \"MCU-EMRE concatemer expression, electrophysiology of mitoplasts, mitochondrial Ca2+ uptake assays, tagged subunit co-expression at defined ratios\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — concatemer approach with electrophysiology and functional assays in single lab, multiple orthogonal methods defining stoichiometry-function relationship\",\n      \"pmids\": [\"32315830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A cryo-EM structure of the MCU-EMRE complex from Tribolium castaneum at 3.5 Å resolution showed EMRE located at the periphery of the transmembrane domain, associating primarily with the first transmembrane helix of MCU in a tetrameric channel. Ca2+ uptake into proteoliposomes reconstituted with the purified MCU-EMRE complex was EMRE-dependent and also required the mitochondrial lipid cardiolipin.\",\n      \"method\": \"Cryo-EM structure determination, functional reconstitution in proteoliposomes, Ca2+ uptake assays\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with functional reconstitution and defined lipid requirement, establishes EMRE's structural position and functional dependence\",\n      \"pmids\": [\"32841658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Using chimeric proteins between EMRE-independent Dictyostelium discoideum MCU and human MCU, a 10-amino acid region in human MCU (the EMRE dependence domain, EDD) was identified as necessary for EMRE dependence. Crosslinking experiments showed EMRE directly interacts with human MCU at its transmembrane domains as well as the EDD. EMRE stabilizes the EDD of MCU, permitting channel opening and Ca2+ conductance.\",\n      \"method\": \"Chimeric MCU constructs, crosslinking experiments, Ca2+ uptake assays in cells lacking endogenous MCU/EMRE\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic chimera mapping plus crosslinking in a single lab, two orthogonal methods identifying the interaction domain\",\n      \"pmids\": [\"32769116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SMDT1 (EMRE) overexpression in PDAC cells led to increased accumulation of pro-apoptotic protein BAX, decrease in anti-apoptotic proteins Bcl-2 and Bcl-xL, and more cytochrome c release. Mechanistically, SMDT1 overexpression promoted mitochondrial fragmentation by increasing phosphorylation of Drp1 and Fis1 while decreasing MFN1, and increased translocation of Drp1 from cytoplasm to mitochondria.\",\n      \"method\": \"SMDT1 overexpression, Western blotting for apoptosis markers, mitochondrial morphology analysis, cell viability/apoptosis assays\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression study with phenotypic readouts but limited mechanistic validation of direct EMRE-Drp1 pathway link\",\n      \"pmids\": [\"30782485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Two patients with SMDT1 variants were characterized showing absence of EMRE protein, induction of MCU subcomplex formation (without EMRE), and impaired mitochondrial Ca2+ uptake in patient fibroblasts. Complementation experiments demonstrated that the SMDT1 variants caused loss of EMRE function. Oxidative phosphorylation enzyme activities, mitochondrial morphology, membrane potential, and routine respiration were not affected.\",\n      \"method\": \"Patient fibroblast analysis, complementation experiments, mitochondrial Ca2+ uptake assays, OXPHOS enzyme activity assays, mitochondrial morphology imaging\",\n      \"journal\": \"Biochimica et Biophysica Acta - Molecular Basis of Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human patient variants with complementation, multiple orthogonal functional assays confirming EMRE's role in MCU-dependent Ca2+ uptake\",\n      \"pmids\": [\"37454773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Quantitative analysis of MCU and EMRE in mouse tissue mitochondria showed that EMRE molecules are fewer than MCU molecules, with MCU:EMRE ratios significantly different among tissues. Statistical modeling suggested most endogenous MCU tetramers in brain bind 2 EMREs; in liver, kidney, and heart predominantly 1 EMRE; with nearly half of MCU tetramers in kidney and heart binding no EMRE, supporting variable stoichiometry of the MCU-EMRE complex in vivo.\",\n      \"method\": \"Quantitative Western blotting with characterized antibodies and standard proteins, stoichiometric calculations from mouse tissue mitochondrial fractions\",\n      \"journal\": \"FEBS Open Bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative protein measurement across multiple tissues with calibrated standards, single lab but systematic approach establishing in vivo stoichiometry\",\n      \"pmids\": [\"35060355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cardiac-specific, tamoxifen-inducible EMRE deletion established that short-term EMRE loss abolished mitochondrial Ca2+ uptake, lowered basal mitochondrial Ca2+ levels, attenuated Ca2+-induced ATP production and mPTP opening, blunted cardiac adrenergic response, and improved maintenance of cardiac function in ex vivo ischemia/reperfusion. Long-term EMRE deletion similarly impaired mitochondrial Ca2+ handling but lost the protection from I/R injury, demonstrating time-dependent adaptive consequences.\",\n      \"method\": \"Conditional cardiac-specific tamoxifen-inducible EMRE knockout mouse, mitochondrial Ca2+ uptake assays, ATP production assays, mPTP opening assays, adrenergic stimulation, ex vivo I/R model\",\n      \"journal\": \"Journal of Molecular and Cellular Cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible cardiac-specific KO with multiple orthogonal functional assays (Ca2+ uptake, ATP production, mPTP, cardiac function) at two time points\",\n      \"pmids\": [\"37230379\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMDT1 (EMRE) is a metazoan-specific, single-pass inner mitochondrial membrane protein (N-terminus in matrix, C-terminus in IMS) that is an essential subunit of the mitochondrial calcium uniporter complex: it physically bridges MCU with the Ca2+-sensing regulators MICU1 and MICU2 via its transmembrane helix and N-terminal PKP motif, gates MCU channel opening by stabilizing the open state, and uses its matrix-localized acidic C-terminus to sense matrix Ca2+ and inhibit MCU, thereby protecting mitochondria from both Ca2+ depletion and overload; in vivo, most endogenous MCU tetramers contain 1–2 EMRE subunits with stoichiometry varying by tissue, and EMRE-dependent uniporter activity is required for Ca2+-stimulated ATP production, mPTP regulation, and cardiac responses to adrenergic stress and ischemia/reperfusion injury.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMDT1 (EMRE) is a metazoan-specific, single-pass inner mitochondrial membrane protein that serves as an essential subunit of the mitochondrial calcium uniporter holocomplex, bridging the Ca2+-conducting MCU channel with the Ca2+-sensing regulators MICU1 and MICU2 [#0]. In its absence, uniporter channel activity is lost despite intact MCU expression and oligomerization, and the interaction of MCU with MICU1/MICU2 fails to form [#0]. EMRE adopts an Nin-Cout topology with its N-terminus in the matrix and C-terminus in the intermembrane space, and it contacts MCU on both sides of the membrane [#2]. Mechanistically, EMRE drives MCU channel opening through its transmembrane helix, which stabilizes the MCU \\\"EMRE dependence domain\\\" and the open conformation, while an N-terminal PKP motif strengthens MCU binding [#4, #7]; a cryo-EM structure places EMRE at the periphery of the tetrameric transmembrane domain in contact with the first MCU helix, with Ca2+ conduction additionally requiring cardiolipin [#6]. EMRE also acts as a matrix Ca2+ sensor: its matrix-localized acidic C-terminus confers matrix Ca2+ inhibition of MCU, and removing or neutralizing it produces constitutive channel activation and Ca2+ overload, coupling Ca2+ sensors on both faces of the inner membrane [#1]. The MCU:EMRE assembly is variable, with most endogenous tetramers binding one or two EMRE subunits and stoichiometry differing across tissues, which tunes the cytoplasmic Ca2+ threshold for channel gating [#5, #10]. In vivo, EMRE is required for rapid mitochondrial Ca2+ uptake [#3], and cardiac-specific deletion abolishes uptake while attenuating Ca2+-stimulated ATP production, mPTP opening, the adrenergic response, and ischemia/reperfusion outcomes in a time-dependent manner [#11]. Loss-of-function SMDT1 variants in patients abolish EMRE protein and impair mitochondrial Ca2+ uptake, establishing a human disease link to defective uniporter function [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"It was unknown how the calcium-sensing MICU proteins coupled to the calcium-conducting MCU; EMRE was identified as the missing essential subunit that bridges them and is required for uniporter channel activity.\",\n      \"evidence\": \"Quantitative MS of affinity-purified uniplex with siRNA knockdown, Co-IP, and electrophysiology\",\n      \"pmids\": [\"24231807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Topology and which membrane faces EMRE contacts MCU not yet defined\",\n        \"Structural basis of the bridging interaction unknown\",\n        \"No in vivo confirmation at this stage\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The membrane orientation of EMRE and the side(s) on which it engages MCU were unresolved; a yeast reconstitution established Nin-Cout topology and showed EMRE contacts MCU on both membrane faces and is required for Ca2+ uptake rather than acting as a stabilizing chaperone.\",\n      \"evidence\": \"Yeast reconstitution with protease-protection topology assays, Ca2+ uptake, and Co-IP\",\n      \"pmids\": [\"27001609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reconstitution in heterologous yeast system may not fully recapitulate mammalian complex\",\n        \"Atomic-level contact sites not mapped\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether EMRE only enables channel opening or also restrains it was open; mutagenesis of its matrix acidic C-terminus showed this tail senses matrix Ca2+ and confers inhibitory gatekeeping requiring MICU1/MICU2 and cytoplasmic Ca2+.\",\n      \"evidence\": \"Mitoplast patch-clamp with C-terminal deletion and charge-neutralization mutants and Ca2+ uptake assays\",\n      \"pmids\": [\"26774479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural mechanism by which the acidic tail transmits inhibition not resolved\",\n        \"Quantitative Ca2+ affinity of the matrix sensor not defined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether EMRE levels influence cell-death decisions was untested; overexpression in PDAC cells linked EMRE to pro-apoptotic signaling and mitochondrial fragmentation.\",\n      \"evidence\": \"SMDT1 overexpression with Western blotting of apoptosis markers and mitochondrial morphology analysis\",\n      \"pmids\": [\"30782485\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Overexpression phenotype without loss-of-function validation of the EMRE-Drp1 link\",\n        \"Direct molecular connection between EMRE and Drp1/Fis1 phosphorylation not established\",\n        \"Not shown to depend on uniporter Ca2+ flux\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"How EMRE mechanically opens MCU was unknown; mutagenesis and chimera/crosslinking work showed the EMRE transmembrane helix stabilizes the MCU open state via a discrete EMRE-dependence domain, while the N-terminal PKP motif strengthens binding.\",\n      \"evidence\": \"Transmembrane and PKP mutagenesis, chimeric MCU constructs, crosslinking, electrophysiology, and Ca2+ uptake assays\",\n      \"pmids\": [\"33296646\", \"32769116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Dynamic conformational transition captured only indirectly\",\n        \"How the gating signal couples to matrix C-terminal sensing not integrated\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The structural placement of EMRE within the channel and its lipid requirements were undefined; a cryo-EM structure positioned EMRE at the periphery contacting the first MCU helix and reconstitution showed Ca2+ conduction requires cardiolipin.\",\n      \"evidence\": \"Cryo-EM of the Tribolium MCU-EMRE complex at 3.5 Å with proteoliposome reconstitution and Ca2+ uptake assays\",\n      \"pmids\": [\"32841658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure from insect ortholog; human-specific features not directly resolved\",\n        \"MICU1/MICU2-bound state not captured\",\n        \"Role of cardiolipin in gating versus assembly not separated\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether EMRE stoichiometry shapes channel behavior was unknown; defined concatemer ratios showed 2EMRE:4MCU recapitulates endogenous gatekeeping and that EMRE abundance sets the cytoplasmic Ca2+ activation threshold.\",\n      \"evidence\": \"MCU-EMRE concatemers at fixed ratios with mitoplast electrophysiology and Ca2+ uptake assays\",\n      \"pmids\": [\"32315830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab concatemer constructs may not reflect native assembly dynamics\",\n        \"How cells regulate EMRE stoichiometry not addressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether EMRE is required for uniporter function in a whole organism was untested; germline knockout mice lost rapid mitochondrial Ca2+ uptake, confirming the in vivo requirement.\",\n      \"evidence\": \"Germline EMRE knockout mouse with Ca2+ uptake in isolated mitochondria and metabolic phenotyping\",\n      \"pmids\": [\"32017711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Tissue-specific consequences not dissected by germline deletion\",\n        \"Disease-modification outcome in dystrophy model not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether the in vitro variable stoichiometry occurs natively was open; quantitative tissue measurements showed EMRE is substoichiometric to MCU with tissue-specific MCU:EMRE ratios.\",\n      \"evidence\": \"Calibrated quantitative Western blotting of mouse tissue mitochondrial fractions with stoichiometric modeling\",\n      \"pmids\": [\"35060355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of tissue-specific ratios not directly measured\",\n        \"Estimates derived from statistical modeling rather than direct counting\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether SMDT1 loss causes human disease was unknown; patient variants abolished EMRE protein and impaired mitochondrial Ca2+ uptake, with complementation confirming loss of function.\",\n      \"evidence\": \"Patient fibroblast analysis, complementation, Ca2+ uptake, OXPHOS activity, and morphology assays\",\n      \"pmids\": [\"37454773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only two patients characterized\",\n        \"Clinical phenotype-genotype relationship not broadly defined\",\n        \"OXPHOS and morphology unaffected, leaving the cellular pathology mechanism open\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The physiological role of EMRE-dependent Ca2+ uptake in the heart and its therapeutic relevance were unclear; inducible cardiac deletion linked EMRE loss to reduced Ca2+-stimulated ATP, attenuated mPTP and adrenergic responses, and time-dependent effects on ischemia/reperfusion injury.\",\n      \"evidence\": \"Tamoxifen-inducible cardiac-specific EMRE knockout with Ca2+ uptake, ATP, mPTP, adrenergic, and ex vivo I/R assays at two time points\",\n      \"pmids\": [\"37230379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of the long-term adaptive loss of I/R protection not defined\",\n        \"Translation to in vivo I/R and other tissues not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EMRE expression and stoichiometry are dynamically regulated to tune uniporter activity across tissues and physiological states, and how its dual matrix-sensing and gating functions are mechanistically coupled, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No mechanism for transcriptional or post-translational control of EMRE levels established\",\n        \"Integration of matrix C-terminal sensing with transmembrane gating not structurally resolved\",\n        \"Human disease spectrum from SMDT1 variants poorly defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006851\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [\n      \"mitochondrial calcium uniporter complex (uniplex)\"\n    ],\n    \"partners\": [\n      \"MCU\",\n      \"MICU1\",\n      \"MICU2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}