{"gene":"MCUR1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2012,"finding":"MCUR1 (CCDC90A) is an integral inner mitochondrial membrane protein that physically binds to MCU and is required for ruthenium-red-sensitive, MCU-dependent mitochondrial Ca2+ uptake. MCUR1 knockdown abrogates Ca2+ uptake by energized mitochondria in intact and permeabilized cells without altering MCU localization. Loss of MCUR1 disrupts oxidative phosphorylation, lowers cellular ATP, and activates AMPK-dependent pro-survival autophagy.","method":"Co-immunoprecipitation (MCU-MCUR1 binding), siRNA knockdown with Ca2+ uptake assays in intact and permeabilized cells, ruthenium red sensitivity assays, ATP measurements, AMPK activation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal functional assays (intact cells, permeabilized cells, ruthenium red), replicated across cell types; foundational paper with extensive controls","pmids":["23178883"],"is_preprint":false},{"year":2015,"finding":"Suppression of CCDC90A (MCUR1) in human fibroblasts produces a specific cytochrome c oxidase (COX) assembly defect, resulting in decreased mitochondrial membrane potential and reduced mitochondrial Ca2+ uptake capacity. The yeast homolog Fmp32 deletion also causes COX deficiency, indicating the function is evolutionarily conserved. This study argues CCDC90A acts indirectly on Ca2+ uptake via membrane potential, not as a direct MCU regulator.","method":"siRNA knockdown in human fibroblasts, COX assembly assays, mitochondrial membrane potential measurements, Ca2+ uptake capacity assays, genetic deletion of yeast homolog fmp32, rescue with wild-type cDNA in COX-deficient patient fibroblasts","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (COX assembly, membrane potential, Ca2+ uptake, genetic rescue), cross-species validation in yeast; challenges the direct MCU-regulator model with rigorous mechanistic evidence","pmids":["25565209"],"is_preprint":false},{"year":2016,"finding":"MCUR1 functions as a scaffold factor for the MCU complex, binding both MCU and EMRE. Loss of MCUR1 in mouse cardiomyocytes and endothelial cells severely impairs mitochondrial Ca2+ uptake current (IMCU). The minimal coiled-coil domains of both MCU and MCUR1 are necessary for heterooligomeric complex formation. Loss of MCUR1 perturbs MCU complex assembly and impairs mitochondrial bioenergetics, cell proliferation, and migration while eliciting autophagy.","method":"Protein binding analyses identifying coiled-coil interaction domains, IMCU current measurements (electrophysiology), Co-IP of MCUR1 with MCU and EMRE, conditional genetic deletion in cardiomyocytes and endothelial cells, cell proliferation and migration assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, electrophysiological current measurements, domain mapping, in vivo conditional knockout with multiple phenotypic readouts; multiple orthogonal methods in single study","pmids":["27184846"],"is_preprint":false},{"year":2016,"finding":"MCUR1 expression regulates the Ca2+ threshold required for mitochondrial permeability transition (mPT). Expression of MCUR1 in Drosophila cells conferred mPT sensitivity to electrophoretic Ca2+ uptake; inhibiting MCUR1 in mammalian cells increased the Ca2+ threshold required to induce mPT. This resistance to Ca2+ overload improved cell survival. The effect was specific to Ca2+-induced permeability transition.","method":"Cross-species complementation (MCUR1 expression in Drosophila cells), MCUR1 knockdown in mammalian cells, mitochondrial permeability transition assays with Ca2+ titration, cell survival assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function and loss-of-function experiments in two cell systems, specific Ca2+-triggered mPT assay, multiple orthogonal approaches in single study","pmids":["26976564"],"is_preprint":false},{"year":2019,"finding":"The head domain of MCUR1 directly interacts with the mitochondrial calcium uniporter (MCU) and is destabilized upon Ca2+ binding. Crystal structures of the related CCDC90B head domain and archaeal Kcr-0859 reveal a conserved head-neck-stalk-anchor architecture with a β-layer neck. MCUR1 and CCDC90B are part of a heterogeneous group of trimeric membrane-anchored coiled-coil proteins conserved from prokaryotes to eukaryotic organelles.","method":"Crystal structure determination of CCDC90B head domain and archaeal Kcr-0859, domain deletion/mutagenesis studies of MCUR1, Ca2+ binding and destabilization assays, sequence analysis defining domain architecture","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures solved, domain function validated by mutagenesis/deletion; single lab but with structural and biochemical orthogonal methods","pmids":["30612859"],"is_preprint":false},{"year":2019,"finding":"MCUR1-mediated mitochondrial Ca2+ uptake activates the ROS/Nrf2/Notch1 pathway, which drives EMT via Snail in hepatocellular carcinoma cells. MCUR1 promotes in vitro invasion and in vivo metastasis. Inhibition of ROS, mitochondrial Ca2+ uptake, Nrf2, or Notch1 suppresses MCUR1-induced EMT. Mitochondrial Ca2+-buffering with parvalbumin inhibits the pathway and MCUR1-induced EMT and metastasis.","method":"MCUR1 knockdown/overexpression in HCC cells, immunofluorescent staining for EMT markers, in vitro invasion assays, in vivo metastasis assays, ROS measurement, pathway inhibition with chemical inhibitors and parvalbumin treatment, Western blot","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function, gain-of-function, and pharmacological rescue experiments with defined pathway placement; single lab, multiple methods but no direct biochemical binding assay","pmids":["30909929"],"is_preprint":false},{"year":2017,"finding":"MCUR1-mediated mitochondrial Ca2+ uptake elevates mitochondrial ROS production, which drives AKT/MDM2-mediated P53 degradation to inhibit intrinsic apoptosis and promote HCC cell survival and proliferation. MCUR1 overexpression enhances MCU-dependent Ca2+ uptake; knockdown impairs it. Mitochondrial Ca2+ buffering with parvalbumin inhibits HCC cell growth.","method":"MCUR1 knockdown/overexpression in HCC cells, mitochondrial Ca2+ uptake measurements, ROS measurement, P53 degradation assays, AKT/MDM2 pathway analysis, in vivo xenograft assays (TUNEL, Ki67 staining), parvalbumin treatment","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss/gain of function with mechanistic pathway placement and in vivo validation; single lab, multiple orthogonal assays","pmids":["28938844"],"is_preprint":false},{"year":2020,"finding":"Yeast homologs of MCUR1, Put6 and Put7, form a large hetero-oligomeric complex tethered to the inner mitochondrial membrane and regulate mitochondrial proline metabolism. Loss of this complex perturbs mitochondrial proline homeostasis and cellular redox balance; cells lacking Put6 or Put7 cannot utilize proline. This defect is rescued by heterologous expression of human MCUR1, demonstrating functional conservation of MCUR1 homologs in mitochondrial metabolic scaffolding beyond Ca2+ regulation.","method":"Genetic deletion of Put6/Put7 in S. cerevisiae, mitochondrial fractionation, hetero-oligomeric complex characterization, proline utilization assays, metabolomics, redox assays, heterologous complementation with human MCUR1","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion with metabolic phenotype, complex characterization, and heterologous rescue with human MCUR1; multiple orthogonal methods establishing conserved metabolic scaffold function","pmids":["32978391"],"is_preprint":false},{"year":2025,"finding":"MCUR1 knockdown reduces mitochondrial Ca2+ uptake and concomitantly increases cytosolic Ca2+, which reduces erythropoiesis via the CAMKK2-AMPK-mTOR signaling axis under both hypoxia and normoxia. A functional SNP (rs61644582) acts as an expression QTL reducing MCUR1 transcription, and attenuates erythropoiesis in Tibetan highlanders.","method":"MCUR1 knockdown with single-cell RNA sequencing, mitochondrial Ca2+ uptake measurements, cytosolic Ca2+ measurements, pharmacological inhibition of CAMKK2-AMPK-mTOR pathway components, erythropoiesis differentiation assays, whole-genome sequencing and eQTL analysis","journal":"Cell genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined pathway placement via pharmacological dissection; single lab, multiple readouts but pathway placement relies partly on inhibitor studies","pmids":["40043709"],"is_preprint":false},{"year":2026,"finding":"A homozygous MCUR1 nonsense mutation in a human patient causes compromised mitochondrial Ca2+ uptake (stimulated by histamine or rising extracellular Ca2+), increased autophagic flux (LAMP2, LC3B markers), and autophagic vacuolar myopathy. Critically, MCUR1 loss-of-function does NOT alter MCU complex assembly, MCU subcellular localization, or resting mitochondrial membrane potential, indicating MCUR1 promotes MCU activity without being required for MCU complex assembly or stability.","method":"Patient fibroblasts and muscle biopsy analysis, mitochondrial Ca2+ uptake assays, autophagy flux assays, Western blot for MCU complex components, histological analysis, mitochondrial membrane potential measurement","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human loss-of-function mutation with multiple orthogonal mechanistic assays; single patient case but with functional validation in two tissue types","pmids":["42087238"],"is_preprint":false},{"year":2025,"finding":"MCUR1 and its paralog CCDC90B form a hetero-oligomeric complex whose stability depends on MCUR1. Loss of MCUR1 exerts a dominant-negative effect on CCDC90B. Deletion of MCUR1/CCDC90B homologs in S. pombe (which lacks MCU) impairs lipid and amino acid metabolism; this is rescued by human MCUR1 expression, indicating a Ca2+-independent scaffold function. MCUR1 deficiency in patient fibroblasts upregulates autophagy, perturbs non-essential amino acid metabolism, and limits biosynthetic capacity.","method":"Complex stability assays (co-IP, protein abundance measurement), S. pombe genetic deletion with metabolic rescue by human MCUR1 expression, patient serum metabolomics, patient fibroblast functional assays (autophagy, amino acid metabolism, proliferation, migration)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species genetic rescue, patient metabolomics, and fibroblast functional assays; preprint not yet peer reviewed, multiple orthogonal methods","pmids":["bio_10.1101_2025.10.14.682030"],"is_preprint":true}],"current_model":"MCUR1 is an integral inner mitochondrial membrane coiled-coil scaffold protein that directly binds MCU (and EMRE) via its conserved head domain to promote MCU-dependent mitochondrial Ca2+ uptake and regulate the Ca2+ threshold for mitochondrial permeability transition; beyond Ca2+ regulation, MCUR1 and its paralog CCDC90B form a conserved hetero-oligomeric scaffold that maintains mitochondrial metabolic homeostasis (including proline, lipid, and amino acid metabolism) independently of MCU, with loss of MCUR1 disrupting oxidative phosphorylation, activating AMPK-dependent autophagy, and causing autophagic vacuolar myopathy in humans."},"narrative":{"mechanistic_narrative":"MCUR1 (CCDC90A) is an integral inner mitochondrial membrane coiled-coil protein that acts as a scaffold for the mitochondrial calcium uniporter and as a broader regulator of mitochondrial metabolic homeostasis [PMID:23178883, PMID:27184846]. It physically binds MCU and EMRE through minimal coiled-coil interaction domains, forming a heterooligomeric complex required for MCU-dependent, ruthenium-red-sensitive mitochondrial Ca2+ uptake and for normal IMCU current [PMID:23178883, PMID:27184846]. The MCUR1 head domain directly engages MCU and is destabilized upon Ca2+ binding, within a conserved head-neck-stalk-anchor architecture shared with its paralog CCDC90B and prokaryotic relatives [PMID:30612859]. MCUR1 sets the Ca2+ threshold for mitochondrial permeability transition, such that its loss raises the threshold and confers resistance to Ca2+ overload [PMID:26976564]. Functionally, MCUR1-dependent Ca2+ uptake supports oxidative phosphorylation and cellular ATP, and its loss disrupts bioenergetics and activates AMPK-dependent autophagy [PMID:23178883, PMID:27184846]; one study links MCUR1 loss specifically to a cytochrome c oxidase assembly defect and reduced membrane potential, arguing its effect on Ca2+ uptake is at least partly indirect [PMID:25565209]. Beyond Ca2+ regulation, MCUR1 and CCDC90B form an MCUR1-stabilized hetero-oligomeric scaffold whose conserved function in proline, lipid, and amino acid metabolism is retained in yeast lacking MCU and rescuable by human MCUR1 [PMID:32978391, PMID:bio_10.1101_2025.10.14.682030]. In hepatocellular carcinoma, MCUR1-driven mitochondrial Ca2+ uptake elevates ROS to promote survival via AKT/MDM2-mediated p53 degradation and EMT/metastasis via the Nrf2/Notch1/Snail axis [PMID:30909929, PMID:28938844]. A homozygous MCUR1 nonsense mutation causes autophagic vacuolar myopathy in humans, with compromised Ca2+ uptake and increased autophagic flux but no change in MCU complex assembly or localization, establishing that MCUR1 promotes MCU activity without being required for complex stability [PMID:42087238].","teleology":[{"year":2012,"claim":"Established MCUR1 as a physical MCU partner required for mitochondrial Ca2+ uptake, defining it as a positive regulator of the uniporter and linking its loss to bioenergetic failure and autophagy.","evidence":"Co-IP of MCU-MCUR1 with siRNA knockdown, Ca2+ uptake assays in intact/permeabilized cells, ruthenium red sensitivity, ATP and AMPK assays","pmids":["23178883"],"confidence":"High","gaps":["Did not resolve whether the Ca2+ uptake defect is direct or secondary to bioenergetic loss","No structural basis for MCU binding","Did not test EMRE involvement"]},{"year":2015,"claim":"Challenged the direct-regulator model by attributing MCUR1's effect on Ca2+ uptake to a cytochrome c oxidase assembly defect and lowered membrane potential, and showed the function is evolutionarily conserved in yeast.","evidence":"siRNA in human fibroblasts, COX assembly and membrane potential assays, yeast fmp32 deletion, cDNA rescue in patient fibroblasts","pmids":["25565209"],"confidence":"High","gaps":["Did not reconcile COX-defect model with direct MCU binding data","Mechanism linking MCUR1 to COX assembly unresolved"]},{"year":2016,"claim":"Defined MCUR1 as a coiled-coil scaffold for MCU complex assembly and showed it regulates the Ca2+ threshold for permeability transition, connecting MCUR1 to both uniporter function and cell survival.","evidence":"Domain mapping of coiled-coil interactions, IMCU electrophysiology, Co-IP with MCU/EMRE, conditional knockout in cardiomyocytes and endothelial cells; Drosophila complementation and mPT Ca2+ titration assays","pmids":["27184846","26976564"],"confidence":"High","gaps":["Structural detail of the heterooligomer not resolved","Whether scaffold and mPT-threshold roles are mechanistically separable unclear"]},{"year":2019,"claim":"Provided the structural framework for MCUR1, defining a conserved head-neck-stalk-anchor architecture, a head domain that directly binds MCU and is Ca2+-destabilized, and a paralog relationship with CCDC90B.","evidence":"Crystal structures of CCDC90B head domain and archaeal Kcr-0859, MCUR1 domain mutagenesis, Ca2+ binding/destabilization assays","pmids":["30612859"],"confidence":"High","gaps":["No full-length MCUR1 structure","No co-structure of MCUR1 with MCU","Functional consequence of Ca2+-induced destabilization in cells untested"]},{"year":2017,"claim":"Placed MCUR1-driven Ca2+ uptake within a cancer survival circuit, showing it elevates mitochondrial ROS to drive AKT/MDM2-mediated p53 degradation and suppress apoptosis.","evidence":"MCUR1 knockdown/overexpression in HCC cells, Ca2+ and ROS measurements, p53 degradation and AKT/MDM2 analysis, xenograft assays, parvalbumin buffering","pmids":["28938844"],"confidence":"Medium","gaps":["No direct biochemical binding linking MCUR1 to the AKT/MDM2 axis","Pathway placement inferred from pharmacological buffering"]},{"year":2019,"claim":"Extended the MCUR1-ROS axis to EMT and metastasis, showing MCUR1-dependent Ca2+ uptake activates Nrf2/Notch1/Snail signaling to promote invasion.","evidence":"MCUR1 knockdown/overexpression in HCC, EMT marker staining, invasion/metastasis assays, ROS measurement, chemical and parvalbumin pathway inhibition","pmids":["30909929"],"confidence":"Medium","gaps":["No direct molecular binding assay","Causality relies on inhibitor and buffering experiments"]},{"year":2020,"claim":"Revealed a Ca2+-independent metabolic scaffold function by showing yeast homologs Put6/Put7 form an inner-membrane hetero-oligomer governing proline metabolism, rescuable by human MCUR1.","evidence":"Put6/Put7 deletion in S. cerevisiae, mitochondrial fractionation, complex characterization, proline utilization, metabolomics, redox assays, heterologous human MCUR1 complementation","pmids":["32978391"],"confidence":"High","gaps":["Direct substrate/enzyme partners of the scaffold not defined","Mechanism connecting scaffold to proline metabolism unresolved","Conservation of proline role in human cells not directly tested"]},{"year":2025,"claim":"Connected MCUR1 to physiology by showing its loss raises cytosolic Ca2+ and limits erythropoiesis through the CAMKK2-AMPK-mTOR axis, with a human eQTL variant tuning MCUR1 expression in highlanders.","evidence":"MCUR1 knockdown with scRNA-seq, mitochondrial/cytosolic Ca2+ measurements, pharmacological pathway dissection, erythropoiesis assays, whole-genome sequencing and eQTL analysis","pmids":["40043709"],"confidence":"Medium","gaps":["Pathway placement partly inhibitor-dependent","Direct link from cytosolic Ca2+ to CAMKK2 not biochemically shown"]},{"year":2026,"claim":"Established MCUR1 as a Mendelian disease gene, showing a homozygous nonsense mutation causes autophagic vacuolar myopathy with impaired Ca2+ uptake but intact MCU assembly, separating MCUR1's activating role from a structural requirement.","evidence":"Patient fibroblast and muscle biopsy analysis, Ca2+ uptake and autophagy flux assays, Western blot for MCU components, histology, membrane potential measurement","pmids":["42087238"],"confidence":"Medium","gaps":["Single patient case","Mechanism by which MCUR1 promotes MCU activity without affecting assembly not defined"]},{"year":2025,"claim":"Defined the MCUR1-CCDC90B hetero-oligomer as MCUR1-stabilized and demonstrated a conserved, MCU-independent scaffold role in lipid and amino acid metabolism underlying the human disease phenotype.","evidence":"Complex stability/Co-IP assays, S. pombe deletion with human MCUR1 rescue, patient serum metabolomics and fibroblast functional assays (preprint)","pmids":["bio_10.1101_2025.10.14.682030"],"confidence":"Medium","gaps":["Preprint not yet peer reviewed","Molecular substrates of the metabolic scaffold not identified","Mechanism of dominant-negative effect on CCDC90B unresolved"]},{"year":null,"claim":"How MCUR1 mechanistically reconciles its direct MCU-scaffold role with its MCU-independent metabolic scaffold function — and which is primary in the human myopathy — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of MCUR1 bound to MCU or to CCDC90B","Direct enzymatic partners of the metabolic scaffold unidentified","Relative contributions of Ca2+ and metabolic functions to disease undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,10]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,7]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,7,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,2,9]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,2,3]}],"complexes":["MCU complex (uniporter)","MCUR1-CCDC90B hetero-oligomer"],"partners":["MCU","EMRE","CCDC90B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96AQ8","full_name":"Mitochondrial calcium uniporter regulator 1","aliases":["Coiled-coil domain-containing protein 90A, mitochondrial"],"length_aa":359,"mass_kda":39.7,"function":"Key regulator of mitochondrial calcium uniporter (MCU) required for calcium entry into mitochondrion (PubMed:23178883, PubMed:26445506, PubMed:26976564, PubMed:27184846). Plays a direct role in uniporter-mediated calcium uptake via a direct interaction with MCU (PubMed:23178883). Probably involved in the assembly of the membrane components of the uniporter complex (uniplex) (PubMed:27184846)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q96AQ8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MCUR1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MCUR1","total_profiled":1310},"omim":[{"mim_id":"620753","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 90B; CCDC90B","url":"https://www.omim.org/entry/620753"},{"mim_id":"616952","title":"MITOCHONDRIAL CALCIUM UNIPORTER REGULATOR 1; MCUR1","url":"https://www.omim.org/entry/616952"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"retina","ntpm":75.6}],"url":"https://www.proteinatlas.org/search/MCUR1"},"hgnc":{"alias_symbol":["FLJ20958"],"prev_symbol":["C6orf79","CCDC90A"]},"alphafold":{"accession":"Q96AQ8","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AQ8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AQ8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AQ8-F1-predicted_aligned_error_v6.png","plddt_mean":69.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MCUR1","jax_strain_url":"https://www.jax.org/strain/search?query=MCUR1"},"sequence":{"accession":"Q96AQ8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96AQ8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96AQ8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AQ8"}},"corpus_meta":[{"pmid":"23178883","id":"PMC_23178883","title":"MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism.","date":"2012","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23178883","citation_count":447,"is_preprint":false},{"pmid":"27184846","id":"PMC_27184846","title":"MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27184846","citation_count":184,"is_preprint":false},{"pmid":"30909929","id":"PMC_30909929","title":"MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30909929","citation_count":128,"is_preprint":false},{"pmid":"25565209","id":"PMC_25565209","title":"CCDC90A (MCUR1) is a cytochrome c oxidase assembly factor and not a regulator of the mitochondrial calcium uniporter.","date":"2015","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25565209","citation_count":105,"is_preprint":false},{"pmid":"26976564","id":"PMC_26976564","title":"Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26976564","citation_count":87,"is_preprint":false},{"pmid":"28938844","id":"PMC_28938844","title":"MCUR1-Mediated Mitochondrial Calcium Signaling Facilitates Cell Survival of Hepatocellular Carcinoma via Reactive Oxygen Species-Dependent P53 Degradation.","date":"2017","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/28938844","citation_count":62,"is_preprint":false},{"pmid":"32978391","id":"PMC_32978391","title":"Yeast homologs of human MCUR1 regulate mitochondrial proline metabolism.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32978391","citation_count":24,"is_preprint":false},{"pmid":"30612859","id":"PMC_30612859","title":"Characterization of MCU-Binding Proteins MCUR1 and CCDC90B - Representatives of a Protein Family Conserved in Prokaryotes and Eukaryotic Organelles.","date":"2019","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/30612859","citation_count":20,"is_preprint":false},{"pmid":"34285508","id":"PMC_34285508","title":"Key Role of MCUR1 in Malignant Progression of Breast Cancer.","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34285508","citation_count":6,"is_preprint":false},{"pmid":"37145034","id":"PMC_37145034","title":"Mitochondrial Calcium Uniporter Regulator 1 (MCUR1) Relieves Mitochondrial Damage Induced by Lipopolysaccharide by Mediating Mitochondrial Ca2+ Homeostasis in Bovine Mammary Epithelial Cells.","date":"2023","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37145034","citation_count":6,"is_preprint":false},{"pmid":"40043709","id":"PMC_40043709","title":"A highland-adaptation variant near MCUR1 reduces its transcription and attenuates erythrogenesis in Tibetans.","date":"2025","source":"Cell genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40043709","citation_count":4,"is_preprint":false},{"pmid":"37153048","id":"PMC_37153048","title":"miR‑4732‑5p promotes ovarian cancer mobility by targeting MCUR1.","date":"2023","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/37153048","citation_count":3,"is_preprint":false},{"pmid":"42087238","id":"PMC_42087238","title":"Biallelic MCUR1 nonsense mutation associated with vacuolar myopathy and altered mitochondrial calcium signaling.","date":"2026","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/42087238","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.17.25338070","title":"Biallelic  <i>MCUR1</i>  nonsense mutation associated with vacuolar myopathy and altered mitochondrial calcium signaling","date":"2025-10-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.17.25338070","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.14.682030","title":"MCUR1–CCDC90B complex is a conserved mitochondrial scaffold regulating metabolic homeostasis","date":"2025-10-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.14.682030","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9321,"output_tokens":3591,"usd":0.040914,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11435,"output_tokens":4081,"usd":0.0796,"stage2_stop_reason":"end_turn"},"total_usd":0.120514,"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\": 2012,\n      \"finding\": \"MCUR1 (CCDC90A) is an integral inner mitochondrial membrane protein that physically binds to MCU and is required for ruthenium-red-sensitive, MCU-dependent mitochondrial Ca2+ uptake. MCUR1 knockdown abrogates Ca2+ uptake by energized mitochondria in intact and permeabilized cells without altering MCU localization. Loss of MCUR1 disrupts oxidative phosphorylation, lowers cellular ATP, and activates AMPK-dependent pro-survival autophagy.\",\n      \"method\": \"Co-immunoprecipitation (MCU-MCUR1 binding), siRNA knockdown with Ca2+ uptake assays in intact and permeabilized cells, ruthenium red sensitivity assays, ATP measurements, AMPK activation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal functional assays (intact cells, permeabilized cells, ruthenium red), replicated across cell types; foundational paper with extensive controls\",\n      \"pmids\": [\"23178883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Suppression of CCDC90A (MCUR1) in human fibroblasts produces a specific cytochrome c oxidase (COX) assembly defect, resulting in decreased mitochondrial membrane potential and reduced mitochondrial Ca2+ uptake capacity. The yeast homolog Fmp32 deletion also causes COX deficiency, indicating the function is evolutionarily conserved. This study argues CCDC90A acts indirectly on Ca2+ uptake via membrane potential, not as a direct MCU regulator.\",\n      \"method\": \"siRNA knockdown in human fibroblasts, COX assembly assays, mitochondrial membrane potential measurements, Ca2+ uptake capacity assays, genetic deletion of yeast homolog fmp32, rescue with wild-type cDNA in COX-deficient patient fibroblasts\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (COX assembly, membrane potential, Ca2+ uptake, genetic rescue), cross-species validation in yeast; challenges the direct MCU-regulator model with rigorous mechanistic evidence\",\n      \"pmids\": [\"25565209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MCUR1 functions as a scaffold factor for the MCU complex, binding both MCU and EMRE. Loss of MCUR1 in mouse cardiomyocytes and endothelial cells severely impairs mitochondrial Ca2+ uptake current (IMCU). The minimal coiled-coil domains of both MCU and MCUR1 are necessary for heterooligomeric complex formation. Loss of MCUR1 perturbs MCU complex assembly and impairs mitochondrial bioenergetics, cell proliferation, and migration while eliciting autophagy.\",\n      \"method\": \"Protein binding analyses identifying coiled-coil interaction domains, IMCU current measurements (electrophysiology), Co-IP of MCUR1 with MCU and EMRE, conditional genetic deletion in cardiomyocytes and endothelial cells, cell proliferation and migration assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, electrophysiological current measurements, domain mapping, in vivo conditional knockout with multiple phenotypic readouts; multiple orthogonal methods in single study\",\n      \"pmids\": [\"27184846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MCUR1 expression regulates the Ca2+ threshold required for mitochondrial permeability transition (mPT). Expression of MCUR1 in Drosophila cells conferred mPT sensitivity to electrophoretic Ca2+ uptake; inhibiting MCUR1 in mammalian cells increased the Ca2+ threshold required to induce mPT. This resistance to Ca2+ overload improved cell survival. The effect was specific to Ca2+-induced permeability transition.\",\n      \"method\": \"Cross-species complementation (MCUR1 expression in Drosophila cells), MCUR1 knockdown in mammalian cells, mitochondrial permeability transition assays with Ca2+ titration, cell survival assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function and loss-of-function experiments in two cell systems, specific Ca2+-triggered mPT assay, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"26976564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The head domain of MCUR1 directly interacts with the mitochondrial calcium uniporter (MCU) and is destabilized upon Ca2+ binding. Crystal structures of the related CCDC90B head domain and archaeal Kcr-0859 reveal a conserved head-neck-stalk-anchor architecture with a β-layer neck. MCUR1 and CCDC90B are part of a heterogeneous group of trimeric membrane-anchored coiled-coil proteins conserved from prokaryotes to eukaryotic organelles.\",\n      \"method\": \"Crystal structure determination of CCDC90B head domain and archaeal Kcr-0859, domain deletion/mutagenesis studies of MCUR1, Ca2+ binding and destabilization assays, sequence analysis defining domain architecture\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures solved, domain function validated by mutagenesis/deletion; single lab but with structural and biochemical orthogonal methods\",\n      \"pmids\": [\"30612859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MCUR1-mediated mitochondrial Ca2+ uptake activates the ROS/Nrf2/Notch1 pathway, which drives EMT via Snail in hepatocellular carcinoma cells. MCUR1 promotes in vitro invasion and in vivo metastasis. Inhibition of ROS, mitochondrial Ca2+ uptake, Nrf2, or Notch1 suppresses MCUR1-induced EMT. Mitochondrial Ca2+-buffering with parvalbumin inhibits the pathway and MCUR1-induced EMT and metastasis.\",\n      \"method\": \"MCUR1 knockdown/overexpression in HCC cells, immunofluorescent staining for EMT markers, in vitro invasion assays, in vivo metastasis assays, ROS measurement, pathway inhibition with chemical inhibitors and parvalbumin treatment, Western blot\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function, gain-of-function, and pharmacological rescue experiments with defined pathway placement; single lab, multiple methods but no direct biochemical binding assay\",\n      \"pmids\": [\"30909929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MCUR1-mediated mitochondrial Ca2+ uptake elevates mitochondrial ROS production, which drives AKT/MDM2-mediated P53 degradation to inhibit intrinsic apoptosis and promote HCC cell survival and proliferation. MCUR1 overexpression enhances MCU-dependent Ca2+ uptake; knockdown impairs it. Mitochondrial Ca2+ buffering with parvalbumin inhibits HCC cell growth.\",\n      \"method\": \"MCUR1 knockdown/overexpression in HCC cells, mitochondrial Ca2+ uptake measurements, ROS measurement, P53 degradation assays, AKT/MDM2 pathway analysis, in vivo xenograft assays (TUNEL, Ki67 staining), parvalbumin treatment\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss/gain of function with mechanistic pathway placement and in vivo validation; single lab, multiple orthogonal assays\",\n      \"pmids\": [\"28938844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Yeast homologs of MCUR1, Put6 and Put7, form a large hetero-oligomeric complex tethered to the inner mitochondrial membrane and regulate mitochondrial proline metabolism. Loss of this complex perturbs mitochondrial proline homeostasis and cellular redox balance; cells lacking Put6 or Put7 cannot utilize proline. This defect is rescued by heterologous expression of human MCUR1, demonstrating functional conservation of MCUR1 homologs in mitochondrial metabolic scaffolding beyond Ca2+ regulation.\",\n      \"method\": \"Genetic deletion of Put6/Put7 in S. cerevisiae, mitochondrial fractionation, hetero-oligomeric complex characterization, proline utilization assays, metabolomics, redox assays, heterologous complementation with human MCUR1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion with metabolic phenotype, complex characterization, and heterologous rescue with human MCUR1; multiple orthogonal methods establishing conserved metabolic scaffold function\",\n      \"pmids\": [\"32978391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MCUR1 knockdown reduces mitochondrial Ca2+ uptake and concomitantly increases cytosolic Ca2+, which reduces erythropoiesis via the CAMKK2-AMPK-mTOR signaling axis under both hypoxia and normoxia. A functional SNP (rs61644582) acts as an expression QTL reducing MCUR1 transcription, and attenuates erythropoiesis in Tibetan highlanders.\",\n      \"method\": \"MCUR1 knockdown with single-cell RNA sequencing, mitochondrial Ca2+ uptake measurements, cytosolic Ca2+ measurements, pharmacological inhibition of CAMKK2-AMPK-mTOR pathway components, erythropoiesis differentiation assays, whole-genome sequencing and eQTL analysis\",\n      \"journal\": \"Cell genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined pathway placement via pharmacological dissection; single lab, multiple readouts but pathway placement relies partly on inhibitor studies\",\n      \"pmids\": [\"40043709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A homozygous MCUR1 nonsense mutation in a human patient causes compromised mitochondrial Ca2+ uptake (stimulated by histamine or rising extracellular Ca2+), increased autophagic flux (LAMP2, LC3B markers), and autophagic vacuolar myopathy. Critically, MCUR1 loss-of-function does NOT alter MCU complex assembly, MCU subcellular localization, or resting mitochondrial membrane potential, indicating MCUR1 promotes MCU activity without being required for MCU complex assembly or stability.\",\n      \"method\": \"Patient fibroblasts and muscle biopsy analysis, mitochondrial Ca2+ uptake assays, autophagy flux assays, Western blot for MCU complex components, histological analysis, mitochondrial membrane potential measurement\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human loss-of-function mutation with multiple orthogonal mechanistic assays; single patient case but with functional validation in two tissue types\",\n      \"pmids\": [\"42087238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MCUR1 and its paralog CCDC90B form a hetero-oligomeric complex whose stability depends on MCUR1. Loss of MCUR1 exerts a dominant-negative effect on CCDC90B. Deletion of MCUR1/CCDC90B homologs in S. pombe (which lacks MCU) impairs lipid and amino acid metabolism; this is rescued by human MCUR1 expression, indicating a Ca2+-independent scaffold function. MCUR1 deficiency in patient fibroblasts upregulates autophagy, perturbs non-essential amino acid metabolism, and limits biosynthetic capacity.\",\n      \"method\": \"Complex stability assays (co-IP, protein abundance measurement), S. pombe genetic deletion with metabolic rescue by human MCUR1 expression, patient serum metabolomics, patient fibroblast functional assays (autophagy, amino acid metabolism, proliferation, migration)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species genetic rescue, patient metabolomics, and fibroblast functional assays; preprint not yet peer reviewed, multiple orthogonal methods\",\n      \"pmids\": [\"bio_10.1101_2025.10.14.682030\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MCUR1 is an integral inner mitochondrial membrane coiled-coil scaffold protein that directly binds MCU (and EMRE) via its conserved head domain to promote MCU-dependent mitochondrial Ca2+ uptake and regulate the Ca2+ threshold for mitochondrial permeability transition; beyond Ca2+ regulation, MCUR1 and its paralog CCDC90B form a conserved hetero-oligomeric scaffold that maintains mitochondrial metabolic homeostasis (including proline, lipid, and amino acid metabolism) independently of MCU, with loss of MCUR1 disrupting oxidative phosphorylation, activating AMPK-dependent autophagy, and causing autophagic vacuolar myopathy in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MCUR1 (CCDC90A) is an integral inner mitochondrial membrane coiled-coil protein that acts as a scaffold for the mitochondrial calcium uniporter and as a broader regulator of mitochondrial metabolic homeostasis [#0, #2]. It physically binds MCU and EMRE through minimal coiled-coil interaction domains, forming a heterooligomeric complex required for MCU-dependent, ruthenium-red-sensitive mitochondrial Ca2+ uptake and for normal IMCU current [#0, #2]. The MCUR1 head domain directly engages MCU and is destabilized upon Ca2+ binding, within a conserved head-neck-stalk-anchor architecture shared with its paralog CCDC90B and prokaryotic relatives [#4]. MCUR1 sets the Ca2+ threshold for mitochondrial permeability transition, such that its loss raises the threshold and confers resistance to Ca2+ overload [#3]. Functionally, MCUR1-dependent Ca2+ uptake supports oxidative phosphorylation and cellular ATP, and its loss disrupts bioenergetics and activates AMPK-dependent autophagy [#0, #2]; one study links MCUR1 loss specifically to a cytochrome c oxidase assembly defect and reduced membrane potential, arguing its effect on Ca2+ uptake is at least partly indirect [#1]. Beyond Ca2+ regulation, MCUR1 and CCDC90B form an MCUR1-stabilized hetero-oligomeric scaffold whose conserved function in proline, lipid, and amino acid metabolism is retained in yeast lacking MCU and rescuable by human MCUR1 [#7, #10]. In hepatocellular carcinoma, MCUR1-driven mitochondrial Ca2+ uptake elevates ROS to promote survival via AKT/MDM2-mediated p53 degradation and EMT/metastasis via the Nrf2/Notch1/Snail axis [#5, #6]. A homozygous MCUR1 nonsense mutation causes autophagic vacuolar myopathy in humans, with compromised Ca2+ uptake and increased autophagic flux but no change in MCU complex assembly or localization, establishing that MCUR1 promotes MCU activity without being required for complex stability [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established MCUR1 as a physical MCU partner required for mitochondrial Ca2+ uptake, defining it as a positive regulator of the uniporter and linking its loss to bioenergetic failure and autophagy.\",\n      \"evidence\": \"Co-IP of MCU-MCUR1 with siRNA knockdown, Ca2+ uptake assays in intact/permeabilized cells, ruthenium red sensitivity, ATP and AMPK assays\",\n      \"pmids\": [\"23178883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether the Ca2+ uptake defect is direct or secondary to bioenergetic loss\", \"No structural basis for MCU binding\", \"Did not test EMRE involvement\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Challenged the direct-regulator model by attributing MCUR1's effect on Ca2+ uptake to a cytochrome c oxidase assembly defect and lowered membrane potential, and showed the function is evolutionarily conserved in yeast.\",\n      \"evidence\": \"siRNA in human fibroblasts, COX assembly and membrane potential assays, yeast fmp32 deletion, cDNA rescue in patient fibroblasts\",\n      \"pmids\": [\"25565209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile COX-defect model with direct MCU binding data\", \"Mechanism linking MCUR1 to COX assembly unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined MCUR1 as a coiled-coil scaffold for MCU complex assembly and showed it regulates the Ca2+ threshold for permeability transition, connecting MCUR1 to both uniporter function and cell survival.\",\n      \"evidence\": \"Domain mapping of coiled-coil interactions, IMCU electrophysiology, Co-IP with MCU/EMRE, conditional knockout in cardiomyocytes and endothelial cells; Drosophila complementation and mPT Ca2+ titration assays\",\n      \"pmids\": [\"27184846\", \"26976564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the heterooligomer not resolved\", \"Whether scaffold and mPT-threshold roles are mechanistically separable unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural framework for MCUR1, defining a conserved head-neck-stalk-anchor architecture, a head domain that directly binds MCU and is Ca2+-destabilized, and a paralog relationship with CCDC90B.\",\n      \"evidence\": \"Crystal structures of CCDC90B head domain and archaeal Kcr-0859, MCUR1 domain mutagenesis, Ca2+ binding/destabilization assays\",\n      \"pmids\": [\"30612859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length MCUR1 structure\", \"No co-structure of MCUR1 with MCU\", \"Functional consequence of Ca2+-induced destabilization in cells untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed MCUR1-driven Ca2+ uptake within a cancer survival circuit, showing it elevates mitochondrial ROS to drive AKT/MDM2-mediated p53 degradation and suppress apoptosis.\",\n      \"evidence\": \"MCUR1 knockdown/overexpression in HCC cells, Ca2+ and ROS measurements, p53 degradation and AKT/MDM2 analysis, xenograft assays, parvalbumin buffering\",\n      \"pmids\": [\"28938844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical binding linking MCUR1 to the AKT/MDM2 axis\", \"Pathway placement inferred from pharmacological buffering\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the MCUR1-ROS axis to EMT and metastasis, showing MCUR1-dependent Ca2+ uptake activates Nrf2/Notch1/Snail signaling to promote invasion.\",\n      \"evidence\": \"MCUR1 knockdown/overexpression in HCC, EMT marker staining, invasion/metastasis assays, ROS measurement, chemical and parvalbumin pathway inhibition\",\n      \"pmids\": [\"30909929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct molecular binding assay\", \"Causality relies on inhibitor and buffering experiments\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a Ca2+-independent metabolic scaffold function by showing yeast homologs Put6/Put7 form an inner-membrane hetero-oligomer governing proline metabolism, rescuable by human MCUR1.\",\n      \"evidence\": \"Put6/Put7 deletion in S. cerevisiae, mitochondrial fractionation, complex characterization, proline utilization, metabolomics, redox assays, heterologous human MCUR1 complementation\",\n      \"pmids\": [\"32978391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate/enzyme partners of the scaffold not defined\", \"Mechanism connecting scaffold to proline metabolism unresolved\", \"Conservation of proline role in human cells not directly tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected MCUR1 to physiology by showing its loss raises cytosolic Ca2+ and limits erythropoiesis through the CAMKK2-AMPK-mTOR axis, with a human eQTL variant tuning MCUR1 expression in highlanders.\",\n      \"evidence\": \"MCUR1 knockdown with scRNA-seq, mitochondrial/cytosolic Ca2+ measurements, pharmacological pathway dissection, erythropoiesis assays, whole-genome sequencing and eQTL analysis\",\n      \"pmids\": [\"40043709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway placement partly inhibitor-dependent\", \"Direct link from cytosolic Ca2+ to CAMKK2 not biochemically shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established MCUR1 as a Mendelian disease gene, showing a homozygous nonsense mutation causes autophagic vacuolar myopathy with impaired Ca2+ uptake but intact MCU assembly, separating MCUR1's activating role from a structural requirement.\",\n      \"evidence\": \"Patient fibroblast and muscle biopsy analysis, Ca2+ uptake and autophagy flux assays, Western blot for MCU components, histology, membrane potential measurement\",\n      \"pmids\": [\"42087238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient case\", \"Mechanism by which MCUR1 promotes MCU activity without affecting assembly not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the MCUR1-CCDC90B hetero-oligomer as MCUR1-stabilized and demonstrated a conserved, MCU-independent scaffold role in lipid and amino acid metabolism underlying the human disease phenotype.\",\n      \"evidence\": \"Complex stability/Co-IP assays, S. pombe deletion with human MCUR1 rescue, patient serum metabolomics and fibroblast functional assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.14.682030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer reviewed\", \"Molecular substrates of the metabolic scaffold not identified\", \"Mechanism of dominant-negative effect on CCDC90B unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MCUR1 mechanistically reconciles its direct MCU-scaffold role with its MCU-independent metabolic scaffold function — and which is primary in the human myopathy — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of MCUR1 bound to MCU or to CCDC90B\", \"Direct enzymatic partners of the metabolic scaffold unidentified\", \"Relative contributions of Ca2+ and metabolic functions to disease undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 7, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [\"MCU complex (uniporter)\", \"MCUR1-CCDC90B hetero-oligomer\"],\n    \"partners\": [\"MCU\", \"EMRE\", \"CCDC90B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}