{"gene":"SLC25A23","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2014,"finding":"SLC25A23 interacts directly with the mitochondrial Ca2+ uniporter (MCU/CCDC109A) and MICU1 (CBARA1), and its knockdown decreases mitochondrial Ca2+ uptake and reduces cytosolic Ca2+ clearance after histamine stimulation. EF-hand domain mutants of SLC25A23 act as dominant negatives, reducing mitochondrial Ca2+ uptake. Reconstitution with shRNA-insensitive SLC25A23 cDNA restores mitochondrial Ca2+ uptake and superoxide production.","method":"RNA interference knockdown, ectopic overexpression, EF-hand domain mutagenesis (dominant-negative), Co-immunoprecipitation with MCU and MICU1, shRNA-insensitive reconstitution, mitochondrial Ca2+ uptake assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function knockdown, dominant-negative mutagenesis, and reconstitution all in one study with multiple orthogonal methods","pmids":["24430870"],"is_preprint":false},{"year":2014,"finding":"SLC25A23 knockdown lowers basal mitochondrial reactive oxygen species (mROS) accumulation, attenuates oxidant-induced ATP decline, and reduces cell death, linking SLC25A23-mediated mitochondrial Ca2+ uptake to oxidative stress and cell death signaling.","method":"RNA interference knockdown, mROS measurement, ATP assay, cell death assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with defined cellular phenotypes (ROS, ATP, cell death), single lab, multiple readouts","pmids":["24430870"],"is_preprint":false},{"year":2005,"finding":"SLC25A23 (SCaMC-3) encodes a 468 amino acid protein with a bipartite structure: an N-terminal region containing three canonical EF-hand calcium-binding domains and a C-terminal mitochondrial solute carrier domain. The protein localizes to mitochondria when transfected into HeLa cells, and binds calcium as demonstrated by Ca2+-dependent mobility shift assays.","method":"Transfection into HeLa cells with subcellular localization imaging, Ca2+-dependent mobility shift assay, Northern blot for tissue expression, alternative splicing analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional calcium-binding validation, single lab, two orthogonal methods","pmids":["15716113"],"is_preprint":false},{"year":2023,"finding":"SLC25A23 interacts with the E3 ubiquitin ligase Trim31 and interferes with Trim31 binding to MAVS, thereby suppressing K63-linked polyubiquitination and subsequent aggregation of MAVS. SLC25A23 knockdown increases MAVS K63-polyubiquitination and aggregation, promoting type I IFN production upon RNA virus infection. Mice with SLC25A23 knockdown are more resistant to RNA virus infection in vivo.","method":"Genome-wide CRISPR/Cas9 screen, Co-immunoprecipitation (SLC25A23–Trim31 interaction), SLC25A23 knockdown in cells and mice, K63-ubiquitination assay, MAVS aggregation assay, IFN production assay, viral challenge in vivo","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus Co-IP plus functional knockdown in vitro and in vivo with multiple mechanistic readouts in one study","pmids":["37695673"],"is_preprint":false},{"year":2024,"finding":"SLC25A23 was identified as a vulnerability of senescent cancer cells via CRISPR/Cas9 genetic screen. Suppression of SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, elevating reactive oxygen species and upregulating death receptor 5 via JNK pathway activation, leading to senescent cell death.","method":"CRISPR/Cas9 genetic screen, SLC25A23 suppression, ROS measurement, oxidative phosphorylation assay, calcium homeostasis assay, JNK pathway activation assay, DR5 expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus functional suppression with multiple mechanistic readouts, single lab","pmids":["39693343"],"is_preprint":false},{"year":2005,"finding":"SLC25A23 protein was identified as a binding partner of hepatitis B virus complete S protein using a yeast two-hybrid screen of a human liver cDNA library.","method":"Yeast two-hybrid screen","journal":"World journal of gastroenterology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid screen only, no biochemical validation of interaction","pmids":["15991290"],"is_preprint":false}],"current_model":"SLC25A23 is an inner mitochondrial membrane solute carrier with N-terminal EF-hand Ca2+-binding domains that localizes to mitochondria, augments mitochondrial Ca2+ uptake by interacting with the MCU–MICU1 complex, promotes mitochondrial ROS production and ATP-dependent cell death signaling, and also acts as a negative regulator of innate antiviral immunity by binding Trim31 and preventing MAVS K63-ubiquitination and aggregation."},"narrative":{"mechanistic_narrative":"SLC25A23 (SCaMC-3) is an EF-hand-containing mitochondrial solute carrier that couples calcium handling to mitochondrial redox and cell-death signaling [PMID:15716113, PMID:24430870]. The protein has a bipartite architecture—an N-terminal region with three canonical EF-hand Ca2+-binding domains and a C-terminal mitochondrial carrier domain—localizes to mitochondria, and binds calcium directly [PMID:15716113]. It augments mitochondrial Ca2+ uptake by interacting with the MCU uniporter and MICU1; its EF-hand domains are functionally required, as EF-hand mutants act as dominant negatives and knockdown reduces both mitochondrial Ca2+ uptake and downstream superoxide production [PMID:24430870]. Through this calcium-handling role, SLC25A23 supports basal mitochondrial ROS accumulation, oxidant-induced ATP decline, and cell death, and its suppression elevates ROS and triggers JNK-dependent death-receptor-5 upregulation and selective death of senescent cancer cells [PMID:24430870, PMID:39693343]. Independently of its carrier function, SLC25A23 negatively regulates innate antiviral immunity: it binds the E3 ligase Trim31 and blocks Trim31-mediated K63-linked polyubiquitination and aggregation of MAVS, so that its loss enhances type I interferon production and confers resistance to RNA virus infection in vivo [PMID:37695673].","teleology":[{"year":2005,"claim":"Established the basic identity of SLC25A23 as a mitochondrial calcium-binding carrier, defining the bipartite EF-hand/carrier architecture that would later explain its calcium-handling role.","evidence":"Transfection/localization imaging in HeLa cells and Ca2+-dependent mobility shift assay, with tissue expression and splicing analysis","pmids":["15716113"],"confidence":"Medium","gaps":["Did not demonstrate a transport substrate for the carrier domain","No functional link to a calcium-handling pathway established at this stage"]},{"year":2005,"claim":"A yeast two-hybrid screen flagged SLC25A23 as a candidate binding partner of hepatitis B virus S protein, raising an early but unvalidated host-pathogen connection.","evidence":"Yeast two-hybrid screen of a human liver cDNA library","pmids":["15991290"],"confidence":"Low","gaps":["Single Y2H hit with no biochemical or cellular validation","Interaction never confirmed by co-IP or functional assay","No mechanistic consequence of the interaction defined"]},{"year":2014,"claim":"Placed SLC25A23 mechanistically within the mitochondrial calcium uptake machinery, showing it physically engages the MCU-MICU1 complex and that its EF-hands are required to drive uptake.","evidence":"Reciprocal co-IP with MCU and MICU1, shRNA knockdown, EF-hand dominant-negative mutagenesis, and shRNA-insensitive reconstitution with Ca2+ uptake assays","pmids":["24430870"],"confidence":"High","gaps":["Stoichiometry and architecture of the SLC25A23-MCU-MICU1 assembly not resolved","Whether SLC25A23 transports a metabolite while modulating uptake unaddressed"]},{"year":2014,"claim":"Connected SLC25A23-dependent mitochondrial Ca2+ uptake to downstream physiology, linking it to mitochondrial ROS, ATP balance, and oxidant-induced cell death.","evidence":"shRNA knockdown with mROS, ATP, and cell death readouts","pmids":["24430870"],"confidence":"Medium","gaps":["Causal chain from Ca2+ uptake to ROS to death not dissected step-by-step","Cell-type generality of the death phenotype untested"]},{"year":2023,"claim":"Revealed a moonlighting, transport-independent role: SLC25A23 restrains antiviral signaling by sequestering Trim31 away from MAVS, defining it as a negative regulator of type I interferon.","evidence":"Genome-wide CRISPR screen, co-IP of SLC25A23-Trim31, K63-ubiquitination and MAVS aggregation assays, IFN readouts, and viral challenge in knockdown mice","pmids":["37695673"],"confidence":"High","gaps":["Whether the antiviral role depends on mitochondrial Ca2+/carrier activity is unresolved","Structural basis of the SLC25A23-Trim31 interaction unknown"]},{"year":2024,"claim":"Identified SLC25A23 as a selective vulnerability of senescent cancer cells, tying its calcium/redox function to a JNK-DR5 death axis.","evidence":"CRISPR/Cas9 screen with SLC25A23 suppression and calcium, OXPHOS, ROS, JNK, and DR5 readouts","pmids":["39693343"],"confidence":"Medium","gaps":["Mechanism linking calcium disruption to JNK activation not fully defined","Single-lab finding without orthogonal genetic confirmation"]},{"year":null,"claim":"It remains unknown what metabolite the C-terminal carrier domain transports and whether the mitochondrial calcium and antiviral/Trim31 functions are mechanistically coupled or independent.","evidence":"","pmids":[],"confidence":"Low","gaps":["No transported substrate identified for the carrier domain","No structural model of SLC25A23 in any complex","Relationship between calcium-handling and Trim31-MAVS functions unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,0]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,4]}],"complexes":[],"partners":["MCU","MICU1","TRIM31"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BV35","full_name":"Mitochondrial adenyl nucleotide antiporter SLC25A23","aliases":["Mitochondrial ATP-Mg/Pi carrier protein 2","Short calcium-binding mitochondrial carrier protein 3","SCaMC-3","Solute carrier family 25 member 23"],"length_aa":468,"mass_kda":52.4,"function":"Electroneutral antiporter that mediates the transport of adenine nucleotides through the inner mitochondrial membrane. Originally identified as an ATP-magnesium/inorganic phosphate antiporter, it also acts as a broad specificity adenyl nucleotide antiporter. By regulating the mitochondrial matrix adenine nucleotide pool could adapt to changing cellular energetic demands and indirectly regulate adenine nucleotide-dependent metabolic pathways (PubMed:15123600). Also acts as a regulator of mitochondrial calcium uptake and can probably transport trace amounts of other divalent metal cations in complex with ATP (PubMed:24430870, PubMed:28695448). In vitro, a low activity is also observed with guanyl and pyrimidine nucleotides (PubMed:15123600)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q9BV35/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC25A23","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC25A23","total_profiled":1310},"omim":[{"mim_id":"608746","title":"SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, PHOSPHATE CARRIER), MEMBER 23; SLC25A23","url":"https://www.omim.org/entry/608746"},{"mim_id":"608745","title":"SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, PHOSPHATE CARRIER), MEMBER 25; SLC25A25","url":"https://www.omim.org/entry/608745"},{"mim_id":"608744","title":"SOLUTE CARRIER FAMILY 25 (MITOCHONDRIAL CARRIER, PHOSPHATE CARRIER), MEMBER 24; SLC25A24","url":"https://www.omim.org/entry/608744"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":364.2}],"url":"https://www.proteinatlas.org/search/SLC25A23"},"hgnc":{"alias_symbol":["FLJ30339","MGC2615","APC2"],"prev_symbol":[]},"alphafold":{"accession":"Q9BV35","domains":[{"cath_id":"1.50.40.10","chopping":"176-462","consensus_level":"medium","plddt":84.236,"start":176,"end":462}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BV35","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BV35-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BV35-F1-predicted_aligned_error_v6.png","plddt_mean":78.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC25A23","jax_strain_url":"https://www.jax.org/strain/search?query=SLC25A23"},"sequence":{"accession":"Q9BV35","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BV35.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BV35/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BV35"}},"corpus_meta":[{"pmid":"33296287","id":"PMC_33296287","title":"Molecular nature and physiological role of the mitochondrial calcium uniporter channel.","date":"2020","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33296287","citation_count":138,"is_preprint":false},{"pmid":"24430870","id":"PMC_24430870","title":"SLC25A23 augments mitochondrial Ca²⁺ uptake, interacts with MCU, and induces oxidative stress-mediated cell death.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/24430870","citation_count":130,"is_preprint":false},{"pmid":"29980025","id":"PMC_29980025","title":"Molecular regulation of MCU: Implications in physiology and disease.","date":"2018","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/29980025","citation_count":100,"is_preprint":false},{"pmid":"20122155","id":"PMC_20122155","title":"Identification of endogenous control genes for normalisation of real-time quantitative PCR data in colorectal cancer.","date":"2010","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20122155","citation_count":70,"is_preprint":false},{"pmid":"27993893","id":"PMC_27993893","title":"Genome-wide ChIP-seq analysis of EZH2-mediated H3K27me3 target gene profile highlights differences between low- and high-grade astrocytic tumors.","date":"2017","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/27993893","citation_count":36,"is_preprint":false},{"pmid":"15716113","id":"PMC_15716113","title":"Cellular expression and alternative splicing of SLC25A23, a member of the mitochondrial Ca2+-dependent solute carrier gene family.","date":"2005","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15716113","citation_count":29,"is_preprint":false},{"pmid":"38417574","id":"PMC_38417574","title":"MCU complex: Exploring emerging targets and mechanisms of mitochondrial physiology and pathology.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/38417574","citation_count":28,"is_preprint":false},{"pmid":"39693343","id":"PMC_39693343","title":"An antibiotic that mediates immune destruction of senescent cancer cells.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39693343","citation_count":8,"is_preprint":false},{"pmid":"39341452","id":"PMC_39341452","title":"Integrated proteomic and glycoproteomic analysis reveals heterogeneity and molecular signatures of brain metastases from lung adenocarcinomas.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39341452","citation_count":8,"is_preprint":false},{"pmid":"26161641","id":"PMC_26161641","title":"Unraveling the Rat Intestine, Spleen and Liver Genome-Wide Transcriptome after the Oral Administration of Lavender Oil by a Two-Color Dye-Swap DNA Microarray Approach.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26161641","citation_count":8,"is_preprint":false},{"pmid":"15991290","id":"PMC_15991290","title":"Screening of hepatocyte proteins binding to complete S protein of hepatitis B virus by yeast-two hybrid system.","date":"2005","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/15991290","citation_count":8,"is_preprint":false},{"pmid":"37695673","id":"PMC_37695673","title":"Genome-Wide CRISPR/Cas9 Screening Identifies That Mitochondrial Solute Carrier SLC25A23 Attenuates Type I IFN Antiviral Immunity via Interfering with MAVS Aggregation.","date":"2023","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/37695673","citation_count":3,"is_preprint":false},{"pmid":"41827885","id":"PMC_41827885","title":"Estetrol Enhances Mitochondrial Bioenergetics and Neurite Outgrowth in Cellular Models of Alzheimer's Disease.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41827885","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9017,"output_tokens":1612,"usd":0.025615,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8471,"output_tokens":2511,"usd":0.052565,"stage2_stop_reason":"end_turn"},"total_usd":0.07818,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"SLC25A23 interacts directly with the mitochondrial Ca2+ uniporter (MCU/CCDC109A) and MICU1 (CBARA1), and its knockdown decreases mitochondrial Ca2+ uptake and reduces cytosolic Ca2+ clearance after histamine stimulation. EF-hand domain mutants of SLC25A23 act as dominant negatives, reducing mitochondrial Ca2+ uptake. Reconstitution with shRNA-insensitive SLC25A23 cDNA restores mitochondrial Ca2+ uptake and superoxide production.\",\n      \"method\": \"RNA interference knockdown, ectopic overexpression, EF-hand domain mutagenesis (dominant-negative), Co-immunoprecipitation with MCU and MICU1, shRNA-insensitive reconstitution, mitochondrial Ca2+ uptake assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function knockdown, dominant-negative mutagenesis, and reconstitution all in one study with multiple orthogonal methods\",\n      \"pmids\": [\"24430870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLC25A23 knockdown lowers basal mitochondrial reactive oxygen species (mROS) accumulation, attenuates oxidant-induced ATP decline, and reduces cell death, linking SLC25A23-mediated mitochondrial Ca2+ uptake to oxidative stress and cell death signaling.\",\n      \"method\": \"RNA interference knockdown, mROS measurement, ATP assay, cell death assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with defined cellular phenotypes (ROS, ATP, cell death), single lab, multiple readouts\",\n      \"pmids\": [\"24430870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SLC25A23 (SCaMC-3) encodes a 468 amino acid protein with a bipartite structure: an N-terminal region containing three canonical EF-hand calcium-binding domains and a C-terminal mitochondrial solute carrier domain. The protein localizes to mitochondria when transfected into HeLa cells, and binds calcium as demonstrated by Ca2+-dependent mobility shift assays.\",\n      \"method\": \"Transfection into HeLa cells with subcellular localization imaging, Ca2+-dependent mobility shift assay, Northern blot for tissue expression, alternative splicing analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional calcium-binding validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"15716113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC25A23 interacts with the E3 ubiquitin ligase Trim31 and interferes with Trim31 binding to MAVS, thereby suppressing K63-linked polyubiquitination and subsequent aggregation of MAVS. SLC25A23 knockdown increases MAVS K63-polyubiquitination and aggregation, promoting type I IFN production upon RNA virus infection. Mice with SLC25A23 knockdown are more resistant to RNA virus infection in vivo.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, Co-immunoprecipitation (SLC25A23–Trim31 interaction), SLC25A23 knockdown in cells and mice, K63-ubiquitination assay, MAVS aggregation assay, IFN production assay, viral challenge in vivo\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus Co-IP plus functional knockdown in vitro and in vivo with multiple mechanistic readouts in one study\",\n      \"pmids\": [\"37695673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC25A23 was identified as a vulnerability of senescent cancer cells via CRISPR/Cas9 genetic screen. Suppression of SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation, and interferes with redox signaling, elevating reactive oxygen species and upregulating death receptor 5 via JNK pathway activation, leading to senescent cell death.\",\n      \"method\": \"CRISPR/Cas9 genetic screen, SLC25A23 suppression, ROS measurement, oxidative phosphorylation assay, calcium homeostasis assay, JNK pathway activation assay, DR5 expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus functional suppression with multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"39693343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SLC25A23 protein was identified as a binding partner of hepatitis B virus complete S protein using a yeast two-hybrid screen of a human liver cDNA library.\",\n      \"method\": \"Yeast two-hybrid screen\",\n      \"journal\": \"World journal of gastroenterology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid screen only, no biochemical validation of interaction\",\n      \"pmids\": [\"15991290\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC25A23 is an inner mitochondrial membrane solute carrier with N-terminal EF-hand Ca2+-binding domains that localizes to mitochondria, augments mitochondrial Ca2+ uptake by interacting with the MCU–MICU1 complex, promotes mitochondrial ROS production and ATP-dependent cell death signaling, and also acts as a negative regulator of innate antiviral immunity by binding Trim31 and preventing MAVS K63-ubiquitination and aggregation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC25A23 (SCaMC-3) is an EF-hand-containing mitochondrial solute carrier that couples calcium handling to mitochondrial redox and cell-death signaling [#2, #0]. The protein has a bipartite architecture—an N-terminal region with three canonical EF-hand Ca2+-binding domains and a C-terminal mitochondrial carrier domain—localizes to mitochondria, and binds calcium directly [#2]. It augments mitochondrial Ca2+ uptake by interacting with the MCU uniporter and MICU1; its EF-hand domains are functionally required, as EF-hand mutants act as dominant negatives and knockdown reduces both mitochondrial Ca2+ uptake and downstream superoxide production [#0]. Through this calcium-handling role, SLC25A23 supports basal mitochondrial ROS accumulation, oxidant-induced ATP decline, and cell death, and its suppression elevates ROS and triggers JNK-dependent death-receptor-5 upregulation and selective death of senescent cancer cells [#1, #4]. Independently of its carrier function, SLC25A23 negatively regulates innate antiviral immunity: it binds the E3 ligase Trim31 and blocks Trim31-mediated K63-linked polyubiquitination and aggregation of MAVS, so that its loss enhances type I interferon production and confers resistance to RNA virus infection in vivo [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the basic identity of SLC25A23 as a mitochondrial calcium-binding carrier, defining the bipartite EF-hand/carrier architecture that would later explain its calcium-handling role.\",\n      \"evidence\": \"Transfection/localization imaging in HeLa cells and Ca2+-dependent mobility shift assay, with tissue expression and splicing analysis\",\n      \"pmids\": [\"15716113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not demonstrate a transport substrate for the carrier domain\",\n        \"No functional link to a calcium-handling pathway established at this stage\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A yeast two-hybrid screen flagged SLC25A23 as a candidate binding partner of hepatitis B virus S protein, raising an early but unvalidated host-pathogen connection.\",\n      \"evidence\": \"Yeast two-hybrid screen of a human liver cDNA library\",\n      \"pmids\": [\"15991290\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single Y2H hit with no biochemical or cellular validation\",\n        \"Interaction never confirmed by co-IP or functional assay\",\n        \"No mechanistic consequence of the interaction defined\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed SLC25A23 mechanistically within the mitochondrial calcium uptake machinery, showing it physically engages the MCU-MICU1 complex and that its EF-hands are required to drive uptake.\",\n      \"evidence\": \"Reciprocal co-IP with MCU and MICU1, shRNA knockdown, EF-hand dominant-negative mutagenesis, and shRNA-insensitive reconstitution with Ca2+ uptake assays\",\n      \"pmids\": [\"24430870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and architecture of the SLC25A23-MCU-MICU1 assembly not resolved\",\n        \"Whether SLC25A23 transports a metabolite while modulating uptake unaddressed\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected SLC25A23-dependent mitochondrial Ca2+ uptake to downstream physiology, linking it to mitochondrial ROS, ATP balance, and oxidant-induced cell death.\",\n      \"evidence\": \"shRNA knockdown with mROS, ATP, and cell death readouts\",\n      \"pmids\": [\"24430870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal chain from Ca2+ uptake to ROS to death not dissected step-by-step\",\n        \"Cell-type generality of the death phenotype untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a moonlighting, transport-independent role: SLC25A23 restrains antiviral signaling by sequestering Trim31 away from MAVS, defining it as a negative regulator of type I interferon.\",\n      \"evidence\": \"Genome-wide CRISPR screen, co-IP of SLC25A23-Trim31, K63-ubiquitination and MAVS aggregation assays, IFN readouts, and viral challenge in knockdown mice\",\n      \"pmids\": [\"37695673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the antiviral role depends on mitochondrial Ca2+/carrier activity is unresolved\",\n        \"Structural basis of the SLC25A23-Trim31 interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified SLC25A23 as a selective vulnerability of senescent cancer cells, tying its calcium/redox function to a JNK-DR5 death axis.\",\n      \"evidence\": \"CRISPR/Cas9 screen with SLC25A23 suppression and calcium, OXPHOS, ROS, JNK, and DR5 readouts\",\n      \"pmids\": [\"39693343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking calcium disruption to JNK activation not fully defined\",\n        \"Single-lab finding without orthogonal genetic confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what metabolite the C-terminal carrier domain transports and whether the mitochondrial calcium and antiviral/Trim31 functions are mechanistically coupled or independent.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No transported substrate identified for the carrier domain\",\n        \"No structural model of SLC25A23 in any complex\",\n        \"Relationship between calcium-handling and Trim31-MAVS functions unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005509\", \"supporting_discovery_ids\": [2, 0]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MCU\", \"MICU1\", \"TRIM31\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}