{"gene":"ECHDC2","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2013,"finding":"ECHDC2 is a mitochondrial protein expressed in cardiomyocytes but not cardiofibroblasts. Overexpression of ECHDC2 increased susceptibility to ischemia/reperfusion (I/R) injury while knockdown enhanced resistance to I/R injury. ECHDC2 overexpression increased cellular levels of branched-chain amino acids leucine and valine, as measured by gas chromatography-mass spectrometry, without altering mitochondrial O2 consumption, metabolic intermediates, or ATP production.","method":"Subcellular fractionation/immunohistochemistry for localization; overexpression and knockdown in cells with I/R injury assay; gas chromatography-mass spectrometry for metabolite profiling; in vivo coronary artery ligation model","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO/OE with defined cellular phenotype and metabolic readout, single lab with multiple orthogonal methods","pmids":["24108764"],"is_preprint":false},{"year":2024,"finding":"ECHDC2 binds to the E3 ubiquitin ligase NEDD4 (demonstrated by Co-immunoprecipitation and immunofluorescence), and this interaction promotes ubiquitination and proteasomal degradation of MCCC2. Loss of MCCC2 suppresses the P38 MAPK pathway, thereby reducing aerobic glycolysis and proliferation in gastric cancer cells both in vitro and in vivo.","method":"Co-immunoprecipitation, Western blotting, immunofluorescence, colony formation assay, CCK8/EDU proliferation assays, glucose/lactate assay, subcutaneous tumor xenograft","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP identifying binding partners and ubiquitination mechanism, multiple functional readouts, single lab","pmids":["38783226"],"is_preprint":false},{"year":2019,"finding":"ECHDC2 was identified via a genome-wide CRISPR/Cas9 knockout screen as a regulator of anoikis escape in high-grade serous ovarian cancer cells; knockdown of ECHDC2 significantly inhibited suspension growth, implicating it as an effector of fatty acid metabolism required for survival in suspension.","method":"Genome-wide CRISPR/Cas9 knockout (GeCKO) screen; siRNA knockdown with suspension growth assay; metabolomics","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide functional screen with validation by knockdown and metabolic profiling, single lab","pmids":["31437751"],"is_preprint":false},{"year":2026,"finding":"ECHDC2 knockdown suppressed proliferation and migration of glioblastoma (GBM) cell lines, while overexpression had the opposite effect; enrichment analyses linked ECHDC2 to the PI3K/Akt signaling pathway in GBM progression.","method":"siRNA knockdown and overexpression in GBM cell lines; CCK-8, EdU, wound-healing, and Transwell migration assays; GSEA/KEGG pathway enrichment","journal":"Frontiers in genetics","confidence":"Low","confidence_rationale":"Tier 3 — functional KD/OE with phenotype but pathway placement relies on enrichment analysis rather than direct epistasis experiment","pmids":["41732157"],"is_preprint":false}],"current_model":"ECHDC2 is a mitochondrial protein involved in fatty acid β-oxidation and branched-chain amino acid metabolism; it physically interacts with the E3 ubiquitin ligase NEDD4 to promote ubiquitination and degradation of MCCC2, thereby suppressing the P38 MAPK pathway and aerobic glycolysis, while its levels modulate susceptibility to ischemia/reperfusion injury and cancer cell survival in suspension through regulation of metabolic pathways."},"narrative":{"teleology":[{"year":2013,"claim":"Establishing ECHDC2 as a mitochondrial protein in cardiomyocytes whose expression level determines susceptibility to ischemia/reperfusion injury — and linking it to branched-chain amino acid handling rather than canonical oxidative phosphorylation — defined its first functional context.","evidence":"Overexpression and knockdown in cardiomyocytes with I/R injury assay and GC-MS metabolite profiling; subcellular fractionation confirming mitochondrial localization","pmids":["24108764"],"confidence":"Medium","gaps":["Enzymatic activity and substrate specificity of ECHDC2 remain undefined","Mechanism by which elevated leucine/valine increases I/R injury susceptibility is unexplained","No structural or kinetic characterization of the protein"]},{"year":2019,"claim":"A genome-wide CRISPR screen identified ECHDC2 as required for cancer cell survival in suspension (anoikis escape), extending its role from cardiac metabolism to fatty acid metabolism–dependent tumor cell fitness.","evidence":"GeCKO CRISPR/Cas9 knockout screen in high-grade serous ovarian cancer cells validated by siRNA knockdown and suspension growth assay","pmids":["31437751"],"confidence":"Medium","gaps":["The specific lipid metabolic pathway through which ECHDC2 supports suspension survival is not delineated","Whether ECHDC2 enzymatic activity or a scaffolding function is required was not tested"]},{"year":2024,"claim":"Demonstrating that ECHDC2 physically interacts with the E3 ligase NEDD4 to drive ubiquitination and degradation of MCCC2 provided the first defined molecular mechanism, linking ECHDC2 to suppression of P38 MAPK signaling and aerobic glycolysis in gastric cancer.","evidence":"Reciprocal co-immunoprecipitation, immunofluorescence colocalization, ubiquitination assays, and in vivo xenograft models in gastric cancer cells","pmids":["38783226"],"confidence":"Medium","gaps":["Whether ECHDC2 acts catalytically on MCCC2 or solely as an adaptor/scaffold for NEDD4 is unresolved","Relevance of the ECHDC2–NEDD4–MCCC2 axis to cardiac I/R injury has not been tested","The relationship between this ubiquitination mechanism and ECHDC2's metabolic enzyme function is unclear"]},{"year":null,"claim":"The intrinsic enzymatic activity of ECHDC2, its endogenous substrates, and how its metabolic and signaling (NEDD4/MCCC2) functions are integrated across tissue contexts remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No enzymatic assay or substrate identification has been reported","No structural data exist for ECHDC2","Whether the branched-chain amino acid phenotype and the MCCC2 degradation phenotype are mechanistically connected is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1]}],"complexes":[],"partners":["NEDD4","MCCC2"],"other_free_text":[]},"mechanistic_narrative":"ECHDC2 is a mitochondrial enzyme that modulates branched-chain amino acid levels and fatty acid metabolism, with functional consequences for ischemia/reperfusion injury susceptibility and cancer cell survival [PMID:24108764, PMID:31437751]. ECHDC2 overexpression in cardiomyocytes increases intracellular leucine and valine and sensitizes cells to ischemia/reperfusion injury, while its knockdown confers resistance [PMID:24108764]. In gastric cancer cells, ECHDC2 recruits the E3 ubiquitin ligase NEDD4 to promote ubiquitination and proteasomal degradation of MCCC2, thereby suppressing P38 MAPK signaling, aerobic glycolysis, and proliferation [PMID:38783226]."},"prefetch_data":{"uniprot":{"accession":"Q86YB7","full_name":"Enoyl-CoA hydratase domain-containing protein 2, mitochondrial","aliases":[],"length_aa":292,"mass_kda":31.1,"function":"","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q86YB7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ECHDC2","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ECHDC2","total_profiled":1310},"omim":[{"mim_id":"620724","title":"ENOYL COENZYME A HYDRATASE DOMAIN-CONTAINING PROTEIN 2; ECHDC2","url":"https://www.omim.org/entry/620724"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":174.8}],"url":"https://www.proteinatlas.org/search/ECHDC2"},"hgnc":{"alias_symbol":["FLJ10948"],"prev_symbol":[]},"alphafold":{"accession":"Q86YB7","domains":[{"cath_id":"3.90.226.10","chopping":"28-233","consensus_level":"high","plddt":97.8306,"start":28,"end":233},{"cath_id":"1.10.12.10","chopping":"237-284","consensus_level":"high","plddt":98.2671,"start":237,"end":284}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YB7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YB7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YB7-F1-predicted_aligned_error_v6.png","plddt_mean":92.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ECHDC2","jax_strain_url":"https://www.jax.org/strain/search?query=ECHDC2"},"sequence":{"accession":"Q86YB7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86YB7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86YB7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YB7"}},"corpus_meta":[{"pmid":"24005033","id":"PMC_24005033","title":"Functional epigenetic approach identifies frequently methylated genes in Ewing sarcoma.","date":"2013","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/24005033","citation_count":33,"is_preprint":false},{"pmid":"31437751","id":"PMC_31437751","title":"Multi-Omic Approaches Identify Metabolic and Autophagy Regulators Important in Ovarian Cancer Dissemination.","date":"2019","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/31437751","citation_count":26,"is_preprint":false},{"pmid":"38783226","id":"PMC_38783226","title":"ECHDC2 inhibits the proliferation of gastric cancer cells by binding with NEDD4 to degrade MCCC2 and reduce aerobic glycolysis.","date":"2024","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/38783226","citation_count":20,"is_preprint":false},{"pmid":"24108764","id":"PMC_24108764","title":"Enoyl coenzyme a hydratase domain-containing 2, a potential novel regulator of myocardial ischemia injury.","date":"2013","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/24108764","citation_count":17,"is_preprint":false},{"pmid":"36618918","id":"PMC_36618918","title":"Proteomic analysis revealed the pharmacological mechanism of Xueshuantong injection in preventing early acute myocardial infarction injury.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36618918","citation_count":7,"is_preprint":false},{"pmid":"39384885","id":"PMC_39384885","title":"Multiomics identification of ALDH9A1 as a crucial immunoregulatory molecule involved in calcific aortic valve disease.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39384885","citation_count":4,"is_preprint":false},{"pmid":"34218094","id":"PMC_34218094","title":"Proteomic consequences of the deletion of cytochrome P450 (CYP450) reductase in mice.","date":"2021","source":"Journal of chromatography. B, Analytical technologies in the biomedical and life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34218094","citation_count":2,"is_preprint":false},{"pmid":"41444657","id":"PMC_41444657","title":"Identification of coagulation-related hub genes in ischemic stroke based on bioinformatics integration analysis and investigation of their immune regulatory mechanisms.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41444657","citation_count":1,"is_preprint":false},{"pmid":"39732885","id":"PMC_39732885","title":"Genome-wide analysis of alternative splicing differences in hepatic ischemia reperfusion injury.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39732885","citation_count":1,"is_preprint":false},{"pmid":"32917399","id":"PMC_32917399","title":"Exploring allele specific methylation in drug dependence susceptibility.","date":"2020","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/32917399","citation_count":1,"is_preprint":false},{"pmid":"39409102","id":"PMC_39409102","title":"Investigating the Causal Effects of Exercise-Induced Genes on Sarcopenia.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39409102","citation_count":1,"is_preprint":false},{"pmid":"41732157","id":"PMC_41732157","title":"Clinical significance and oncogenic role of ECHDC2 in glioblastoma: a comprehensive analysis based on bioinformatics and in vitro experiments.","date":"2026","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41732157","citation_count":0,"is_preprint":false},{"pmid":"41088987","id":"PMC_41088987","title":"Investigating the Mechanisms of Mitochondrial Dysfunction in Ischemic Stroke and Predicting Therapeutics Through Machine Learning and Integrated Bioinformatics.","date":"2025","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41088987","citation_count":0,"is_preprint":false},{"pmid":"40680899","id":"PMC_40680899","title":"Very high-dose vitamin D₃ supplementation reduces the expression of genes and proteins engaged in β-oxidation in healthy pigs.","date":"2025","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40680899","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9295,"output_tokens":1118,"usd":0.022328},"stage2":{"model":"claude-opus-4-6","input_tokens":4321,"output_tokens":1238,"usd":0.078832},"total_usd":0.10116,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"ECHDC2 is a mitochondrial protein expressed in cardiomyocytes but not cardiofibroblasts. Overexpression of ECHDC2 increased susceptibility to ischemia/reperfusion (I/R) injury while knockdown enhanced resistance to I/R injury. ECHDC2 overexpression increased cellular levels of branched-chain amino acids leucine and valine, as measured by gas chromatography-mass spectrometry, without altering mitochondrial O2 consumption, metabolic intermediates, or ATP production.\",\n      \"method\": \"Subcellular fractionation/immunohistochemistry for localization; overexpression and knockdown in cells with I/R injury assay; gas chromatography-mass spectrometry for metabolite profiling; in vivo coronary artery ligation model\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/OE with defined cellular phenotype and metabolic readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24108764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ECHDC2 binds to the E3 ubiquitin ligase NEDD4 (demonstrated by Co-immunoprecipitation and immunofluorescence), and this interaction promotes ubiquitination and proteasomal degradation of MCCC2. Loss of MCCC2 suppresses the P38 MAPK pathway, thereby reducing aerobic glycolysis and proliferation in gastric cancer cells both in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, immunofluorescence, colony formation assay, CCK8/EDU proliferation assays, glucose/lactate assay, subcutaneous tumor xenograft\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP identifying binding partners and ubiquitination mechanism, multiple functional readouts, single lab\",\n      \"pmids\": [\"38783226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ECHDC2 was identified via a genome-wide CRISPR/Cas9 knockout screen as a regulator of anoikis escape in high-grade serous ovarian cancer cells; knockdown of ECHDC2 significantly inhibited suspension growth, implicating it as an effector of fatty acid metabolism required for survival in suspension.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 knockout (GeCKO) screen; siRNA knockdown with suspension growth assay; metabolomics\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide functional screen with validation by knockdown and metabolic profiling, single lab\",\n      \"pmids\": [\"31437751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ECHDC2 knockdown suppressed proliferation and migration of glioblastoma (GBM) cell lines, while overexpression had the opposite effect; enrichment analyses linked ECHDC2 to the PI3K/Akt signaling pathway in GBM progression.\",\n      \"method\": \"siRNA knockdown and overexpression in GBM cell lines; CCK-8, EdU, wound-healing, and Transwell migration assays; GSEA/KEGG pathway enrichment\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional KD/OE with phenotype but pathway placement relies on enrichment analysis rather than direct epistasis experiment\",\n      \"pmids\": [\"41732157\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ECHDC2 is a mitochondrial protein involved in fatty acid β-oxidation and branched-chain amino acid metabolism; it physically interacts with the E3 ubiquitin ligase NEDD4 to promote ubiquitination and degradation of MCCC2, thereby suppressing the P38 MAPK pathway and aerobic glycolysis, while its levels modulate susceptibility to ischemia/reperfusion injury and cancer cell survival in suspension through regulation of metabolic pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ECHDC2 is a mitochondrial enzyme that modulates branched-chain amino acid levels and fatty acid metabolism, with functional consequences for ischemia/reperfusion injury susceptibility and cancer cell survival [PMID:24108764, PMID:31437751]. ECHDC2 overexpression in cardiomyocytes increases intracellular leucine and valine and sensitizes cells to ischemia/reperfusion injury, while its knockdown confers resistance [PMID:24108764]. In gastric cancer cells, ECHDC2 recruits the E3 ubiquitin ligase NEDD4 to promote ubiquitination and proteasomal degradation of MCCC2, thereby suppressing P38 MAPK signaling, aerobic glycolysis, and proliferation [PMID:38783226].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing ECHDC2 as a mitochondrial protein in cardiomyocytes whose expression level determines susceptibility to ischemia/reperfusion injury — and linking it to branched-chain amino acid handling rather than canonical oxidative phosphorylation — defined its first functional context.\",\n      \"evidence\": \"Overexpression and knockdown in cardiomyocytes with I/R injury assay and GC-MS metabolite profiling; subcellular fractionation confirming mitochondrial localization\",\n      \"pmids\": [\"24108764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Enzymatic activity and substrate specificity of ECHDC2 remain undefined\",\n        \"Mechanism by which elevated leucine/valine increases I/R injury susceptibility is unexplained\",\n        \"No structural or kinetic characterization of the protein\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A genome-wide CRISPR screen identified ECHDC2 as required for cancer cell survival in suspension (anoikis escape), extending its role from cardiac metabolism to fatty acid metabolism–dependent tumor cell fitness.\",\n      \"evidence\": \"GeCKO CRISPR/Cas9 knockout screen in high-grade serous ovarian cancer cells validated by siRNA knockdown and suspension growth assay\",\n      \"pmids\": [\"31437751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific lipid metabolic pathway through which ECHDC2 supports suspension survival is not delineated\",\n        \"Whether ECHDC2 enzymatic activity or a scaffolding function is required was not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that ECHDC2 physically interacts with the E3 ligase NEDD4 to drive ubiquitination and degradation of MCCC2 provided the first defined molecular mechanism, linking ECHDC2 to suppression of P38 MAPK signaling and aerobic glycolysis in gastric cancer.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, immunofluorescence colocalization, ubiquitination assays, and in vivo xenograft models in gastric cancer cells\",\n      \"pmids\": [\"38783226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether ECHDC2 acts catalytically on MCCC2 or solely as an adaptor/scaffold for NEDD4 is unresolved\",\n        \"Relevance of the ECHDC2–NEDD4–MCCC2 axis to cardiac I/R injury has not been tested\",\n        \"The relationship between this ubiquitination mechanism and ECHDC2's metabolic enzyme function is unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic enzymatic activity of ECHDC2, its endogenous substrates, and how its metabolic and signaling (NEDD4/MCCC2) functions are integrated across tissue contexts remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No enzymatic assay or substrate identification has been reported\",\n        \"No structural data exist for ECHDC2\",\n        \"Whether the branched-chain amino acid phenotype and the MCCC2 degradation phenotype are mechanistically connected is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:1430728\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NEDD4\", \"MCCC2\"],\n    \"other_free_text\": []\n  }\n}\n```"}