{"gene":"LDHD","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2019,"finding":"Loss-of-function variants in LDHD cause elevated D-lactate in humans and zebrafish, establishing LDHD as the enzyme responsible for D-lactate catabolism in vivo. Wild-type LDHD rescued elevated D-lactate in zebrafish LDHD knockdown, while patient variant LDHD did not, confirming enzymatic loss-of-function.","method":"Human genetics (homozygous variants), zebrafish loss-of-function model, rescue experiments with wild-type vs. patient-variant LDHD","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and biochemical validation in two independent patient families plus zebrafish rescue model with orthogonal methods","pmids":["30931947"],"is_preprint":false},{"year":2019,"finding":"A missense mutation in LDHD within the putative catalytic site causes accumulation of D-lactate in blood; excessive renal secretion of D-lactate in exchange for uric acid reabsorption leads to hyperuricemia and gout. LDHD protein was shown to localize to mitochondria in cells overexpressing the human LDHD gene; the p.R370W mutation did not affect mitochondrial localization.","method":"Human genetics, direct measurement of D-lactate levels, overexpression of LDHD with mitochondrial localization assay, D-lactate injection into naive mice producing hyperuricemia","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, biochemistry, subcellular localization, mouse injection model) in a single rigorous study","pmids":["31638601"],"is_preprint":false},{"year":2023,"finding":"CDK7 phosphorylates nuclear YAP1 at S127 and S397, enhancing its transcriptional function, which in turn promotes LDHD protein expression. The CDK7-YAP-LDHD axis enables esophageal squamous cell carcinoma cancer stem cells to catabolize D-lactate (converting it to pyruvate), thereby escaping D-lactate-induced ferroptosis and supporting self-renewal.","method":"Phosphorylation assays, transcriptional reporter assays, LDHD overexpression/knockdown with ferroptosis and stemness readouts","journal":"Signal Transduction and Targeted Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement by epistasis and functional KD/OE, single lab, multiple readouts but abstract-level detail","pmids":["37582812"],"is_preprint":false},{"year":2021,"finding":"Compound heterozygous LDHD variants (splice-site c.469+1dupG and missense p.Thr251Met) cause D-lactate dehydrogenase deficiency with elevated serum D-lactate, and are associated with decreased mitochondrial complex IV activity in patient fibroblasts, suggesting a functional link between LDHD and mitochondrial respiratory chain activity.","method":"Whole-exome sequencing, D-lactate measurement, mitochondrial complex IV enzyme assay in patient skin fibroblasts","journal":"JIMD Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single patient report, biochemical confirmation of loss-of-function and complex IV deficiency, but mechanistic link between LDHD and complex IV not directly established","pmids":["34258137"],"is_preprint":false},{"year":2023,"finding":"Rare homozygous loss-of-function variants in LDHD (three distinct variants in three ethnicities) cause autosomal recessive early-onset gout, with elevated D-lactate in blood and urine and reduced fractional clearance of urate, confirming the renal D-lactate/urate exchange mechanism.","method":"Whole-exome sequencing, targeted gene sequencing, D-lactate measurement by ELISA, fractional clearance of urate","journal":"Rheumatology (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — independently replicated across three unrelated families with different LDHD variants, biochemical D-lactate measurements confirming loss-of-function","pmids":["37021930"],"is_preprint":false},{"year":2026,"finding":"CSRP3 physically binds to LDHD via a specific 33-amino acid region, promoting D-lactate catabolism in skeletal muscle. This CSRP3-LDHD interaction regulates mitochondrial morphology, biogenesis, oxidative phosphorylation efficiency, and TCA cycle activity, driving skeletal muscle fiber type remodeling toward oxidative phenotype.","method":"Co-immunoprecipitation/binding assay identifying the 33-aa interaction domain, AAV-mediated knockdown, live mouse exercise models, mitochondrial functional assays","journal":"Metabolism: Clinical and Experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding interaction mapped to specific domain, functional KO with defined phenotypic readouts, single lab","pmids":["41812695"],"is_preprint":false}],"current_model":"LDHD encodes a mitochondria-localized D-lactate dehydrogenase that catabolizes D-lactate to pyruvate; loss-of-function causes D-lactic acidosis and, via excessive renal D-lactate/uric acid exchange, hyperuricemia and gout; its expression is transcriptionally driven by the CDK7-YAP axis in cancer stem cells, and it physically interacts with CSRP3 to regulate mitochondrial metabolism and skeletal muscle fiber type."},"narrative":{"mechanistic_narrative":"LDHD encodes a mitochondria-localized D-lactate dehydrogenase that catabolizes D-lactate to pyruvate, the enzyme responsible for D-lactate clearance in vivo [PMID:30931947, PMID:31638601]. Loss-of-function variants in humans elevate serum and urinary D-lactate, and wild-type but not patient-variant LDHD rescues elevated D-lactate in zebrafish, confirming an enzymatic loss-of-function mechanism [PMID:30931947]. Pathogenic variants, including a catalytic-site missense mutation, cause D-lactic acidosis and drive hyperuricemia and early-onset gout through excessive renal secretion of D-lactate in exchange for urate reabsorption, reducing fractional clearance of urate [PMID:31638601, PMID:37021930]. Beyond catabolism, LDHD activity is integrated into mitochondrial metabolism: its loss is associated with decreased complex IV activity in patient fibroblasts [PMID:34258137], and physical interaction with CSRP3 via a defined 33-amino-acid region couples D-lactate catabolism to mitochondrial biogenesis, oxidative phosphorylation, TCA cycle activity, and skeletal muscle fiber-type remodeling toward an oxidative phenotype [PMID:41812695]. In esophageal squamous cell carcinoma cancer stem cells, LDHD expression is transcriptionally driven by a CDK7–YAP1 axis, enabling clearance of D-lactate to escape D-lactate-induced ferroptosis and support self-renewal [PMID:37582812].","teleology":[{"year":2019,"claim":"Established LDHD as the enzyme responsible for D-lactate catabolism in vivo, answering which gene clears D-lactate and showing that pathogenic variants act through enzymatic loss-of-function.","evidence":"Human homozygous variants plus zebrafish loss-of-function and rescue with wild-type versus patient-variant LDHD","pmids":["30931947"],"confidence":"High","gaps":["Catalytic mechanism and structural basis of D-lactate-to-pyruvate conversion not resolved","Cofactor/electron acceptor requirements not defined"]},{"year":2019,"claim":"Defined the disease mechanism linking LDHD deficiency to hyperuricemia, showing that accumulated D-lactate drives renal D-lactate/urate exchange, and localized LDHD to mitochondria.","evidence":"Human genetics with a catalytic-site missense variant, mitochondrial localization assay of overexpressed LDHD, and D-lactate injection into naive mice producing hyperuricemia","pmids":["31638601"],"confidence":"High","gaps":["Identity of the renal D-lactate/urate exchanger not established","Whether mitochondrial localization depends on a specific targeting sequence not defined"]},{"year":2021,"claim":"Connected LDHD loss to a broader mitochondrial respiratory defect, raising the question of whether D-lactate dehydrogenase activity influences the respiratory chain.","evidence":"Whole-exome sequencing of compound heterozygous patient and complex IV enzyme assay in patient fibroblasts","pmids":["34258137"],"confidence":"Medium","gaps":["Mechanistic link between LDHD and complex IV not directly established","Single patient report"]},{"year":2023,"claim":"Independently confirmed the LDHD loss-of-function/renal urate mechanism as a cause of autosomal recessive early-onset gout across multiple ethnicities.","evidence":"Whole-exome and targeted sequencing of three unrelated families, D-lactate ELISA, and fractional clearance of urate measurement","pmids":["37021930"],"confidence":"High","gaps":["Molecular identity of the urate exchange transporter not resolved","Penetrance and modifiers of gout phenotype not defined"]},{"year":2023,"claim":"Placed LDHD downstream of a CDK7–YAP1 transcriptional axis in cancer stem cells, showing its D-lactate catabolism protects against ferroptosis and supports self-renewal.","evidence":"Phosphorylation and transcriptional reporter assays, LDHD knockdown/overexpression with ferroptosis and stemness readouts in esophageal squamous cell carcinoma","pmids":["37582812"],"confidence":"Medium","gaps":["Direct binding of YAP1 to the LDHD promoter not detailed","Generalizability beyond esophageal squamous cell carcinoma unknown","Single lab, abstract-level detail"]},{"year":2026,"claim":"Identified CSRP3 as a direct LDHD partner and linked the interaction to mitochondrial biogenesis and muscle fiber-type remodeling, extending LDHD's role beyond simple catabolism.","evidence":"Co-immunoprecipitation mapping a 33-aa interaction domain, AAV-mediated knockdown, mouse exercise models, and mitochondrial functional assays","pmids":["41812695"],"confidence":"Medium","gaps":["Whether CSRP3 modulates LDHD catalytic activity directly not resolved","Reciprocal structural validation of the interaction not performed","Single lab"]},{"year":null,"claim":"How LDHD's enzymatic D-lactate clearance is mechanistically coupled to mitochondrial respiratory chain integrity remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of LDHD catalysis","Causal basis for complex IV deficiency upon LDHD loss unknown","Identity of renal D-lactate/urate exchanger unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,5]}],"complexes":[],"partners":["CSRP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86WU2","full_name":"D-lactate dehydrogenase, mitochondrial","aliases":[],"length_aa":507,"mass_kda":54.9,"function":"The mitochondrial D-lactate dehydrogenase is a stereoselective dehydrogenase that targets a wide variety of D-2-hydroxyacids, particularly those with small to moderately sized hydrophobic groups attached to the C2 atom. It includes D-lactate which is generated in small amounts either endogenously through the methylglyoxal metabolism pathway or exogenously via intestinal bacterial activity and dietary intake. The dehydrogenase acts specifically on D-lactate, not on its stereoisomer L-lactate, and prevents the toxic accumulation of D-lactate in the organism (PubMed:30931947, PubMed:38373542). By converting branched-chain D-2-hydroxyacids into branched-chain ketoacids, it may indirectly regulate branched-chain amino acid metabolism (By similarity)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q86WU2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LDHD","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LDHD","total_profiled":1310},"omim":[{"mim_id":"607490","title":"LACTATE DEHYDROGENASE D; LDHD","url":"https://www.omim.org/entry/607490"},{"mim_id":"245450","title":"D-LACTIC ACIDURIA WITH GOUT; DLACD","url":"https://www.omim.org/entry/245450"},{"mim_id":"138900","title":"URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 1; UAQTL1","url":"https://www.omim.org/entry/138900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":78.8},{"tissue":"liver","ntpm":126.0}],"url":"https://www.proteinatlas.org/search/LDHD"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q86WU2","domains":[{"cath_id":"3.30.43.10","chopping":"30-119","consensus_level":"high","plddt":96.9186,"start":30,"end":119},{"cath_id":"3.30.465.10","chopping":"123-210_241-264","consensus_level":"high","plddt":94.4982,"start":123,"end":264},{"cath_id":"3.30.70.2190","chopping":"267-378","consensus_level":"medium","plddt":95.7503,"start":267,"end":378},{"cath_id":"3.30.70.2740","chopping":"382-468","consensus_level":"medium","plddt":96.1408,"start":382,"end":468}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WU2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WU2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86WU2-F1-predicted_aligned_error_v6.png","plddt_mean":89.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LDHD","jax_strain_url":"https://www.jax.org/strain/search?query=LDHD"},"sequence":{"accession":"Q86WU2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86WU2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86WU2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86WU2"}},"corpus_meta":[{"pmid":"3754003","id":"PMC_3754003","title":"The 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Wild-type LDHD rescued elevated D-lactate in zebrafish LDHD knockdown, while patient variant LDHD did not, confirming enzymatic loss-of-function.\",\n      \"method\": \"Human genetics (homozygous variants), zebrafish loss-of-function model, rescue experiments with wild-type vs. patient-variant LDHD\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and biochemical validation in two independent patient families plus zebrafish rescue model with orthogonal methods\",\n      \"pmids\": [\"30931947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A missense mutation in LDHD within the putative catalytic site causes accumulation of D-lactate in blood; excessive renal secretion of D-lactate in exchange for uric acid reabsorption leads to hyperuricemia and gout. LDHD protein was shown to localize to mitochondria in cells overexpressing the human LDHD gene; the p.R370W mutation did not affect mitochondrial localization.\",\n      \"method\": \"Human genetics, direct measurement of D-lactate levels, overexpression of LDHD with mitochondrial localization assay, D-lactate injection into naive mice producing hyperuricemia\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, biochemistry, subcellular localization, mouse injection model) in a single rigorous study\",\n      \"pmids\": [\"31638601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK7 phosphorylates nuclear YAP1 at S127 and S397, enhancing its transcriptional function, which in turn promotes LDHD protein expression. The CDK7-YAP-LDHD axis enables esophageal squamous cell carcinoma cancer stem cells to catabolize D-lactate (converting it to pyruvate), thereby escaping D-lactate-induced ferroptosis and supporting self-renewal.\",\n      \"method\": \"Phosphorylation assays, transcriptional reporter assays, LDHD overexpression/knockdown with ferroptosis and stemness readouts\",\n      \"journal\": \"Signal Transduction and Targeted Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement by epistasis and functional KD/OE, single lab, multiple readouts but abstract-level detail\",\n      \"pmids\": [\"37582812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Compound heterozygous LDHD variants (splice-site c.469+1dupG and missense p.Thr251Met) cause D-lactate dehydrogenase deficiency with elevated serum D-lactate, and are associated with decreased mitochondrial complex IV activity in patient fibroblasts, suggesting a functional link between LDHD and mitochondrial respiratory chain activity.\",\n      \"method\": \"Whole-exome sequencing, D-lactate measurement, mitochondrial complex IV enzyme assay in patient skin fibroblasts\",\n      \"journal\": \"JIMD Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single patient report, biochemical confirmation of loss-of-function and complex IV deficiency, but mechanistic link between LDHD and complex IV not directly established\",\n      \"pmids\": [\"34258137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rare homozygous loss-of-function variants in LDHD (three distinct variants in three ethnicities) cause autosomal recessive early-onset gout, with elevated D-lactate in blood and urine and reduced fractional clearance of urate, confirming the renal D-lactate/urate exchange mechanism.\",\n      \"method\": \"Whole-exome sequencing, targeted gene sequencing, D-lactate measurement by ELISA, fractional clearance of urate\",\n      \"journal\": \"Rheumatology (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independently replicated across three unrelated families with different LDHD variants, biochemical D-lactate measurements confirming loss-of-function\",\n      \"pmids\": [\"37021930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CSRP3 physically binds to LDHD via a specific 33-amino acid region, promoting D-lactate catabolism in skeletal muscle. This CSRP3-LDHD interaction regulates mitochondrial morphology, biogenesis, oxidative phosphorylation efficiency, and TCA cycle activity, driving skeletal muscle fiber type remodeling toward oxidative phenotype.\",\n      \"method\": \"Co-immunoprecipitation/binding assay identifying the 33-aa interaction domain, AAV-mediated knockdown, live mouse exercise models, mitochondrial functional assays\",\n      \"journal\": \"Metabolism: Clinical and Experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding interaction mapped to specific domain, functional KO with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"41812695\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LDHD encodes a mitochondria-localized D-lactate dehydrogenase that catabolizes D-lactate to pyruvate; loss-of-function causes D-lactic acidosis and, via excessive renal D-lactate/uric acid exchange, hyperuricemia and gout; its expression is transcriptionally driven by the CDK7-YAP axis in cancer stem cells, and it physically interacts with CSRP3 to regulate mitochondrial metabolism and skeletal muscle fiber type.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LDHD encodes a mitochondria-localized D-lactate dehydrogenase that catabolizes D-lactate to pyruvate, the enzyme responsible for D-lactate clearance in vivo [#0, #1]. Loss-of-function variants in humans elevate serum and urinary D-lactate, and wild-type but not patient-variant LDHD rescues elevated D-lactate in zebrafish, confirming an enzymatic loss-of-function mechanism [#0]. Pathogenic variants, including a catalytic-site missense mutation, cause D-lactic acidosis and drive hyperuricemia and early-onset gout through excessive renal secretion of D-lactate in exchange for urate reabsorption, reducing fractional clearance of urate [#1, #4]. Beyond catabolism, LDHD activity is integrated into mitochondrial metabolism: its loss is associated with decreased complex IV activity in patient fibroblasts [#3], and physical interaction with CSRP3 via a defined 33-amino-acid region couples D-lactate catabolism to mitochondrial biogenesis, oxidative phosphorylation, TCA cycle activity, and skeletal muscle fiber-type remodeling toward an oxidative phenotype [#5]. In esophageal squamous cell carcinoma cancer stem cells, LDHD expression is transcriptionally driven by a CDK7–YAP1 axis, enabling clearance of D-lactate to escape D-lactate-induced ferroptosis and support self-renewal [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established LDHD as the enzyme responsible for D-lactate catabolism in vivo, answering which gene clears D-lactate and showing that pathogenic variants act through enzymatic loss-of-function.\",\n      \"evidence\": \"Human homozygous variants plus zebrafish loss-of-function and rescue with wild-type versus patient-variant LDHD\",\n      \"pmids\": [\"30931947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism and structural basis of D-lactate-to-pyruvate conversion not resolved\", \"Cofactor/electron acceptor requirements not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the disease mechanism linking LDHD deficiency to hyperuricemia, showing that accumulated D-lactate drives renal D-lactate/urate exchange, and localized LDHD to mitochondria.\",\n      \"evidence\": \"Human genetics with a catalytic-site missense variant, mitochondrial localization assay of overexpressed LDHD, and D-lactate injection into naive mice producing hyperuricemia\",\n      \"pmids\": [\"31638601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the renal D-lactate/urate exchanger not established\", \"Whether mitochondrial localization depends on a specific targeting sequence not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected LDHD loss to a broader mitochondrial respiratory defect, raising the question of whether D-lactate dehydrogenase activity influences the respiratory chain.\",\n      \"evidence\": \"Whole-exome sequencing of compound heterozygous patient and complex IV enzyme assay in patient fibroblasts\",\n      \"pmids\": [\"34258137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between LDHD and complex IV not directly established\", \"Single patient report\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Independently confirmed the LDHD loss-of-function/renal urate mechanism as a cause of autosomal recessive early-onset gout across multiple ethnicities.\",\n      \"evidence\": \"Whole-exome and targeted sequencing of three unrelated families, D-lactate ELISA, and fractional clearance of urate measurement\",\n      \"pmids\": [\"37021930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the urate exchange transporter not resolved\", \"Penetrance and modifiers of gout phenotype not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed LDHD downstream of a CDK7–YAP1 transcriptional axis in cancer stem cells, showing its D-lactate catabolism protects against ferroptosis and supports self-renewal.\",\n      \"evidence\": \"Phosphorylation and transcriptional reporter assays, LDHD knockdown/overexpression with ferroptosis and stemness readouts in esophageal squamous cell carcinoma\",\n      \"pmids\": [\"37582812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of YAP1 to the LDHD promoter not detailed\", \"Generalizability beyond esophageal squamous cell carcinoma unknown\", \"Single lab, abstract-level detail\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified CSRP3 as a direct LDHD partner and linked the interaction to mitochondrial biogenesis and muscle fiber-type remodeling, extending LDHD's role beyond simple catabolism.\",\n      \"evidence\": \"Co-immunoprecipitation mapping a 33-aa interaction domain, AAV-mediated knockdown, mouse exercise models, and mitochondrial functional assays\",\n      \"pmids\": [\"41812695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CSRP3 modulates LDHD catalytic activity directly not resolved\", \"Reciprocal structural validation of the interaction not performed\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LDHD's enzymatic D-lactate clearance is mechanistically coupled to mitochondrial respiratory chain integrity remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of LDHD catalysis\", \"Causal basis for complex IV deficiency upon LDHD loss unknown\", \"Identity of renal D-lactate/urate exchanger unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CSRP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}