{"gene":"TG_204370","gene_symbol":"MPC2","run_date":"2026-09-08T11:06:14","timeline":{"discoveries":[{"year":2023,"finding":"MPC2 forms a conserved mitochondrial pyruvate carrier (MPC) complex together with MPC1 in T. gondii, and the two subunits together transport cytosol-derived pyruvate into the mitochondrion, providing the missing link between glycolysis and the TCA cycle.","method":"Genetic complementation of yeast MPC-deficient mutant; genetic ablation (KO) of MPC1 and/or MPC2 in T. gondii combined with isotopic glucose metabolic labeling to trace carbon flux","journal":"Microbiology spectrum","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic complementation across species (functional reconstitution), clean KO with defined growth phenotype, and isotopic metabolic labeling providing multiple orthogonal lines of evidence in a single rigorous study","pmids":["36920199"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"finding":"Genetic ablation of MPC2 (or MPC1) reduces parasite growth and impairs synthesis of acetyl-CoA in the mitochondrion, with a global decrease in carbon flux through glycolysis and the TCA cycle, phenocopying deletion of branched-chain ketoacid dehydrogenase (BCKDH).","method":"Genetic KO combined with isotopic glucose (13C) metabolic labeling; epistasis comparison with BCKDH mutants","journal":"Microbiology spectrum","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function with defined metabolic phenotype and epistatic comparison using multiple orthogonal methods (KO + isotope tracing) in a single rigorous study","pmids":["36920199"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"finding":"Disruption of MPC2 exerts only a modest effect on parasite virulence in mice, indicating that the mitochondrion can compensate for loss of cytosolic pyruvate import, consistent with the metabolic plasticity of T. gondii.","method":"Mouse infection model with MPC KO parasites","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo virulence assay in a single study, single lab, demonstrating a negative/modest effect","pmids":["36920199"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"MPC2 forms a heterodimeric mitochondrial pyruvate carrier complex with MPC1 in T. gondii that imports cytosol-derived pyruvate into the mitochondrion, where it serves as the primary source of acetyl-CoA (via BCKDH), thereby coupling glycolysis to the TCA cycle and supporting optimal asexual parasite growth, though its loss is partially compensated by the parasite's metabolic plasticity."},"narrative":{"mechanistic_narrative":"MPC2 is a subunit of the mitochondrial pyruvate carrier (MPC) complex of Toxoplasma gondii, functioning together with MPC1 as a heterodimeric transporter that imports cytosol-derived pyruvate into the mitochondrion and thereby couples glycolysis to the TCA cycle [PMID:36920199]. Genetic ablation of MPC2 impairs mitochondrial acetyl-CoA synthesis and globally reduces carbon flux through glycolysis and the TCA cycle, phenocopying loss of branched-chain ketoacid dehydrogenase (BCKDH) and slowing asexual parasite growth [PMID:36920199]. Consistent with the metabolic plasticity of the parasite, loss of MPC2 exerts only a modest effect on virulence in mice, indicating that alternative routes can partially compensate for the absence of cytosolic pyruvate import [PMID:36920199]. Beyond these transport and metabolic roles, no further mechanistic detail for MPC2 has been characterized in the available corpus.","teleology":[{"year":2023,"claim":"Whether T. gondii possesses a functional link importing glycolytic pyruvate into the mitochondrion was unresolved; establishing MPC2/MPC1 as a conserved pyruvate carrier defined the missing connection between glycolysis and the TCA cycle.","evidence":"Genetic complementation of a yeast MPC-deficient mutant plus KO of MPC1/MPC2 with 13C-glucose flux tracing in T. gondii","pmids":["36920199"],"confidence":"High","gaps":["No structural model of the MPC1/MPC2 heterodimer or stoichiometry","Transport kinetics and substrate specificity not quantified","Regulation of carrier assembly/expression unknown"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"claim":"The metabolic consequence of losing pyruvate import was undefined; KO showed MPC2 loss impairs mitochondrial acetyl-CoA synthesis and reduces glycolytic/TCA carbon flux, placing MPC2 upstream in the same pathway as BCKDH.","evidence":"Genetic KO with 13C-glucose metabolic labeling and epistatic comparison against BCKDH mutants","pmids":["36920199"],"confidence":"High","gaps":["Direct demonstration that imported pyruvate feeds BCKDH rather than another enzyme not shown","Compensatory carbon sources not identified"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"claim":"Whether pyruvate import is essential in vivo was untested; a mouse infection model showed only modest virulence loss, establishing that MPC function is dispensable for infection due to metabolic plasticity.","evidence":"Mouse infection with MPC KO parasites","pmids":["36920199"],"confidence":"Medium","gaps":["Single-lab in vivo assay demonstrating a modest/negative effect","Compensatory pathways sustaining virulence not defined","Effect across life-cycle stages not tested"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"The structural basis of pyruvate translocation, the stoichiometry and assembly of the MPC1/MPC2 complex, and the identity of compensating metabolic routes remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure or transport mechanism","Compensatory carbon-source pathways unidentified","No characterization in other species"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Mitochondrial pyruvate carrier (MPC) complex (MPC1/MPC2 heterodimer)"],"partners":["MPC1"],"other_free_text":["Import of cytosol-derived pyruvate into the mitochondrion couples glycolysis to the TCA cycle [#0].","Supports mitochondrial acetyl-CoA synthesis, acting upstream in the same pathway as BCKDH [#1].","Loss reduces asexual growth but only modestly affects virulence, reflecting T. gondii metabolic plasticity [#1, #2]."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"36920199","id":"PMC_36920199","title":"The Mitochondrial Pyruvate Carrier Coupling Glycolysis and the Tricarboxylic Acid Cycle Is Required for the Asexual Reproduction of Toxoplasma gondii.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/36920199","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3254,"output_tokens":874,"usd":0.011436,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5714,"output_tokens":1879,"usd":0.037773,"stage2_stop_reason":"end_turn"},"total_usd":0.049209,"stage1_batch_id":"msgbatch_01WokvBYTB6JLnYrpD4rXnyV","stage2_batch_id":"msgbatch_01M7hsQDvz6AqVC9DLVjQzzc","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"MPC2 forms a conserved mitochondrial pyruvate carrier (MPC) complex together with MPC1 in T. gondii, and the two subunits together transport cytosol-derived pyruvate into the mitochondrion, providing the missing link between glycolysis and the TCA cycle.\",\n      \"method\": \"Genetic complementation of yeast MPC-deficient mutant; genetic ablation (KO) of MPC1 and/or MPC2 in T. gondii combined with isotopic glucose metabolic labeling to trace carbon flux\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic complementation across species (functional reconstitution), clean KO with defined growth phenotype, and isotopic metabolic labeling providing multiple orthogonal lines of evidence in a single rigorous study\",\n      \"pmids\": [\"36920199\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Genetic ablation of MPC2 (or MPC1) reduces parasite growth and impairs synthesis of acetyl-CoA in the mitochondrion, with a global decrease in carbon flux through glycolysis and the TCA cycle, phenocopying deletion of branched-chain ketoacid dehydrogenase (BCKDH).\",\n      \"method\": \"Genetic KO combined with isotopic glucose (13C) metabolic labeling; epistasis comparison with BCKDH mutants\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function with defined metabolic phenotype and epistatic comparison using multiple orthogonal methods (KO + isotope tracing) in a single rigorous study\",\n      \"pmids\": [\"36920199\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Disruption of MPC2 exerts only a modest effect on parasite virulence in mice, indicating that the mitochondrion can compensate for loss of cytosolic pyruvate import, consistent with the metabolic plasticity of T. gondii.\",\n      \"method\": \"Mouse infection model with MPC KO parasites\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo virulence assay in a single study, single lab, demonstrating a negative/modest effect\",\n      \"pmids\": [\"36920199\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"MPC2 forms a heterodimeric mitochondrial pyruvate carrier complex with MPC1 in T. gondii that imports cytosol-derived pyruvate into the mitochondrion, where it serves as the primary source of acetyl-CoA (via BCKDH), thereby coupling glycolysis to the TCA cycle and supporting optimal asexual parasite growth, though its loss is partially compensated by the parasite's metabolic plasticity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MPC2 is a subunit of the mitochondrial pyruvate carrier (MPC) complex of Toxoplasma gondii, functioning together with MPC1 as a heterodimeric transporter that imports cytosol-derived pyruvate into the mitochondrion and thereby couples glycolysis to the TCA cycle [#0]. Genetic ablation of MPC2 impairs mitochondrial acetyl-CoA synthesis and globally reduces carbon flux through glycolysis and the TCA cycle, phenocopying loss of branched-chain ketoacid dehydrogenase (BCKDH) and slowing asexual parasite growth [#1]. Consistent with the metabolic plasticity of the parasite, loss of MPC2 exerts only a modest effect on virulence in mice, indicating that alternative routes can partially compensate for the absence of cytosolic pyruvate import [#2]. Beyond these transport and metabolic roles, no further mechanistic detail for MPC2 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether T. gondii possesses a functional link importing glycolytic pyruvate into the mitochondrion was unresolved; establishing MPC2/MPC1 as a conserved pyruvate carrier defined the missing connection between glycolysis and the TCA cycle.\",\n      \"evidence\": \"Genetic complementation of a yeast MPC-deficient mutant plus KO of MPC1/MPC2 with 13C-glucose flux tracing in T. gondii\",\n      \"pmids\": [\"36920199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the MPC1/MPC2 heterodimer or stoichiometry\", \"Transport kinetics and substrate specificity not quantified\", \"Regulation of carrier assembly/expression unknown\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The metabolic consequence of losing pyruvate import was undefined; KO showed MPC2 loss impairs mitochondrial acetyl-CoA synthesis and reduces glycolytic/TCA carbon flux, placing MPC2 upstream in the same pathway as BCKDH.\",\n      \"evidence\": \"Genetic KO with 13C-glucose metabolic labeling and epistatic comparison against BCKDH mutants\",\n      \"pmids\": [\"36920199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that imported pyruvate feeds BCKDH rather than another enzyme not shown\", \"Compensatory carbon sources not identified\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether pyruvate import is essential in vivo was untested; a mouse infection model showed only modest virulence loss, establishing that MPC function is dispensable for infection due to metabolic plasticity.\",\n      \"evidence\": \"Mouse infection with MPC KO parasites\",\n      \"pmids\": [\"36920199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vivo assay demonstrating a modest/negative effect\", \"Compensatory pathways sustaining virulence not defined\", \"Effect across life-cycle stages not tested\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of pyruvate translocation, the stoichiometry and assembly of the MPC1/MPC2 complex, and the identity of compensating metabolic routes remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure or transport mechanism\", \"Compensatory carbon-source pathways unidentified\", \"No characterization in other species\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0050833\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006090\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [\"Mitochondrial pyruvate carrier (MPC) complex (MPC1/MPC2 heterodimer)\"],\n    \"partners\": [\"MPC1\"],\n    \"other_free_text\": [\n      \"Import of cytosol-derived pyruvate into the mitochondrion couples glycolysis to the TCA cycle [#0].\",\n      \"Supports mitochondrial acetyl-CoA synthesis, acting upstream in the same pathway as BCKDH [#1].\",\n      \"Loss reduces asexual growth but only modestly affects virulence, reflecting T. gondii metabolic plasticity [#1, #2].\"\n    ]\n  },\n  \"strain_conflicts\": []\n}","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_204370","name":"MPC2","product":"mitochondrial pyruvate carrier protein 2","uniprot_acc":"A0A125YZA0","chromosome":"TGME49_chrVIIa","start_pos":1845245},{"strain":"GT1","gene_id":"TGGT1_204370","name":null,"product":"WD-40 repeat protein","uniprot_acc":null,"chromosome":"TGGT1_chrVIIa","start_pos":1747131},{"strain":"RH88","gene_id":"TGRH88_034750","name":null,"product":"WD-40 repeat protein","uniprot_acc":null,"chromosome":"CM023088","start_pos":1936749},{"strain":"VEG","gene_id":"TGVEG_204370","name":null,"product":"WD-40 repeat protein","uniprot_acc":"B9PU32","chromosome":"TGVEG_chrVIIa","start_pos":1928525}]}