{"gene":"TG_215590","gene_symbol":"SDHA","run_date":"2026-09-08T11:06:29","timeline":{"discoveries":[{"year":2023,"finding":"Toxoplasma gondii SDHA is a bona fide subunit of the succinate dehydrogenase (SDH/complex II) that is essential for SDH assembly and activity, parasite growth, and mitochondrial respiration; disruption of SDHA-containing SDH impairs mitochondrial respiration and triggers spontaneous differentiation into bradyzoites.","method":"Conditional knockdown/genetic disruption of SDH subunits, mitochondrial respiration assays, parasite growth assays, differentiation phenotype analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (growth, respiration, assembly, differentiation) in a single rigorous study with defined phenotypic readouts","pmids":["38079448"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"finding":"TgSdhA (SDHA) and TgSdhB form the catalytic core of the Toxoplasma SDH complex; the myzozoan-specific membrane protein TgMPODD is required to anchor TgSdhA and TgSdhB to the membrane component of the complex, and loss of TgMPODD abolishes SDH activity.","method":"Genetic tagging, Co-immunoprecipitation/complexome analysis, conditional knockdown, SDH activity assays, O2 consumption assays, proliferation assays","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal protein interaction data combined with enzymatic activity assays and loss-of-function phenotypes, multiple orthogonal methods in one study","pmids":["38835243"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2021,"finding":"Complexome profiling assigned SDHA to complex II (succinate dehydrogenase) of the Toxoplasma mitochondrial electron transport chain, establishing its position within the mETC proteome.","method":"Complexome profiling (size-exclusion chromatography coupled with quantitative mass spectrometry)","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — large-scale complexome profiling assigns subunit to complex but provides no direct functional validation of SDHA specifically","pmids":["33651838"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2025,"finding":"Genetic deletion of SDHA in Toxoplasma gondii renders parasites nearly avirulent in a mouse model and reduces asexual reproduction, but is not required for parasite survival; SDHA localizes to the parasite mitochondrion and supports the TCA cycle during the lytic cycle.","method":"Genetic knockout, mouse virulence model, subcellular localization (mitochondrial marker), metabolic phenotyping","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean knockout with defined in vivo phenotype and localization, single lab, single study","pmids":["40050648"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"Toxoplasma gondii SDHA forms the catalytic core of the divergent, nine-subunit succinate dehydrogenase (complex II) together with SdhB, localizes to the mitochondrion, requires myzozoan-specific membrane subunits (including TgMPODD) for membrane anchoring and SDH activity, and is important for mitochondrial respiration, optimal parasite proliferation, prevention of spontaneous bradyzoite differentiation, and full virulence in the host, though it is dispensable for basic parasite survival."},"narrative":{"mechanistic_narrative":"In Toxoplasma gondii, SDHA (TgSdhA) is the catalytic core subunit of succinate dehydrogenase (complex II) of the mitochondrial electron transport chain, together with TgSdhB, and localizes to the parasite mitochondrion [PMID:38835243, PMID:33651838, PMID:40050648]. Membrane anchoring of the TgSdhA/TgSdhB catalytic core and full SDH enzymatic activity depend on the myzozoan-specific membrane subunit TgMPODD, whose loss abolishes SDH activity [PMID:38835243]. Through this SDH function, TgSdhA supports mitochondrial respiration and the TCA cycle during the lytic cycle, and its disruption impairs respiration, reduces asexual proliferation, and triggers spontaneous differentiation into bradyzoites [PMID:38079448, PMID:40050648]. SDHA is important for optimal proliferation and for full virulence in mice, yet is dispensable for basic parasite survival [PMID:38079448, PMID:40050648].","teleology":[{"year":2021,"claim":"Establishing where SDHA sits in the parasite's respiratory proteome was the first step; complexome profiling assigned it to complex II, placing SDHA within the Toxoplasma mitochondrial electron transport chain.","evidence":"Complexome profiling (size-exclusion chromatography coupled to quantitative mass spectrometry)","pmids":["33651838"],"confidence":"Medium","gaps":["No direct functional validation of SDHA-specific enzymatic contribution","Membrane-anchoring architecture unresolved"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"claim":"Whether SDHA-containing SDH is functionally required was answered by showing it is essential for SDH assembly and activity and links respiration to developmental fate, since its disruption impaired respiration and triggered bradyzoite differentiation.","evidence":"Conditional knockdown/genetic disruption of SDH subunits with respiration, growth, assembly, and differentiation readouts","pmids":["38079448"],"confidence":"High","gaps":["Mechanism linking respiratory failure to differentiation not defined","Membrane subunit requirements not yet identified"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"claim":"How the catalytic core attaches to the divergent membrane component was resolved by identifying the myzozoan-specific subunit TgMPODD as the anchor for TgSdhA/TgSdhB, defining the assembly logic of the parasite's atypical complex II.","evidence":"Genetic tagging, co-immunoprecipitation/complexome analysis, conditional knockdown, SDH activity and O2 consumption assays","pmids":["38835243"],"confidence":"High","gaps":["Structure of the assembled myzozoan SDH not determined","Roles of other membrane subunits beyond TgMPODD not fully dissected"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2025,"claim":"The physiological consequence of losing SDHA in vivo was defined: clean deletion renders parasites nearly avirulent and reduces asexual reproduction while remaining dispensable for survival, establishing SDHA as a virulence/proliferation determinant rather than an absolute essential gene.","evidence":"Genetic knockout, mouse virulence model, mitochondrial localization, metabolic phenotyping","pmids":["40050648"],"confidence":"Medium","gaps":["Single-lab, single-study in vivo phenotype","Metabolic rewiring enabling survival without SDHA not defined"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"The molecular basis by which respiratory/SDH failure drives spontaneous bradyzoite differentiation, and the compensatory metabolism permitting survival despite SDHA loss, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Signal coupling respiration to differentiation unknown","No structural model of the myzozoan SDH complex","Metabolic bypass supporting viability uncharacterized"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Succinate dehydrogenase (complex II) — divergent myzozoan nine-subunit form"],"partners":["TGSDHB (CATALYTIC CORE PARTNER)","TGMPODD (MYZOZOAN-SPECIFIC MEMBRANE ANCHOR SUBUNIT)"],"other_free_text":["SDHA disruption triggers spontaneous differentiation into bradyzoites [#0].","SDHA is important for full virulence in mice and optimal asexual proliferation but is dispensable for parasite survival [#0, #3]."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"33651838","id":"PMC_33651838","title":"Complexome profile of Toxoplasma gondii mitochondria identifies divergent subunits of respiratory chain complexes including new subunits of cytochrome bc1 complex.","date":"2021","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/33651838","citation_count":53,"is_preprint":false},{"pmid":"38079448","id":"PMC_38079448","title":"Functional and biochemical characterization of the Toxoplasma gondii succinate dehydrogenase complex.","date":"2023","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/38079448","citation_count":11,"is_preprint":false},{"pmid":"40050648","id":"PMC_40050648","title":"Metabolic crosstalk between the mitochondrion and the nucleus is essential for Toxoplasma gondii infection.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/40050648","citation_count":4,"is_preprint":false},{"pmid":"38835243","id":"PMC_38835243","title":"A myzozoan-specific protein is an essential membrane-anchoring component of the succinate dehydrogenase complex in Toxoplasma parasites.","date":"2024","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/38835243","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4328,"output_tokens":1101,"usd":0.01475,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6065,"output_tokens":2273,"usd":0.043575,"stage2_stop_reason":"end_turn"},"total_usd":0.058325,"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\": \"Toxoplasma gondii SDHA is a bona fide subunit of the succinate dehydrogenase (SDH/complex II) that is essential for SDH assembly and activity, parasite growth, and mitochondrial respiration; disruption of SDHA-containing SDH impairs mitochondrial respiration and triggers spontaneous differentiation into bradyzoites.\",\n      \"method\": \"Conditional knockdown/genetic disruption of SDH subunits, mitochondrial respiration assays, parasite growth assays, differentiation phenotype analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (growth, respiration, assembly, differentiation) in a single rigorous study with defined phenotypic readouts\",\n      \"pmids\": [\"38079448\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TgSdhA (SDHA) and TgSdhB form the catalytic core of the Toxoplasma SDH complex; the myzozoan-specific membrane protein TgMPODD is required to anchor TgSdhA and TgSdhB to the membrane component of the complex, and loss of TgMPODD abolishes SDH activity.\",\n      \"method\": \"Genetic tagging, Co-immunoprecipitation/complexome analysis, conditional knockdown, SDH activity assays, O2 consumption assays, proliferation assays\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal protein interaction data combined with enzymatic activity assays and loss-of-function phenotypes, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38835243\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Complexome profiling assigned SDHA to complex II (succinate dehydrogenase) of the Toxoplasma mitochondrial electron transport chain, establishing its position within the mETC proteome.\",\n      \"method\": \"Complexome profiling (size-exclusion chromatography coupled with quantitative mass spectrometry)\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — large-scale complexome profiling assigns subunit to complex but provides no direct functional validation of SDHA specifically\",\n      \"pmids\": [\"33651838\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic deletion of SDHA in Toxoplasma gondii renders parasites nearly avirulent in a mouse model and reduces asexual reproduction, but is not required for parasite survival; SDHA localizes to the parasite mitochondrion and supports the TCA cycle during the lytic cycle.\",\n      \"method\": \"Genetic knockout, mouse virulence model, subcellular localization (mitochondrial marker), metabolic phenotyping\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean knockout with defined in vivo phenotype and localization, single lab, single study\",\n      \"pmids\": [\"40050648\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"Toxoplasma gondii SDHA forms the catalytic core of the divergent, nine-subunit succinate dehydrogenase (complex II) together with SdhB, localizes to the mitochondrion, requires myzozoan-specific membrane subunits (including TgMPODD) for membrane anchoring and SDH activity, and is important for mitochondrial respiration, optimal parasite proliferation, prevention of spontaneous bradyzoite differentiation, and full virulence in the host, though it is dispensable for basic parasite survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"In Toxoplasma gondii, SDHA (TgSdhA) is the catalytic core subunit of succinate dehydrogenase (complex II) of the mitochondrial electron transport chain, together with TgSdhB, and localizes to the parasite mitochondrion [#1, #2, #3]. Membrane anchoring of the TgSdhA/TgSdhB catalytic core and full SDH enzymatic activity depend on the myzozoan-specific membrane subunit TgMPODD, whose loss abolishes SDH activity [#1]. Through this SDH function, TgSdhA supports mitochondrial respiration and the TCA cycle during the lytic cycle, and its disruption impairs respiration, reduces asexual proliferation, and triggers spontaneous differentiation into bradyzoites [#0, #3]. SDHA is important for optimal proliferation and for full virulence in mice, yet is dispensable for basic parasite survival [#0, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing where SDHA sits in the parasite's respiratory proteome was the first step; complexome profiling assigned it to complex II, placing SDHA within the Toxoplasma mitochondrial electron transport chain.\",\n      \"evidence\": \"Complexome profiling (size-exclusion chromatography coupled to quantitative mass spectrometry)\",\n      \"pmids\": [\"33651838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional validation of SDHA-specific enzymatic contribution\", \"Membrane-anchoring architecture unresolved\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether SDHA-containing SDH is functionally required was answered by showing it is essential for SDH assembly and activity and links respiration to developmental fate, since its disruption impaired respiration and triggered bradyzoite differentiation.\",\n      \"evidence\": \"Conditional knockdown/genetic disruption of SDH subunits with respiration, growth, assembly, and differentiation readouts\",\n      \"pmids\": [\"38079448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking respiratory failure to differentiation not defined\", \"Membrane subunit requirements not yet identified\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"How the catalytic core attaches to the divergent membrane component was resolved by identifying the myzozoan-specific subunit TgMPODD as the anchor for TgSdhA/TgSdhB, defining the assembly logic of the parasite's atypical complex II.\",\n      \"evidence\": \"Genetic tagging, co-immunoprecipitation/complexome analysis, conditional knockdown, SDH activity and O2 consumption assays\",\n      \"pmids\": [\"38835243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the assembled myzozoan SDH not determined\", \"Roles of other membrane subunits beyond TgMPODD not fully dissected\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The physiological consequence of losing SDHA in vivo was defined: clean deletion renders parasites nearly avirulent and reduces asexual reproduction while remaining dispensable for survival, establishing SDHA as a virulence/proliferation determinant rather than an absolute essential gene.\",\n      \"evidence\": \"Genetic knockout, mouse virulence model, mitochondrial localization, metabolic phenotyping\",\n      \"pmids\": [\"40050648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, single-study in vivo phenotype\", \"Metabolic rewiring enabling survival without SDHA not defined\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis by which respiratory/SDH failure drives spontaneous bradyzoite differentiation, and the compensatory metabolism permitting survival despite SDHA loss, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signal coupling respiration to differentiation unknown\", \"No structural model of the myzozoan SDH complex\", \"Metabolic bypass supporting viability uncharacterized\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008177\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0006099\", \"supporting_discovery_ids\": [3], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0045273\", \"supporting_discovery_ids\": [1, 2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0022904\", \"supporting_discovery_ids\": [0, 2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0006099\", \"supporting_discovery_ids\": [3], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [\n      \"Succinate dehydrogenase (complex II) — divergent myzozoan nine-subunit form\"\n    ],\n    \"partners\": [\n      \"TgSdhB (catalytic core partner)\",\n      \"TgMPODD (myzozoan-specific membrane anchor subunit)\"\n    ],\n    \"other_free_text\": [\n      \"SDHA disruption triggers spontaneous differentiation into bradyzoites [#0].\",\n      \"SDHA is important for full virulence in mice and optimal asexual proliferation but is dispensable for parasite survival [#0, #3].\"\n    ]\n  },\n  \"strain_conflicts\": []\n}","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_215590","name":"SDHA","product":"flavoprotein subunit of succinate dehydrogenase SDHA","uniprot_acc":"A0A125YI83","chromosome":"TGME49_chrX","start_pos":7030865},{"strain":"GT1","gene_id":"TGGT1_215590","name":null,"product":"flavoprotein subunit of succinate dehydrogenase","uniprot_acc":null,"chromosome":"TGGT1_chrX","start_pos":6924001},{"strain":"RH88","gene_id":"TGRH88_039020","name":null,"product":"flavoprotein subunit of succinate dehydrogenase","uniprot_acc":null,"chromosome":"CM023091","start_pos":494476},{"strain":"VEG","gene_id":"TGVEG_215590","name":null,"product":"flavoprotein subunit of succinate dehydrogenase","uniprot_acc":"B9PZU5","chromosome":"TGVEG_chrX","start_pos":6964389}]}