{"gene":"PF3D7_0412100","run_date":"2026-09-07T10:55:51","timeline":{"discoveries":[{"year":2020,"finding":"PF3D7_0412100 (PfmtRPS12) localizes to the mitochondrion of P. falciparum, as verified by immuno-EM showing the mitoribosome is closely associated with the mitochondrial inner membrane.","method":"Immuno-electron microscopy (immuno-EM) with CRISPR/Cas9-based conditional knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immuno-EM localization combined with conditional knockdown, single lab, two orthogonal methods","pmids":["32273345"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"CRISPR/Cas9-based conditional knockdown of PF3D7_0412100 (PfmtRPS12) confirmed it is essential for parasite viability and mitochondrial membrane potential maintenance.","method":"CRISPR/Cas9-based conditional knockdown with viability and mitochondrial membrane potential assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockdown with defined cellular phenotype (loss of viability, loss of membrane potential), single lab","pmids":["32273345"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Knockdown of PF3D7_0412100 (PfmtRPS12) rendered parasites hypersensitive to inhibitors of mitochondrial Complex III (bc1 complex), dihydroorotate dehydrogenase (DHOD), and the F1F0-ATP synthase, placing the mitoribosome upstream of these metabolic pathways.","method":"CRISPR/Cas9-based conditional knockdown combined with pharmacological sensitivity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via knockdown plus drug sensitivity readout, single lab, multiple inhibitors tested","pmids":["32273345"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Knockdown of PF3D7_0412100 (PfmtRPS12) blocked the pyrimidine biosynthesis pathway and reduced the cellular pool of pyrimidine nucleotides, demonstrating that the mitoribosome is required for sustaining mitochondrial metabolic capacity linked to DHOD-dependent pyrimidine synthesis.","method":"CRISPR/Cas9-based conditional knockdown with metabolite quantification of pyrimidine nucleotide pools","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockdown with metabolomics readout, single lab, direct metabolic measurement","pmids":["32273345"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0412100 (PfmtRPS12) is a component of the small subunit of the P. falciparum mitoribosome, localizes to the mitochondrial inner membrane, is essential for parasite viability and mitochondrial membrane potential, and is required to sustain the metabolic capacity of the mitochondrion—including electron transport chain function and DHOD-dependent pyrimidine biosynthesis—as demonstrated by conditional knockdown causing hypersensitivity to mitochondrial inhibitors and depletion of pyrimidine nucleotide pools."},"narrative":{"mechanistic_narrative":"PF3D7_0412100 (mtRPS12) is a component of the small subunit of the Plasmodium falciparum mitoribosome that is essential for asexual parasite viability [PMID:32273345]. It localizes to the mitochondrion, where immuno-EM places the mitoribosome in close association with the mitochondrial inner membrane [PMID:32273345]. Conditional knockdown of PF3D7_0412100 collapses the mitochondrial membrane potential [PMID:32273345] and renders parasites hypersensitive to inhibitors of Complex III (bc1), dihydroorotate dehydrogenase, and the F1F0-ATP synthase, placing mitoribosomal function upstream of these metabolic activities [PMID:32273345]. Consistent with this, knockdown blocks pyrimidine biosynthesis and depletes cellular pyrimidine nucleotide pools, establishing that PF3D7_0412100 is required to sustain the mitochondrion's metabolic capacity, including DHOD-dependent pyrimidine synthesis [PMID:32273345]. Beyond its role as an essential mitoribosomal subunit sustaining mitochondrial metabolism, no further molecular detail of PF3D7_0412100 itself—such as specific translation substrates or direct binding partners within the mitoribosome—has been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Whether PF3D7_0412100 functions in the parasite mitochondrion was unknown; localizing it established it as a bona fide mitochondrial mitoribosomal component physically tied to the inner membrane.","evidence":"Immuno-EM with CRISPR/Cas9 conditional knockdown in P. falciparum","pmids":["32273345"],"confidence":"Medium","gaps":["No structural placement of the protein within the small subunit","Direct mitoribosomal partners of PF3D7_0412100 not defined","Mechanism of inner-membrane association not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"It was unclear whether the mitoribosome is dispensable in blood-stage parasites; conditional knockdown showed PF3D7_0412100 is essential for viability and for maintaining mitochondrial membrane potential.","evidence":"CRISPR/Cas9 conditional knockdown with viability and membrane-potential assays in P. falciparum","pmids":["32273345"],"confidence":"Medium","gaps":["Molecular events linking loss of the subunit to membrane-potential collapse not traced","Stage specificity of essentiality not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"The metabolic dependencies downstream of the mitoribosome were undefined; knockdown-induced hypersensitivity to bc1, DHOD, and ATP synthase inhibitors placed PF3D7_0412100 upstream of core mitochondrial metabolic pathways.","evidence":"Conditional knockdown combined with pharmacological sensitivity assays in P. falciparum","pmids":["32273345"],"confidence":"Medium","gaps":["Which mitochondrially encoded transcripts require the mitoribosome not identified","Direct effect on individual ETC complex assembly not measured"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Whether mitoribosome loss functionally impairs pyrimidine synthesis was unknown; metabolite measurement showed knockdown blocks the pathway and depletes pyrimidine nucleotide pools, tying PF3D7_0412100 to DHOD-dependent metabolism.","evidence":"Conditional knockdown with metabolite quantification of pyrimidine nucleotide pools in P. falciparum","pmids":["32273345"],"confidence":"Medium","gaps":["Whether pyrimidine depletion is the proximate cause of lethality not established","Kinetics relating mitoribosome loss to metabolite decline not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The molecular activity of PF3D7_0412100 within the mitoribosome—its specific translation substrates, structural placement, and direct protein/RNA contacts—remains uncharacterized in the available corpus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified mitochondrially encoded translation products","No structural or interaction map for the subunit","No biochemical reconstitution of the P. falciparum small subunit"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["mitochondrial small ribosomal subunit (mitoribosome)"],"partners":[],"other_free_text":["Essential for asexual P. falciparum viability by conditional knockdown [#1]","Required for maintenance of mitochondrial membrane potential [#1]","Knockdown confers hypersensitivity to Complex III (bc1), DHOD, and F1F0-ATP synthase inhibitors [#2]","Knockdown depletes pyrimidine nucleotide pools, linking the mitoribosome to DHOD-dependent pyrimidine biosynthesis [#3]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"32273345","id":"PMC_32273345","title":"Genetic ablation of the mitoribosome in the malaria parasite Plasmodium falciparum sensitizes it to antimalarials that target mitochondrial functions.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32273345","citation_count":30,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["S12","PfmtRPS12"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3491,"output_tokens":1065,"usd":0.013224,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5944,"output_tokens":2344,"usd":0.04416,"stage2_stop_reason":"end_turn"},"total_usd":0.057384,"stage1_batch_id":"msgbatch_01DbiymDmubkPpYvdbAu5a7V","stage2_batch_id":"msgbatch_012TbrWvMRH129T7PQ4SmvrJ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"PF3D7_0412100 (PfmtRPS12) localizes to the mitochondrion of P. falciparum, as verified by immuno-EM showing the mitoribosome is closely associated with the mitochondrial inner membrane.\",\n      \"method\": \"Immuno-electron microscopy (immuno-EM) with CRISPR/Cas9-based conditional knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immuno-EM localization combined with conditional knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"32273345\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRISPR/Cas9-based conditional knockdown of PF3D7_0412100 (PfmtRPS12) confirmed it is essential for parasite viability and mitochondrial membrane potential maintenance.\",\n      \"method\": \"CRISPR/Cas9-based conditional knockdown with viability and mitochondrial membrane potential assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockdown with defined cellular phenotype (loss of viability, loss of membrane potential), single lab\",\n      \"pmids\": [\"32273345\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of PF3D7_0412100 (PfmtRPS12) rendered parasites hypersensitive to inhibitors of mitochondrial Complex III (bc1 complex), dihydroorotate dehydrogenase (DHOD), and the F1F0-ATP synthase, placing the mitoribosome upstream of these metabolic pathways.\",\n      \"method\": \"CRISPR/Cas9-based conditional knockdown combined with pharmacological sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via knockdown plus drug sensitivity readout, single lab, multiple inhibitors tested\",\n      \"pmids\": [\"32273345\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of PF3D7_0412100 (PfmtRPS12) blocked the pyrimidine biosynthesis pathway and reduced the cellular pool of pyrimidine nucleotides, demonstrating that the mitoribosome is required for sustaining mitochondrial metabolic capacity linked to DHOD-dependent pyrimidine synthesis.\",\n      \"method\": \"CRISPR/Cas9-based conditional knockdown with metabolite quantification of pyrimidine nucleotide pools\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockdown with metabolomics readout, single lab, direct metabolic measurement\",\n      \"pmids\": [\"32273345\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0412100 (PfmtRPS12) is a component of the small subunit of the P. falciparum mitoribosome, localizes to the mitochondrial inner membrane, is essential for parasite viability and mitochondrial membrane potential, and is required to sustain the metabolic capacity of the mitochondrion—including electron transport chain function and DHOD-dependent pyrimidine biosynthesis—as demonstrated by conditional knockdown causing hypersensitivity to mitochondrial inhibitors and depletion of pyrimidine nucleotide pools.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0412100 (mtRPS12) is a component of the small subunit of the Plasmodium falciparum mitoribosome that is essential for asexual parasite viability [#1]. It localizes to the mitochondrion, where immuno-EM places the mitoribosome in close association with the mitochondrial inner membrane [#0]. Conditional knockdown of PF3D7_0412100 collapses the mitochondrial membrane potential [#1] and renders parasites hypersensitive to inhibitors of Complex III (bc1), dihydroorotate dehydrogenase, and the F1F0-ATP synthase, placing mitoribosomal function upstream of these metabolic activities [#2]. Consistent with this, knockdown blocks pyrimidine biosynthesis and depletes cellular pyrimidine nucleotide pools, establishing that PF3D7_0412100 is required to sustain the mitochondrion's metabolic capacity, including DHOD-dependent pyrimidine synthesis [#3]. Beyond its role as an essential mitoribosomal subunit sustaining mitochondrial metabolism, no further molecular detail of PF3D7_0412100 itself—such as specific translation substrates or direct binding partners within the mitoribosome—has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether PF3D7_0412100 functions in the parasite mitochondrion was unknown; localizing it established it as a bona fide mitochondrial mitoribosomal component physically tied to the inner membrane.\",\n      \"evidence\": \"Immuno-EM with CRISPR/Cas9 conditional knockdown in P. falciparum\",\n      \"pmids\": [\"32273345\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No structural placement of the protein within the small subunit\",\n        \"Direct mitoribosomal partners of PF3D7_0412100 not defined\",\n        \"Mechanism of inner-membrane association not resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"It was unclear whether the mitoribosome is dispensable in blood-stage parasites; conditional knockdown showed PF3D7_0412100 is essential for viability and for maintaining mitochondrial membrane potential.\",\n      \"evidence\": \"CRISPR/Cas9 conditional knockdown with viability and membrane-potential assays in P. falciparum\",\n      \"pmids\": [\"32273345\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular events linking loss of the subunit to membrane-potential collapse not traced\",\n        \"Stage specificity of essentiality not addressed\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The metabolic dependencies downstream of the mitoribosome were undefined; knockdown-induced hypersensitivity to bc1, DHOD, and ATP synthase inhibitors placed PF3D7_0412100 upstream of core mitochondrial metabolic pathways.\",\n      \"evidence\": \"Conditional knockdown combined with pharmacological sensitivity assays in P. falciparum\",\n      \"pmids\": [\"32273345\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Which mitochondrially encoded transcripts require the mitoribosome not identified\",\n        \"Direct effect on individual ETC complex assembly not measured\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether mitoribosome loss functionally impairs pyrimidine synthesis was unknown; metabolite measurement showed knockdown blocks the pathway and depletes pyrimidine nucleotide pools, tying PF3D7_0412100 to DHOD-dependent metabolism.\",\n      \"evidence\": \"Conditional knockdown with metabolite quantification of pyrimidine nucleotide pools in P. falciparum\",\n      \"pmids\": [\"32273345\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Whether pyrimidine depletion is the proximate cause of lethality not established\",\n        \"Kinetics relating mitoribosome loss to metabolite decline not defined\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular activity of PF3D7_0412100 within the mitoribosome—its specific translation substrates, structural placement, and direct protein/RNA contacts—remains uncharacterized in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No identified mitochondrially encoded translation products\",\n        \"No structural or interaction map for the subunit\",\n        \"No biochemical reconstitution of the P. falciparum small subunit\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003735\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0032543\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0006207\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0022904\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"mitochondrial small ribosomal subunit (mitoribosome)\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Essential for asexual P. falciparum viability by conditional knockdown [#1]\",\n      \"Required for maintenance of mitochondrial membrane potential [#1]\",\n      \"Knockdown confers hypersensitivity to Complex III (bc1), DHOD, and F1F0-ATP synthase inhibitors [#2]\",\n      \"Knockdown depletes pyrimidine nucleotide pools, linking the mitoribosome to DHOD-dependent pyrimidine biosynthesis [#3]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0412100","name":null,"product":"ribosomal protein S12, mitochondrial","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0613400","name":null,"product":"ribosomal protein S12, mitochondrial, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0310300","name":null,"product":"ribosomal protein S12, mitochondrial, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"mtRPS12","evaluation":null}