{"data":[{"assessment":{"basis":"likely","coverage":"keysteps","relationship":"responsive","specificity":"includes","version":"v2"},"confidence_level":"medium","ke_aop_context":["AOP 130","AOP 144","AOP 178","AOP 200","AOP 205","AOP 207","AOP 256","AOP 258","AOP 273","AOP 3","AOP 335","AOP 34","AOP 362","AOP 377","AOP 423","AOP 437","AOP 447","AOP 464","AOP 476","AOP 479","AOP 48","AOP 480","AOP 481","AOP 497","AOP 500","AOP 509","AOP 511","AOP 530","AOP 587","AOP 588","AOP 589","AOP 595","AOP 622","AOP 624","AOP 625","AOP 626","AOP 77","AOP 78","AOP 79","AOP 80","AOP 87","AOP 472"],"ke_bio_level":"Cellular","ke_id":"KE 177","ke_name":"Increase, Mitochondrial dysfunction","pathway_description":"The mitochondrial pyruvate dehydrogenase (PDH) complex catalyzes the oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis. PDH inactivation is crucial for glucose conservation when glucose is scarce, while adequate PDH activity is required to allow both ATP and fatty acid production from glucose. The mechanisms that control human PDH activity include its phosphorylation (inactivation) by pyruvate dehydrogenase kinases (PDK 1-4) and its dephosphorylation (activation, reactivation) by pyruvate dehydrogenase phosphate phosphatases (PDP 1 and 2). Isoform-specific differences in kinetic parameters, regulation, and phosphorylation site specificity of the PDKs introduce variations in the regulation of PDC activity in differing endocrine and metabolic states (Sugden and Holness 2003). Further, PDH is inhibited by SIRT4 and the drug dichloroacetic acid (DCA).","pathway_name":"Regulation of pyruvate dehydrogenase (PDH) complex","provenance":{"approved_at":"2026-05-18T09:56:15.283980","approved_by":"github:marvinm2","proposed_by":"github:marvinm2","suggestion_score":0.7912},"reactome_gene_count":15,"reactome_id":"R-HSA-204174","species":"Homo sapiens","uuid":"71037286-2bae-4c9d-9b0d-cc536f2a5c0a"},{"assessment":{"basis":null,"coverage":null,"relationship":null,"specificity":null,"version":"v1"},"confidence_level":"medium","ke_aop_context":["AOP 12","AOP 13","AOP 144","AOP 17","AOP 264","AOP 265","AOP 266","AOP 268","AOP 273","AOP 278","AOP 281","AOP 324","AOP 331","AOP 377","AOP 38","AOP 479","AOP 48","AOP 490","AOP 494","AOP 530","AOP 596","AOP 599","AOP 624","AOP 625","AOP 626","AOP 627","AOP 628","AOP 629"],"ke_bio_level":"Cellular","ke_id":"KE 55","ke_name":"Increase, Cell injury/death","pathway_description":"Caspases, a family of cysteine proteases, execute apoptotic cell death. Caspases exist as inactive zymogens in cells and undergo a cascade of catalytic activation at the onset of apoptosis. Initiation of apoptosis occurs through either a cell-intrinsic or cell-extrinsic pathway. Extrinsic pathway cell death signals originate at the plasma membrane where: An extracellular ligand (e.g., FasL) binds to its cell surface transmembrane \u201cdeath receptor\u201d (e.g., Fas receptor), inducing oligomerization of the receptor (Trauth et al. 1989; Itoh and Nagata 1993; Danial and Korsmeyer 2004). The \"death receptors\" are specialized cell-surface receptors including Fas/CD95, tumor necrosis factor-alpha (TNF-alpha) receptor 1, and two receptors, DR4 and DR5, that bind to the TNF-alpha related apoptosis-inducing ligand (TRAIL). Ligand binding promotes clustering of proteins that bind to the intracellular domain of the receptor (e.g., FADD, or Fas-associated death domain-containing protein), which then binds to the prodomain of initiator caspases (e.g.caspase-8 or -10) to promote their dimerization and activation. Active caspase-8/-10 can then directly cleave and activate effector caspases, such as caspase-3 or it can cleave Bid, which facilitates mitochondrial cytochrome c release. Unique group of proteins termed dependence receptors (DpRs) transduce positive (often prosurvival or progrowth) signals when engaged by ligand, but emit proapoptotic signals in the absence of ligand (Goldschneider and Mehlen 2010). DpR family includes p75 neurotrophin receptor (p75NTR), deleted in colon cancer (DCC), and UNC5 homologs, among others. cell-surface membrane receptors.","pathway_name":"Caspase activation via extrinsic apoptotic signalling pathway","provenance":{"approved_at":"2026-05-08T20:24:34.033794","approved_by":"github:marvinm2","proposed_by":"github:marvinm2","suggestion_score":0.5641},"reactome_gene_count":28,"reactome_id":"R-HSA-5357769","species":"Homo sapiens","uuid":"740dfd23-5797-4423-a8a4-4d5872814f70"},{"assessment":{"basis":null,"coverage":null,"relationship":null,"specificity":null,"version":"v1"},"confidence_level":"high","ke_aop_context":["AOP 12","AOP 13","AOP 144","AOP 17","AOP 264","AOP 265","AOP 266","AOP 268","AOP 273","AOP 278","AOP 281","AOP 324","AOP 331","AOP 377","AOP 38","AOP 479","AOP 48","AOP 490","AOP 494","AOP 530","AOP 596","AOP 599","AOP 624","AOP 625","AOP 626","AOP 627","AOP 628","AOP 629"],"ke_bio_level":"Cellular","ke_id":"KE 55","ke_name":"Increase, Cell injury/death","pathway_description":"Activation of tumor necrosis factor receptor 1 (TNFR1) can trigger multiple signal transduction pathways to induce cell survival or cell death (Ward C et al. 1999; Micheau O and Tschopp J 2003; Widera D et al. 2006). While pro-survival signaling is initiated and regulated via the activated TNFR1 receptor complex at the cell membrane, cell death signals are induced upon the release of TRADD:TRAF2:RIP1 complex from the membrane to the cytosol where it forms death-inducing signaling complex (DISC) (Micheau O and Tschopp J 2003; Schneider-Brachert W et al. 2004). Upon apoptotic stimulation procaspase-8 or 10 is recruited into the DISC, and close proximity promotes the dimerization, autocatalytic processing, and activation of the initiator caspase-8 (and/or caspase-10) (Wang J et al. 2001; Boatright KM and Salvesen GS 2003). The initiator caspases then process and activate the downstream effector caspases such as caspase-3 in a proteolytic cascade (Stennicke HR et al. 1998). The effector caspases in turn cleave many diverse substrates, ultimately inducing cell death.","pathway_name":"TNFR1-induced proapoptotic signaling","provenance":{"approved_at":"2026-05-08T20:22:43.423053","approved_by":"github:marvinm2","proposed_by":"github:marvinm2","suggestion_score":0.5655},"reactome_gene_count":26,"reactome_id":"R-HSA-5357786","species":"Homo sapiens","uuid":"31ef20c0-9dd7-4a6c-96e2-fe226c52f871"}],"pagination":{"next":null,"page":1,"per_page":50,"prev":null,"total":3,"total_pages":1}}