id: MODULE:cardiolipin_metabolism title: Mitochondrial cardiolipin metabolism — TAMM41 CDP-diacylglycerol synthesis, PGS1/PTPMT1 phosphatidylglycerol synthesis, CRLS1 cardiolipin synthase and deacylation-reacylation remodelling by phospholipases and tafazzin description: >- Cardiolipin is a dimeric phospholipid, two phosphatidyl groups joined through a central glycerol and carrying four acyl chains, that is made in and largely confined to the mitochondrial inner membrane, where it supports the respiratory chain complexes, ATP synthase, the ADP/ATP carrier and cristae structure. Its synthesis is a four-step pathway on the matrix side of the inner membrane. Phosphatidic acid, which must first be moved from the outer to the inner membrane by the intermembrane-space PRELID1-TRIAP1 lipid transfer complex, is activated with CTP to CDP-diacylglycerol by the mitochondrial CDP-diacylglycerol synthase TAMM41. PGS1 transfers the phosphatidyl group of CDP-diacylglycerol to sn-glycerol 3-phosphate, forming phosphatidylglycerophosphate, the committed step. The protein tyrosine phosphatase-like enzyme PTPMT1 dephosphorylates it to phosphatidylglycerol, and cardiolipin synthase CRLS1 condenses phosphatidylglycerol with a second CDP-diacylglycerol to give nascent cardiolipin and CMP. Nascent cardiolipin carries mixed, often saturated acyl chains and is remodelled to its mature, unsaturated (in heart mostly tetralinoleoyl) form by deacylation and reacylation. A phospholipase removes one acyl chain to give monolysocardiolipin; candidates are the alpha/beta hydrolase ABHD18 and the calcium-independent phospholipases A2 PLA2G6 (iPLA2-beta) and PNPLA8 (iPLA2-gamma). The CoA-independent transacylase tafazzin (TAFAZZIN) then transfers an acyl chain from another phospholipid, mainly phosphatidylcholine, to monolysocardiolipin; acyl-CoA-dependent monolysocardiolipin acyltransferase activity of the trifunctional protein alpha subunit (HADHA) has also been reported. Loss of tafazzin causes Barth syndrome, with monolysocardiolipin accumulation and cardiomyopathy, and biallelic variants in TAMM41, PTPMT1 and CRLS1 cause mitochondrial disease. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0001344 title: cardiolipin metabolic pathway statement: >- The module boundary follows the de novo synthesis and remodelling branches of the RGD Pathway Ontology record and diagram for this term. The diagram draws phosphatidic acid and CTP forming CDP-diacylglycerol, CDP-diacylglycerol to phosphatidylglycerophosphate, phosphatidylglycerophosphate to phosphatidylglycerol, phosphatidylglycerol to cardiolipin and Taz acting on cardiolipin, and then cardiolipin translocated to the outer membrane and associated with Ckmt1, CKMT1B, Nme4 and Plscr3, and peroxidised by Cycs as an input to the intrinsic apoptotic (PW:0000104) and mitochondrial autophagy (PW:0001842) pathways. The RGD human gene set is CKMT1A, CKMT1B, CRLS1, CYCS, NME4, PGS1, PLSCR3, PTPMT1, TAMM41 and TAFAZZIN. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0001344.yaml). - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0001344.yaml title: RGD PW:0001344 record text (project snapshot) statement: >- The RGD record divides cardiolipin metabolism into a four-step de novo synthesis and a deacylation-reacylation remodelling branch, the two branches modelled here. supporting_text: In the biosynthesis of CL, a series of four steps generate an initial CL molecule which then undergoes remodeling, through a deacylation-reacylation cycle that can follow several routes to produce the final, mature CL. - source_id: GO:0032048 title: cardiolipin metabolic process statement: >- The skos:closeMatch GO mapping of PW:0001344 (PW definition xref and lexical match; projects/RGD_PATHWAY_ONTOLOGY/data/module_seeds.yaml). Used as the module-level concept; its children GO:0032049 cardiolipin biosynthetic process and GO:0035965 cardiolipin acyl-chain remodeling are placed on the synthesis and remodelling parts. - source_id: PMID:19075029 title: The microsomal cardiolipin remodeling enzyme acyl-CoA lysocardiolipin acyltransferase is an acyltransferase of multiple anionic lysophospholipids. statement: >- Boundary evidence for leaving the ER acyltransferase LCLAT1 (ALCAT1) out of the remodelling parts: knockdown of the human enzyme lowers lysophosphatidylinositol and lysophosphatidylglycerol acyltransferase activity but not lysocardiolipin acyltransferase activity. supporting_text: Reduced expression of ALCAT1 in Hela cells resulted in significant reductions of LPIAT and LPGAT activities, but not ALCAT activity. - source_id: PMID:16620771 title: 'Functional characterization of human 1-acylglycerol-3-phosphate acyltransferase isoform 8: cloning, tissue distribution, gene structure, and enzymatic activity.' statement: >- A second study of the same human protein (as AGPAT8) found lysophosphatidic acid acyltransferase activity and no lysocardiolipin acyltransferase activity in cell lysates. supporting_text: lacks acyl-CoA:lysocardiolipin acyltransferase activity proposed_new_terms: - proposed_name: phospholipid:monolysocardiolipin acyltransferase activity (CoA-independent) proposed_definition: >- Catalysis of the transfer of an acyl group from a glycerophospholipid, such as phosphatidylcholine, to monolysocardiolipin without an acyl-CoA intermediate, forming cardiolipin and a lysophospholipid. justification: >- Tafazzin's activity has no exact GO term. GO:0032577 phosphatidylcholine:cardiolipin O-linoleoyltransferase activity, used on the tafazzin annoton, restricts the acyl group to linoleoyl, and GO:0047184 on TAFAZZIN is an acyl-CoA-dependent term. proposed_parent: id: GO:0016747 label: acyltransferase activity, transferring groups other than amino-acyl groups supported_by: - reference_id: PMID:17082194 supporting_text: catalyzed both forward and reverse transacylations between cardiolipin and phosphatidylcholine, but was unable to utilize CoA or acyl-CoA as substrates. module: id: cardiolipin_metabolism label: Mitochondrial cardiolipin metabolism module_type: METABOLIC_PATHWAY concepts: - preferred_term: cardiolipin metabolic process term: id: GO:0032048 label: cardiolipin metabolic process description: >- The closeMatch of PW:0001344, covering both de novo synthesis and acyl-chain remodelling. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: mitochondrial inner membrane term: id: GO:0005743 label: mitochondrial inner membrane description: >- Where cardiolipin is made and where mature cardiolipin resides. The synthetic enzymes act on its matrix face; the PA transfer complex and tafazzin act from the intermembrane space side. parts: - order: 1 role: phosphatidic acid supply to the inner membrane optional: true node: id: pa_intermembrane_transfer label: PRELID1-TRIAP1 transfer of phosphatidic acid across the intermembrane space module_type: TRANSPORT_STEP description: >- Phosphatidic acid made in the endoplasmic reticulum reaches the outer mitochondrial membrane and is carried across the intermembrane space to the inner membrane by a heterodimer of the PRELI-domain lipid transfer protein PRELID1 and its chaperone TRIAP1, a mammalian counterpart of the yeast Ups1-Mdm35 pair. Loss of either subunit lowers cardiolipin and is bypassed by supplying phosphatidylglycerol. Marked optional because it delivers the substrate rather than performing a step of cardiolipin chemistry, and because the RGD diagram does not draw it. concepts: - preferred_term: intermembrane phospholipid transfer term: id: GO:0120010 label: intermembrane phospholipid transfer evidence: - source_id: PMID:23931759 statement: TRIAP1/PRELI complexes in the IMS transfer lipid and supply PA for CL synthesis in the inner membrane. supporting_text: TRIAP1/PRELI complexes exert lipid transfer activity in vitro and supply phosphatidic acid (PA) for CL synthesis in the inner membrane. annotons: - id: prelid1_pa_transfer label: PRELID1 phosphatidic acid transfer (with TRIAP1) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PRELID1 term: id: UniProtKB:Q9Y255 label: PRELI domain-containing protein 1, mitochondrial function: preferred_term: phosphatidic acid transfer activity term: id: GO:1990050 label: phosphatidic acid transfer activity substrates: - preferred_term: phosphatidic acid term: id: CHEBI:58608 label: 1,2-diacyl-sn-glycerol 3-phosphate(2-) processes: - preferred_term: intermembrane phospholipid transfer term: id: GO:0120010 label: intermembrane phospholipid transfer locations: - preferred_term: mitochondrial intermembrane space term: id: GO:0005758 label: mitochondrial intermembrane space role_description: >- The lipid-binding subunit; its PRELI domain holds the phospholipid. GOA records the activity as contributes_to GO:1990050 (IMP, PMID:23931759), reflecting that it works as a heterodimer. evidence: - source_id: PMID:23931759 statement: Loss of TRIAP1 or PRELI impairs cardiolipin accumulation. supporting_text: Loss of TRIAP1 or PRELI impairs the accumulation of CL - id: triap1_pa_transfer label: TRIAP1 phosphatidic acid transfer (with PRELID1) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TRIAP1 term: id: UniProtKB:O43715 label: TP53-regulated inhibitor of apoptosis 1 function: preferred_term: phosphatidic acid transfer activity term: id: GO:1990050 label: phosphatidic acid transfer activity locations: - preferred_term: mitochondrial intermembrane space term: id: GO:0005758 label: mitochondrial intermembrane space role_description: >- Small CHCH-type intermembrane-space chaperone that stabilises PRELID1 and is required for the transfer activity (contributes_to GO:1990050, IDA, PMID:23931759 and PMID:26071602). evidence: - source_id: PMID:26071602 statement: Crystal structures of TRIAP1 and a TRIAP1-PRELI-domain complex show how TRIAP1 chaperones the PRELI domain in the intermembrane space. supporting_text: Crystal structures of free TRIAP1 and the TRIAP1-SLMO1 complex reveal how the PRELI domain is chaperoned during import into the intermembrane mitochondrial space. - order: 2 role: CDP-diacylglycerol synthesis in the inner membrane node: id: mito_cdp_dag_synthesis label: TAMM41 mitochondrial CDP-diacylglycerol synthase module_type: REACTION description: >- TAMM41 activates phosphatidic acid with CTP to CDP-diacylglycerol on the matrix face of the inner membrane, supplying the CDP-diacylglycerol used twice in the pathway, by PGS1 and by CRLS1. The ER CDS1/CDS2 enzymes make the CDP-diacylglycerol pool for phosphatidylinositol synthesis and cannot replace TAMM41 for cardiolipin. The fungal counterpart is the mito_tam41 variant of the cdp_dag_phospholipid_synthesis module; it is not included by module_ref because that node is fungal-scoped and would bring yeast exemplars into a human module (see notes). concepts: - preferred_term: CDP-diacylglycerol biosynthetic process term: id: GO:0016024 label: CDP-diacylglycerol biosynthetic process annotons: - id: tamm41_cdp_dag_synthase label: TAMM41 phosphatidate cytidylyltransferase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TAMM41 term: id: UniProtKB:Q96BW9 label: Phosphatidate cytidylyltransferase, mitochondrial function: preferred_term: phosphatidate cytidylyltransferase activity term: id: GO:0004605 label: phosphatidate cytidylyltransferase activity substrates: - preferred_term: phosphatidic acid term: id: CHEBI:58608 label: 1,2-diacyl-sn-glycerol 3-phosphate(2-) - preferred_term: CTP term: id: CHEBI:37563 label: CTP(4-) products: - preferred_term: CDP-diacylglycerol term: id: CHEBI:58332 label: CDP-diacylglycerol(2-) - preferred_term: diphosphate term: id: CHEBI:33019 label: diphosphate(3-) processes: - preferred_term: CDP-diacylglycerol biosynthetic process term: id: GO:0016024 label: CDP-diacylglycerol biosynthetic process - preferred_term: cardiolipin biosynthetic process term: id: GO:0032049 label: cardiolipin biosynthetic process locations: - preferred_term: mitochondrial inner membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- Peripheral matrix-side inner-membrane enzyme (RHEA:16229). Human TAMM41 has no experimental molecular function row in GOA; GO:0004605 rests on ISS/IBA and on the direct assay of the yeast orthologue (PMID:23623749), and patient missense variants fail to complement the yeast mutant. evidence: - source_id: PMID:23623749 statement: Yeast Tam41 directly converts PA to CDP-DAG with CTP. supporting_text: Taken together, we conclude that Tam41 directly catalyzes the conversion of PA to CDP-DAG in the presence of CTP. - source_id: PMID:35321494 statement: Human TAMM41 deficiency lowers muscle cardiolipin and the patient missense variants fail to rescue the yeast tam41 respiratory growth defect. supporting_text: All three mutants failed to rescue the growth defect gocam_associations: - model: gomodel:67b1629100002092 activity: gomodel:67b1629100002092/67b1629100002105 title: Cardiolipin metabolic process (GO:0032048) (Human) description: TAMM41 GO:0004605 in the mitochondrial matrix, part of GO:0016024, directly positively regulating PGS1. - order: 3 role: phosphatidylglycerophosphate synthesis (committed step) node: id: pgp_synthesis label: PGS1 phosphatidylglycerophosphate synthase module_type: REACTION description: >- PGS1 transfers the phosphatidyl group of CDP-diacylglycerol to sn-glycerol 3-phosphate, releasing CMP. This is the committed step of phosphatidylglycerol and cardiolipin synthesis. concepts: - preferred_term: phosphatidylglycerol biosynthetic process term: id: GO:0006655 label: phosphatidylglycerol biosynthetic process annotons: - id: pgs1_pgp_synthase label: PGS1 CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PGS1 term: id: UniProtKB:Q32NB8 label: CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase, mitochondrial function: preferred_term: CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase activity term: id: GO:0008444 label: CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase activity substrates: - preferred_term: CDP-diacylglycerol term: id: CHEBI:58332 label: CDP-diacylglycerol(2-) - preferred_term: sn-glycerol 3-phosphate term: id: CHEBI:57597 label: sn-glycerol 3-phosphate(2-) products: - preferred_term: phosphatidylglycerophosphate term: id: CHEBI:60110 label: 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) - preferred_term: CMP term: id: CHEBI:60377 label: cytidine 5'-monophosphate(2-) processes: - preferred_term: cardiolipin biosynthetic process term: id: GO:0032049 label: cardiolipin biosynthetic process locations: - preferred_term: mitochondrial inner membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- CDP-alcohol phosphatidyltransferase (RHEA:12593). Human PGS1 has no experimental molecular function row in GOA; GO:0008444 rests on ISS/IBA and on the hamster enzyme, purified from CHO mitochondria and shown to be encoded by PGS1 (PMID:11171073). evidence: - source_id: PMID:11171073 statement: Mammalian PGP synthase catalyses the committed step and is separate from PGP phosphatase. supporting_text: Phosphatidylglycerophosphate (PGP) synthase catalyses the committed step in the biosynthesis of phosphatidylglycerol and cardiolipin in mammalian cells. gocam_associations: - model: gomodel:67b1629100002092 activity: gomodel:67b1629100002092/67b1629100002101 title: Cardiolipin metabolic process (GO:0032048) (Human) description: PGS1 GO:0008444 in the mitochondrial matrix, part of GO:0032049, directly positively regulating PTPMT1. - order: 4 role: phosphatidylglycerophosphate dephosphorylation to phosphatidylglycerol node: id: pgp_dephosphorylation label: PTPMT1 phosphatidylglycerophosphatase module_type: REACTION description: >- PTPMT1, a PTEN-like member of the protein tyrosine phosphatase superfamily, removes the terminal phosphate of phosphatidylglycerophosphate to give phosphatidylglycerol. It is the mammalian counterpart of yeast Gep4, which belongs to a different phosphatase family. concepts: - preferred_term: phosphatidylglycerol biosynthetic process term: id: GO:0006655 label: phosphatidylglycerol biosynthetic process annotons: - id: ptpmt1_pgp_phosphatase label: PTPMT1 phosphatidylglycerophosphatase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTPMT1 term: id: UniProtKB:Q8WUK0 label: Phosphatidylglycerophosphatase and protein-tyrosine phosphatase 1 function: preferred_term: phosphatidylglycerophosphatase activity term: id: GO:0008962 label: phosphatidylglycerophosphatase activity substrates: - preferred_term: phosphatidylglycerophosphate term: id: CHEBI:60110 label: 1-(3-sn-phosphatidyl)-sn-glycerol 3-phosphate(3-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: phosphatidylglycerol term: id: CHEBI:64716 label: 1,2-diacyl-sn-glycero-3-phospho-(1'-sn-glycerol)(1-) - preferred_term: phosphate term: id: CHEBI:43474 label: hydrogenphosphate processes: - preferred_term: cardiolipin biosynthetic process term: id: GO:0032049 label: cardiolipin biosynthetic process locations: - preferred_term: mitochondrial inner membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- Peripheral matrix-side inner-membrane phosphatase (RHEA:33751). GO:0008962 for human PTPMT1 rests on ISS/IBA from the mouse enzyme, which dephosphorylates PGP specifically in vitro and whose loss accumulates PGP (PMID:21641550); human loss-of-function variants lower cardiolipin (GO:0032049, IMP, PMID:39279645). evidence: - source_id: PMID:21641550 statement: Mouse PTPMT1 dephosphorylates PGP in vitro and its loss accumulates PGP and depletes cardiolipin. supporting_text: We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. - source_id: PMID:39279645 statement: Biallelic human PTPMT1 variants impair cardiolipin biosynthesis. supporting_text: These studies revealed that loss of PTPMT1 impairs cardiolipin biosynthesis, OXPHOS and mitochondrial morphology gocam_associations: - model: gomodel:67b1629100002092 activity: gomodel:67b1629100002092/67b1629100002097 title: Cardiolipin metabolic process (GO:0032048) (Human) description: PTPMT1 GO:0008962 in mitochondrion, part of GO:0032049, directly positively regulating CRLS1. - order: 5 role: cardiolipin synthesis node: id: cardiolipin_synthesis label: CRLS1 cardiolipin synthase (CMP-forming) module_type: REACTION description: >- CRLS1 transfers the phosphatidyl group of a second CDP-diacylglycerol to phosphatidylglycerol, forming nascent cardiolipin and CMP. This eukaryotic CDP-alcohol phosphotransferase-type synthase differs from the phospholipase D-type cardiolipin synthases of bacteria, which condense two phosphatidylglycerols. concepts: - preferred_term: cardiolipin biosynthetic process term: id: GO:0032049 label: cardiolipin biosynthetic process annotons: - id: crls1_cardiolipin_synthase label: CRLS1 cardiolipin synthase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CRLS1 term: id: UniProtKB:Q9UJA2 label: Cardiolipin synthase (CMP-forming) function: preferred_term: cardiolipin synthase (CMP-forming) activity term: id: GO:0043337 label: cardiolipin synthase (CMP-forming) activity substrates: - preferred_term: CDP-diacylglycerol term: id: CHEBI:58332 label: CDP-diacylglycerol(2-) - preferred_term: phosphatidylglycerol term: id: CHEBI:64716 label: 1,2-diacyl-sn-glycero-3-phospho-(1'-sn-glycerol)(1-) products: - preferred_term: cardiolipin (nascent) term: id: CHEBI:62237 label: cardiolipin(2-) - preferred_term: CMP term: id: CHEBI:60377 label: cytidine 5'-monophosphate(2-) processes: - preferred_term: cardiolipin biosynthetic process term: id: GO:0032049 label: cardiolipin biosynthetic process locations: - preferred_term: mitochondrial inner membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- Multi-pass inner-membrane enzyme (RHEA:32931). GO:0043337 is its experimental GOA function (IDA, PMID:16678169 and PMID:16716149) and the core function of the CRLS1 gene review. evidence: - source_id: PMID:16716149 statement: Recombinant human CLS1 makes cardiolipin from CDP-DAG and PG. supporting_text: The recombinant hCLS1 enzyme expressed in COS-7 cells catalysed efficiently the synthesis of cardiolipin in vitro using CDP-DAG and PG as substrates. - source_id: PMID:16678169 statement: The human cDNA complements the cardiolipin synthase-deficient yeast crd1 mutant. supporting_text: confirmed that it indeed encodes human cardiolipin synthase - source_id: PMID:35147173 statement: CRLS1 patient fibroblasts have less cardiolipin and more phosphatidylglycerol. supporting_text: significantly increased levels of phosphatidylglycerol, the substrate of CRLS1 gocam_associations: - model: gomodel:67b1629100002092 activity: gomodel:67b1629100002092/67b1629100002093 title: Cardiolipin metabolic process (GO:0032048) (Human) description: CRLS1 GO:0043337 in mitochondrial membrane, part of GO:0032049, directly positively regulating PLA2G6. - order: 6 role: cardiolipin deacylation to monolysocardiolipin (first half of remodelling) node: id: cardiolipin_deacylation label: Phospholipase deacylation of cardiolipin (ABHD18, PLA2G6, PNPLA8) module_type: REACTION description: >- A phospholipase removes one acyl chain from nascent cardiolipin to give monolysocardiolipin, the acceptor for reacylation (RHEA:32935). Which enzyme carries most of this flux in human tissues is not settled, so three candidates with direct evidence are modelled as alternatives. ABHD18 is the functional homologue of yeast Cld1 and deacylates cardiolipin in mouse cells and flies, with preference for the saturated, less unsaturated species of nascent cardiolipin. The calcium-independent phospholipases A2 PLA2G6 and PNPLA8 hydrolyse cardiolipin in vitro; PLA2G6 yields mainly monolysocardiolipin, and PNPLA8 is the main enzyme releasing oxidised acyl chains from cardiolipin. concepts: - preferred_term: cardiolipin acyl-chain remodeling term: id: GO:0035965 label: cardiolipin acyl-chain remodeling variant_sets: - id: cardiolipin_deacylase label: Cardiolipin deacylating phospholipase axis: enzyme family (alpha/beta-hydrolase ABHD18 versus patatin-like calcium-independent phospholipases A2) selection: ONE_OR_MORE variants: - id: abhd18_variant label: ABHD18 cardiolipin lipase module_type: REACTION annotons: - id: abhd18_cardiolipin_deacylase label: ABHD18 cardiolipin deacylation participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ABHD18 term: id: UniProtKB:Q0P651 label: Protein ABHD18 function: preferred_term: A2-type glycerophospholipase activity term: id: GO:0004623 label: A2-type glycerophospholipase activity substrates: - preferred_term: cardiolipin term: id: CHEBI:62237 label: cardiolipin(2-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: monolysocardiolipin term: id: CHEBI:64743 label: 2-monolysocardiolipin(2-) - preferred_term: fatty acid term: id: CHEBI:28868 label: fatty acid anion processes: - preferred_term: cardiolipin acyl-chain remodeling term: id: GO:0035965 label: cardiolipin acyl-chain remodeling locations: - preferred_term: mitochondrion term: id: GO:0005739 label: mitochondrion role_description: >- GO:0004623 is the core function of the ABHD18 gene review, which also proposes a new cardiolipin deacylase activity term; human GOA has no experimental molecular function row for ABHD18. The evidence is from mouse myoblasts and Drosophila, and ABHD18 also removes further acyl chains to dilysocardiolipin. evidence: - source_id: PMID:40378955 statement: ABHD18 is the cardiolipin lipase in mice and flies and deacylates beyond MLCL. supporting_text: Our data demonstrate that ABHD18 is the elusive lipase that hydrolyzes CL in mice and flies and presumably in other organisms. - id: pla2g6_variant label: PLA2G6 (iPLA2-beta) module_type: REACTION annotons: - id: pla2g6_cardiolipin_deacylase label: PLA2G6 cardiolipin deacylation participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PLA2G6 (iPLA2-beta) term: id: UniProtKB:O60733 label: 85/88 kDa calcium-independent phospholipase A2 function: preferred_term: A2-type glycerophospholipase activity term: id: GO:0004623 label: A2-type glycerophospholipase activity substrates: - preferred_term: cardiolipin term: id: CHEBI:62237 label: cardiolipin(2-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: monolysocardiolipin term: id: CHEBI:64743 label: 2-monolysocardiolipin(2-) - preferred_term: fatty acid term: id: CHEBI:28868 label: fatty acid anion processes: - preferred_term: cardiolipin acyl-chain remodeling term: id: GO:0035965 label: cardiolipin acyl-chain remodeling locations: - preferred_term: mitochondrion term: id: GO:0005739 label: mitochondrion role_description: >- Broad-specificity group VIA phospholipase. GO:0004623 and GO:0035965 are experimental GOA rows (IDA, PMID:23533611), from an in vitro assay with cardiolipin as substrate; inhibition of the Drosophila orthologue iPLA2-VIA suppresses the tafazzin mutant phenotype. The human GO-CAM places it between CRLS1 and tafazzin. evidence: - source_id: PMID:23533611 statement: Group VIA iPLA2 hydrolyses cardiolipin and accumulates monolysocardiolipin, unlike secreted PLA2s, which accumulate dilysocardiolipin. supporting_text: The sPLA2s caused an accumulation of dilyso-cardiolipin, in contrast to iPLA2 which caused an accumulation of monolyso-cardiolipin. gocam_associations: - model: gomodel:67b1629100002092 activity: gomodel:67b1629100002092/67b1629100002132 title: Cardiolipin metabolic process (GO:0032048) (Human) description: PLA2G6 GO:0004623 in mitochondrion, part of GO:0035965, directly positively regulating TAFAZZIN. - id: pnpla8_variant label: PNPLA8 (iPLA2-gamma) module_type: REACTION annotons: - id: pnpla8_cardiolipin_deacylase label: PNPLA8 cardiolipin deacylation participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PNPLA8 (iPLA2-gamma) term: id: UniProtKB:Q9NP80 label: Calcium-independent phospholipase A2-gamma function: preferred_term: A2-type glycerophospholipase activity term: id: GO:0004623 label: A2-type glycerophospholipase activity substrates: - preferred_term: cardiolipin term: id: CHEBI:62237 label: cardiolipin(2-) - preferred_term: water term: id: CHEBI:15377 label: water products: - preferred_term: monolysocardiolipin term: id: CHEBI:64743 label: 2-monolysocardiolipin(2-) - preferred_term: fatty acid term: id: CHEBI:28868 label: fatty acid anion locations: - preferred_term: mitochondrion term: id: GO:0005739 label: mitochondrion role_description: >- Membrane-bound group VIB phospholipase found in mitochondria and peroxisomes. GO:0004623 is an experimental GOA row (IDA, several papers) and GO:0032048 cardiolipin metabolic process is IDA (PMID:28442572). Its shown role is hydrolysis of oxidised cardiolipin to release oxidised fatty acid signals, so it is given no remodelling process here; its share of routine remodelling deacylation is not established. evidence: - source_id: PMID:28442572 statement: iPLA2-gamma is the major enzyme releasing oxidised aliphatic chains from cardiolipin. supporting_text: we demonstrated that iPLA2γ is the major enzyme responsible for the release of oxidized aliphatic chains from CL - order: 7 role: transacylation of monolysocardiolipin to mature cardiolipin (second half of remodelling) node: id: tafazzin_transacylation label: Tafazzin phospholipid-monolysocardiolipin transacylase module_type: REACTION description: >- Tafazzin transfers an acyl chain, preferentially linoleoyl, from phosphatidylcholine (and other phospholipids) to monolysocardiolipin without acyl-CoA, regenerating cardiolipin and releasing lysophosphatidylcholine (RHEA:33731). The reaction is reversible, and repeated cycles of deacylation and transacylation enrich cardiolipin in the unsaturated species favoured by membrane packing rather than by tafazzin's own specificity. Its loss in Barth syndrome causes monolysocardiolipin accumulation and loss of tetralinoleoyl cardiolipin. concepts: - preferred_term: cardiolipin acyl-chain remodeling term: id: GO:0035965 label: cardiolipin acyl-chain remodeling annotons: - id: tafazzin_transacylase label: TAFAZZIN phosphatidylcholine:monolysocardiolipin transacylase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TAFAZZIN term: id: UniProtKB:Q16635 label: Tafazzin function: preferred_term: phosphatidylcholine:cardiolipin O-linoleoyltransferase activity term: id: GO:0032577 label: phosphatidylcholine:cardiolipin O-linoleoyltransferase activity substrates: - preferred_term: monolysocardiolipin term: id: CHEBI:64743 label: 2-monolysocardiolipin(2-) - preferred_term: phosphatidylcholine term: id: CHEBI:57643 label: 1,2-diacyl-sn-glycero-3-phosphocholine products: - preferred_term: cardiolipin (remodelled) term: id: CHEBI:62237 label: cardiolipin(2-) - preferred_term: lysophosphatidylcholine term: id: CHEBI:58168 label: 1-O-acyl-sn-glycero-3-phosphocholine processes: - preferred_term: cardiolipin acyl-chain remodeling term: id: GO:0035965 label: cardiolipin acyl-chain remodeling locations: - preferred_term: mitochondrial membrane term: id: GO:0031966 label: mitochondrial membrane role_description: >- CoA-independent phospholipid-lysophospholipid transacylase. The function term is authored here (see notes): GOA's experimental molecular function row is GO:0047184, an acyl-CoA-dependent lysophosphatidylcholine acyltransferase, which tafazzin is not, and the human GO-CAM uses the generic GO:0016747. GO:0035965 is experimental (IDA and IMP rows). Tafazzin faces the intermembrane space on both inner and outer membranes, hence the general mitochondrial membrane term. evidence: - source_id: PMID:17082194 statement: Purified tafazzin catalyses forward and reverse transacylation between cardiolipin and phosphatidylcholine and cannot use CoA or acyl-CoA. supporting_text: catalyzed both forward and reverse transacylations between cardiolipin and phosphatidylcholine, but was unable to utilize CoA or acyl-CoA as substrates. - source_id: PMID:19700766 statement: The human full-length and exon 5-lacking isoforms have transacylase activity and restore cardiolipin in tafazzin-deficient flies. supporting_text: only full-length tafazzin (FL) and tafazzin lacking exon 5 (Delta5) had transacylase activity gocam_associations: - model: gomodel:67b1629100002092 activity: gomodel:67b1629100002092/67b1629100002152 title: Cardiolipin metabolic process (GO:0032048) (Human) description: TAFAZZIN GO:0016747 in mitochondrion, part of GO:0035965, directly positively regulating HADHA. - order: 8 role: acyl-CoA-dependent reacylation of monolysocardiolipin optional: true node: id: coa_dependent_mlcl_reacylation label: HADHA monolysocardiolipin acyltransferase module_type: REACTION description: >- An acyl-CoA-dependent route to reacylate monolysocardiolipin (RHEA:35839) reported for the alpha subunit of the mitochondrial trifunctional protein. Optional because tafazzin loss alone produces the Barth syndrome cardiolipin defect, showing that this route does not compensate for it; the ER acyl-CoA:lysocardiolipin acyltransferase LCLAT1 is not included (see notes). concepts: - preferred_term: cardiolipin acyl-chain remodeling term: id: GO:0035965 label: cardiolipin acyl-chain remodeling annotons: - id: hadha_mlcl_acyltransferase label: HADHA acyl-CoA:monolysocardiolipin acyltransferase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: HADHA term: id: UniProtKB:P40939 label: Trifunctional enzyme subunit alpha, mitochondrial function: preferred_term: acyltransferase activity, transferring groups other than amino-acyl groups term: id: GO:0016747 label: acyltransferase activity, transferring groups other than amino-acyl groups substrates: - preferred_term: monolysocardiolipin term: id: CHEBI:64743 label: 2-monolysocardiolipin(2-) - preferred_term: acyl-CoA term: id: CHEBI:58342 label: acyl-CoA(4-) products: - preferred_term: cardiolipin term: id: CHEBI:62237 label: cardiolipin(2-) - preferred_term: coenzyme A term: id: CHEBI:57287 label: coenzyme A(4-) processes: - preferred_term: cardiolipin acyl-chain remodeling term: id: GO:0035965 label: cardiolipin acyl-chain remodeling locations: - preferred_term: mitochondrial inner membrane term: id: GO:0005743 label: mitochondrial inner membrane role_description: >- A secondary activity of the beta-oxidation enzyme. The function term follows the HADHA gene review's core function for this activity; GO:0035965 is experimental (IDA, PMID:23152787). evidence: - source_id: PMID:23152787 statement: Purified human alpha-TFP acylates MLCL to cardiolipin with acyl-CoA donors. supporting_text: Purified human recombinant αTFP exhibited acyl-CoA acyltransferase activity in the acylation of MLCL to CL with linoleoyl-CoA, oleoyl-CoA and palmitoyl-CoA as substrates. gocam_associations: - model: gomodel:67b1629100002092 activity: gomodel:67b1629100002092/67b1629100002145 title: Cardiolipin metabolic process (GO:0032048) (Human) description: >- HADHA in the mitochondrial inner membrane, part of GO:0035965, downstream of tafazzin; the model types it as GO:0052816 long-chain fatty acyl-CoA hydrolase activity, which the HADHA review judges a wrong-paper attribution (see notes). connections: - source: pa_intermembrane_transfer target: mito_cdp_dag_synthesis connection_type: PROVIDES_INPUT_FOR description: Phosphatidic acid delivered to the inner membrane is the TAMM41 substrate. - source: mito_cdp_dag_synthesis target: pgp_synthesis connection_type: PROVIDES_INPUT_FOR description: CDP-diacylglycerol is the phosphatidyl donor for PGS1. - source: mito_cdp_dag_synthesis target: cardiolipin_synthesis connection_type: PROVIDES_INPUT_FOR description: A second CDP-diacylglycerol is the phosphatidyl donor for CRLS1. - source: pgp_synthesis target: pgp_dephosphorylation connection_type: PROVIDES_INPUT_FOR description: Phosphatidylglycerophosphate made by PGS1 is dephosphorylated by PTPMT1. - source: pgp_dephosphorylation target: cardiolipin_synthesis connection_type: PROVIDES_INPUT_FOR description: Phosphatidylglycerol is the phosphatidyl acceptor for CRLS1. - source: cardiolipin_synthesis target: cardiolipin_deacylation connection_type: PROVIDES_INPUT_FOR description: Nascent cardiolipin is deacylated to monolysocardiolipin. - source: cardiolipin_deacylation target: tafazzin_transacylation connection_type: PROVIDES_INPUT_FOR description: Monolysocardiolipin is reacylated by tafazzin from phosphatidylcholine. - source: cardiolipin_deacylation target: coa_dependent_mlcl_reacylation connection_type: PROVIDES_INPUT_FOR description: Monolysocardiolipin can also be reacylated from acyl-CoA by HADHA. knowledge_gaps: - gap_statement: >- Which phospholipase performs most cardiolipin deacylation in human tissues, ABHD18 or the iPLA2 enzymes PLA2G6 and PNPLA8, and whether they act on nascent cardiolipin, on damaged or oxidised cardiolipin, or both, has not been settled; the ABHD18 evidence is from mouse cells and flies and the iPLA2 evidence is largely in vitro or concerns oxidised cardiolipin. boundary: Deacylation step of cardiolipin remodelling. gap_kind: - BIOLOGY - gap_statement: >- How much the acyl-CoA-dependent monolysocardiolipin acyltransferases (HADHA, LCLAT1) contribute to cardiolipin remodelling in vivo, relative to tafazzin, is not known. boundary: Reacylation step of cardiolipin remodelling. gap_kind: - BIOLOGY notes: >- Derived from the RGD Pathway Ontology record and diagram PW:0001344 (cardiolipin metabolic pathway) through the RGD_PATHWAY_ONTOLOGY project's diagram->module route; GO mapping GO:0032048 cardiolipin metabolic process (skos:closeMatch). Of the 10 RGD human genes, TAMM41, PGS1, PTPMT1, CRLS1 and TAFAZZIN are participants. The module is modelled as eight parts, two of them optional: (1, optional) PRELID1-TRIAP1 phosphatidic acid transfer; (2) TAMM41 CDP-diacylglycerol synthesis; (3) PGS1; (4) PTPMT1; (5) CRLS1; (6) a variant set of deacylating phospholipases (ABHD18, PLA2G6, PNPLA8); (7) tafazzin transacylation; and (8, optional) HADHA acyl-CoA-dependent monolysocardiolipin reacylation. ChEBI ids are the Rhea participants of RHEA:16229, RHEA:12593, RHEA:33751, RHEA:32931, RHEA:32935, RHEA:33731 and RHEA:35839, with labels checked against OLS. RGD record error: the record text says that in the first step "Tamm41 uses cytidine triphosphate and phosphatidylglycerol"; the substrate is phosphatidic acid, as the RGD diagram itself draws (phosphatidic acid and CTP to CDP-diacylglycerol). The module follows the diagram. Boundary decisions. (a) The outer branch of the RGD diagram is not modelled: translocation of cardiolipin to the outer membrane (with CKMT1A, CKMT1B and NME4 bridging the membranes and the scramblase PLSCR3), its peroxidation by cytochrome c (CYCS), and its signalling roles in mitophagy and apoptosis. These genes do not make or remodel cardiolipin; cardiolipin is their binding partner or substrate, and their roles belong to modules/mitophagy.yaml and modules/intrinsic_apoptotic_signaling.yaml (RGD PW:0001842 and PW:0000104, mentioned here only as diagram links). Creatine kinase and nucleoside diphosphate kinase are also kinases of energy transfer, not lipid enzymes. The diagram's downstream outputs (electron transport chain, ATP synthesis, metabolite carriers) are uses of cardiolipin and are likewise out of scope. (b) PRELID1-TRIAP1 is included as an optional transport step rather than context because it performs the delivery of the TAMM41 substrate to the inner membrane (direct lipid transfer activity, PMID:23931759), not merely because it is required; it is optional because it is substrate supply and is not drawn by RGD. Other PRELI-domain pairs (PRELID3B with TRIAP1, transferring phosphatidylserine for PE synthesis) are not part of this pathway. (c) The CDP-diacylglycerol step is modelled directly with human TAMM41 rather than by module_ref to cdp_dag_phospholipid_synthesis#cdp_dag_synthesis (or its mito_tam41 variant): that module is scoped to Fungi with S. cerevisiae and S. pombe exemplars, and a module_ref node carries no annotons, so referencing it would drop TAMM41, an RGD-curated human member, and assert fungal proteins in a concrete human module. The two modules describe the same reaction, and the fungal module's PGS1, GEP4 and CRD1 nodes are the fungal counterparts of parts 3 to 5. The ER CDS1/CDS2 synthases are not included: they supply phosphatidylinositol synthesis, not mitochondrial cardiolipin. (d) Remodelling. Deacylation is a variant set because no single human enzyme is established: ABHD18 (mouse and fly genetics, PMID:40378955), PLA2G6 (in vitro cardiolipin hydrolysis, PMID:23533611; the human GO-CAM uses it) and PNPLA8 (oxidised cardiolipin, PMID:28442572; no remodelling process asserted on it). Tafazzin is a required part because its loss alone causes Barth syndrome. HADHA is an optional acyl-CoA-dependent reacylation route. LCLAT1 (ALCAT1, AGPAT8), an ER multi-pass acyltransferase that UniProt describes as an acyl-CoA:lysocardiolipin acyltransferase only by similarity, is not included: two studies of the human protein found no lysocardiolipin acyltransferase activity attributable to it (PMID:19075029, PMID:16620771), its experimental GOA function is lysophosphatidic acid acyltransferase activity, and its ER location places it away from the inner-membrane cardiolipin pool. It could be added as an optional variant of part 8 if later human evidence supports it. Other phospholipases reported to act on cardiolipin (secreted and cytosolic PLA2s) are not included. (e) Fly and bacterial counterparts: modules/dmel_cardiolipin_biosynthesis_remodeling.yaml models the same Pgs1-Ptpmt1-Cls-Taz chain with Abhd18 and iPLA2-VIA deacylation (it leaves tafazzin without a function term); modules/bacterial_phosphatidylglycerol_cardiolipin_biosynthesis.yaml covers the bacterial route, whose phospholipase D-type cardiolipin synthase condenses two phosphatidylglycerols. Neither is referenced as a part. (f) Not modelled: cardiolipin degradation beyond remodelling, the regulatory condensate scaffold SPATA18 (Mieap) present in the GO-CAM as a positive regulator of the enzymes, and transcriptional control. Molecular functions (QuickGO, checked 2026-11-10). Backed by experimental human GOA rows: CRLS1 GO:0043337 (IDA, PMID:16678169, PMID:16716149; CRLS1 review core function); PLA2G6 GO:0004623 (IDA, PMID:23533611); PNPLA8 GO:0004623 (IDA, several papers); PRELID1 and TRIAP1 GO:1990050 (contributes_to, IMP/IDA, PMID:23931759, PMID:26071602). Not backed by an experimental human GOA row: TAMM41 GO:0004605, PGS1 GO:0008444 and PTPMT1 GO:0008962 (ISS/IBA, and the GO-CAM; supported by the yeast, hamster and mouse enzymes cited on each annoton); ABHD18 GO:0004623 (the ABHD18 review's core function); HADHA GO:0016747 (the HADHA review's core function for this activity). Tafazzin GO:0032577 phosphatidylcholine:cardiolipin O-linoleoyltransferase activity is authored here: it is the only GO term describing transfer of an acyl group from phosphatidylcholine to cardiolipin, and tafazzin prefers linoleoyl groups (PMID:17082194), but the acceptor is strictly monolysocardiolipin and the enzyme is not linoleoyl-specific, so a term for CoA-independent phospholipid:monolysocardiolipin transacylase activity, requested in proposed_new_terms, would fit better. Comparator check for processes: GO:0032049 is placed on the four synthetic enzymes and GO:0035965 on the deacylases and reacylating enzymes; GO:0120010 on PRELID1, which transfers lipid, and not on TRIAP1, whose experimental process row is the parent GO:0015914; neither transfer subunit is given GO:0032049. Possible upstream issues. (1) The TAFAZZIN GO:0047184 1-acylglycerophosphocholine O-acyltransferase activity IDA row (PMID:12930833) uses an acyl-CoA-dependent EC 2.3.1.23 term for a CoA-independent transacylase; the cited paper is a yeast complementation study of splice variants and does not assay acyl-CoA acyltransferase activity in its abstract. (2) In GO-CAM gomodel:67b1629100002092 the HADHA activity is typed GO:0052816 long-chain fatty acyl-CoA hydrolase activity, which the HADHA gene review traces to a wrong-paper attribution; the monolysocardiolipin acyltransferase activity would be an acyltransferase term. (3) The same model places TAMM41 and PGS1 in the mitochondrial matrix (GO:0005759); both act at the matrix face of the inner membrane (TAMM41 peripheral, PGS1 membrane-associated), so the inner membrane would be more precise. (4) The model's causal chain CRLS1 -> PLA2G6 -> TAFAZZIN -> HADHA uses directly-positively-regulates edges for what are substrate hand-offs; HADHA and tafazzin are alternative reacylation routes, not sequential steps. GO-CAM: gomodel:67b1629100002092 (Cardiolipin metabolic process, Human; the seed's best_gocam lead, which here is the pathway itself) contains TAMM41, PGS1, PTPMT1, CRLS1, PLA2G6, TAFAZZIN, HADHA and SPATA18; all but SPATA18 are linked at activity level. No production GO-CAM in gocams/index.tsv contains PRELID1, TRIAP1, PNPLA8 or ABHD18. Gene reviews exist for CRLS1, ABHD18 and HADHA among the participants (and CKMT1A and CYCS among the excluded RGD genes); TAMM41, PGS1, PTPMT1, TAFAZZIN, PLA2G6, PNPLA8, PRELID1 and TRIAP1 have none. PANTHER family ids and PTNs are deliberately not asserted. Abstract-only caches: PMID:17082194, PMID:19700766, PMID:28442572, PMID:16620771, PMID:11171073, PMID:23931759 and others; full text is cached for PMID:21641550, PMID:35321494, PMID:39279645 and PMID:23533611.