module: dmel_cardiolipin_biosynthesis_remodeling
title: Cardiolipin biosynthesis and remodelling in Drosophila melanogaster
label: Cardiolipin biosynthesis and remodelling
module_type: METABOLIC_PATHWAY
description: >-
  Cardiolipin is the signature phospholipid of the inner mitochondrial
  membrane, where it supports respiratory chain complexes and cristae
  structure. It is made in mitochondria from CDP-diacylglycerol: Pgs1 forms
  phosphatidylglycerol phosphate, the phosphatase Ptpmt1 dephosphorylates it to
  phosphatidylglycerol, and cardiolipin synthase (Cls) joins phosphatidylglycerol
  with a second CDP-diacylglycerol to make nascent cardiolipin. Nascent
  cardiolipin is then remodelled: a lipase removes an acyl chain to form
  monolysocardiolipin, and the transacylase tafazzin (Taz) transfers an acyl
  chain from another phospholipid to monolysocardiolipin, giving cardiolipin its
  mature acyl composition. ABHD18 deacylates cardiolipin in flies and mice, and
  the calcium-independent phospholipase A2 iPLA2-VIA has also been implicated in
  cardiolipin deacylation. Loss of tafazzin causes monolysocardiolipin to
  accumulate and models Barth syndrome in flies.
summary: >-
  Mitochondrial cardiolipin synthesis (Pgs1, Ptpmt1, Cls) followed by
  deacylation-reacylation remodelling (Abhd18, iPLA2-VIA, Taz).
concepts:
  - {id: GO:0032049, label: cardiolipin biosynthetic process}
  - {id: GO:0035965, label: cardiolipin acyl-chain remodeling}
cellular_components:
  - {id: GO:0005743, label: mitochondrial inner membrane}
parts:
  - id: pgp_synthesis
    label: Phosphatidylglycerol phosphate synthesis
    role: CDP-diacylglycerol + glycerol 3-phosphate to PGP
    genes: [Pgs1]
    function: {id: GO:0008444, label: CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase activity}
  - id: pgp_dephosphorylation
    label: Phosphatidylglycerol phosphate dephosphorylation
    role: PGP to phosphatidylglycerol
    genes: [Ptpmt1]
    function: {id: GO:0008962, label: phosphatidylglycerophosphatase activity}
  - id: cardiolipin_synthesis
    label: Cardiolipin synthesis
    role: phosphatidylglycerol + CDP-diacylglycerol to nascent cardiolipin
    genes: [Cls]
    function: {id: GO:0043337, label: cardiolipin synthase (CMP-forming) activity}
  - id: cardiolipin_deacylation
    label: Cardiolipin deacylation
    role: cardiolipin to monolysocardiolipin
    description: >-
      Abhd18 hydrolyses acyl chains from cardiolipin (its loss raises
      cardiolipin and lowers deacylated species in tafazzin-deficient flies);
      iPLA2-VIA is a calcium-independent A2 phospholipase also implicated in
      cardiolipin deacylation.
    genes: [Abhd18, iPLA2-VIA]
    complex: false
    unit_functions:
      iPLA2-VIA: {id: GO:0004623, label: A2-type glycerophospholipase activity}
  - id: cardiolipin_transacylation
    label: Monolysocardiolipin transacylation
    role: monolysocardiolipin to mature cardiolipin
    description: >-
      Tafazzin transfers an acyl chain from another phospholipid to
      monolysocardiolipin.
    genes: [Taz]
connections:
  - source: pgp_synthesis
    target: pgp_dephosphorylation
    connection_type: PRECEDES
    description: PGP made by Pgs1 is dephosphorylated by Ptpmt1.
  - source: pgp_dephosphorylation
    target: cardiolipin_synthesis
    connection_type: PRECEDES
    description: Phosphatidylglycerol is the substrate of cardiolipin synthase.
  - source: cardiolipin_synthesis
    target: cardiolipin_deacylation
    connection_type: PRECEDES
    description: Nascent cardiolipin is deacylated to monolysocardiolipin.
  - source: cardiolipin_deacylation
    target: cardiolipin_transacylation
    connection_type: PRECEDES
    description: Monolysocardiolipin is reacylated by tafazzin.
knowledge_gaps:
  - gap_statement: >-
      How the work of cardiolipin deacylation is divided between Abhd18 and
      iPLA2-VIA in Drosophila tissues, and whether ABHD18-type lipases remove one
      acyl chain or deacylate cardiolipin further in vivo, is not settled.
    boundary: Deacylation step of cardiolipin remodelling.
    gap_kind: [BIOLOGY]
notes: >-
  Boundary. The module covers the six FlyBase members. CDP-diacylglycerol
  synthesis (CdsA) is upstream context. No GO molecular function term
  specifically describes tafazzin transacylase activity or ABHD18 cardiolipin
  deacylase activity, so these are left unassigned.
evidence:
  - source_id: PMID:40378955
    title: ABHD18 degrades cardiolipin by stepwise hydrolysis of fatty acids.
    statement: >-
      Shows that ABHD18 is a cardiolipin lipase in mice and flies and that its
      inactivation in Drosophila raises cardiolipin and suppresses deacylated
      cardiolipin accumulation in tafazzin-deficient flies.
    supporting_text: >-
      Our data demonstrate that ABHD18 is the elusive lipase that hydrolyzes CL
      in mice and flies and presumably in other organisms.
group: CARLIPB