id: P51174
gene_symbol: Acadl
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:10090
  label: Mus musculus
description: >-
  Acadl encodes long-chain specific acyl-CoA dehydrogenase (LCAD), a mitochondrial matrix flavoenzyme
  that catalyzes the first, FAD-dependent step of each mitochondrial fatty acid beta-oxidation cycle:
  the alpha,beta-dehydrogenation of a saturated (or unsaturated) long-chain acyl-CoA to the
  corresponding (2E)-enoyl-CoA, passing electrons to the electron-transfer flavoprotein (ETF). LCAD
  acts on acyl-CoAs of roughly C6-C24, with a substrate range that overlaps the very-long/long-chain
  enzymes VLCAD (ACADVL) and ACAD9, and it is the principal dehydrogenase for unsaturated and
  methyl-branched long-chain substrates. The mature enzyme is a homotetramer with one non-covalently
  bound FAD per subunit. Unlike in humans - where VLCAD dominates long-chain oxidation and LCAD is a
  minor activity - LCAD is a physiologically important long-chain dehydrogenase in rodents, and the
  Acadl-knockout mouse is a well-characterized model showing hepatic and cardiac lipidosis,
  hypoglycemia, dicarboxylic aciduria, gestational loss, and cold intolerance / impaired non-shivering
  thermogenesis. These whole-organism knockout phenotypes are the biological basis of LCAD's
  thermoregulation and lipid-homeostasis annotations, and several were mis-propagated by orthology to
  human ACADVL, where they do not belong.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically inferred cytoplasmic localization. LCAD is a mitochondrial matrix enzyme;
      "cytoplasm" is an over-general parent that does not capture the precise compartment.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The precise, experimentally supported location is the mitochondrial matrix (GO:0005759); the
      IBA "cytoplasm" call is an uninformative over-general placeholder.
- term:
    id: GO:0004466
    label: long-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred long-chain acyl-CoA dehydrogenase activity - the defining, correct
      molecular function of LCAD, at the right level of specificity and independently supported by
      direct experimental data.
    action: ACCEPT
    reason: >-
      Core molecular function of LCAD; concordant with the IDA/ISO evidence and the knockout phenotype.
    supported_by:
    - reference_id: PMID:9861014
      supporting_text: "long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation"
      full_text_unavailable: false
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically inferred mitochondrial localization, consistent with all evidence but less
      specific than the mitochondrial matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment; the mitochondrial matrix (GO:0005759) is the core location.
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred participation in the acyl-CoA-dehydrogenase step of beta-oxidation -
      the defining process for LCAD, strongly supported by IDA and IMP evidence.
    action: ACCEPT
    reason: >-
      Core biological process; LCAD performs the acyl-CoA dehydrogenase step of long-chain FAO.
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetically inferred FAD binding. LCAD is a flavoprotein with one non-covalently bound FAD
      per subunit; FAD is the redox cofactor essential for the dehydrogenation.
    action: ACCEPT
    reason: >-
      Cofactor binding required for catalysis; a genuine core molecular function of this flavoenzyme.
- term:
    id: GO:0019254
    label: carnitine metabolic process, CoA-linked
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred link to CoA-linked carnitine metabolism, reflecting the
      acyl-CoA/acylcarnitine interconversion that feeds mitochondrial FAO; peripheral to the core
      dehydrogenase function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Related to LCAD's role in long-chain FAO (acylcarnitine flux) but not its core catalytic
      function; retained as non-core.
- term:
    id: GO:0042758
    label: long-chain fatty acid catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetically inferred long-chain fatty acid catabolism - the chain-length-appropriate
      catabolic process for LCAD.
    action: ACCEPT
    reason: >-
      Core biological process matching LCAD's long-chain substrate specificity.
- term:
    id: GO:0003995
    label: acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro electronic annotation to the general acyl-CoA dehydrogenase activity. Correct but a
      broad parent of the specific long-chain activity (GO:0004466).
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate parent term subsumed by the specific long-chain acyl-CoA dehydrogenase activity.
- term:
    id: GO:0004466
    label: long-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (multi-method) assignment of the long-chain acyl-CoA dehydrogenase activity,
      duplicating the IBA/IDA core-function call.
    action: ACCEPT
    reason: >-
      Core molecular function of LCAD, corroborated across electronic, phylogenetic and experimental
      evidence.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      ARBA electronic mitochondrion annotation; correct compartment, less specific than the matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment; mitochondrial matrix (GO:0005759) is the core location.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic (UniProt subcellular-location) annotation to the mitochondrial matrix - the correct,
      specific compartment for this soluble matrix enzyme.
    action: ACCEPT
    reason: >-
      The precise, core location of LCAD.
- term:
    id: GO:0016627
    label: oxidoreductase activity, acting on the CH-CH group of donors
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro electronic annotation to the parent oxidoreductase (CH-CH donor) class - the reaction
      chemistry of acyl-CoA dehydrogenases.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate parent term subsumed by the specific long-chain acyl-CoA dehydrogenase activity.
- term:
    id: GO:0017099
    label: very-long-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: >-
      Rhea-based electronic annotation of very-long-chain acyl-CoA dehydrogenase activity. LCAD's
      substrate range extends into longer chains and overlaps VLCAD, but its defining specificity is
      long-chain; the dedicated very-long-chain enzyme is VLCAD (ACADVL). Annotating LCAD with a
      very-long-chain-specific MF overstates its specificity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      LCAD's core specificity is long-chain (GO:0004466); the very-long-chain-specific term
      mischaracterizes it (parallel to the ACAD9 GO:0017099 chain-length over-annotation).
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation to the acyl-CoA-dehydrogenase step of beta-oxidation, duplicating the
      core process call.
    action: ACCEPT
    reason: >-
      Core biological process for LCAD.
- term:
    id: GO:0042758
    label: long-chain fatty acid catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro electronic annotation to long-chain fatty acid catabolism, duplicating the core
      chain-length-appropriate process.
    action: ACCEPT
    reason: >-
      Core biological process matching LCAD's long-chain specificity.
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro electronic FAD-binding annotation, duplicating the cofactor core function.
    action: ACCEPT
    reason: >-
      Cofactor binding required for catalysis.
- term:
    id: GO:0070991
    label: medium-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic annotation of medium-chain acyl-CoA dehydrogenase activity. LCAD's broad range
      overlaps medium chains, but the dedicated medium-chain enzyme is MCAD (ACADM); assigning LCAD a
      medium-chain-specific MF overstates its specificity.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      LCAD's core specificity is long-chain; the medium-chain-specific term mischaracterizes it.
- term:
    id: GO:0004466
    label: long-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  qualifier: enables
  review:
    summary: >-
      Orthology-based (from human/rat) long-chain acyl-CoA dehydrogenase activity, duplicating the
      core-function call.
    action: ACCEPT
    reason: >-
      Core molecular function of LCAD.
- term:
    id: GO:0004466
    label: long-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000119
  qualifier: enables
  review:
    summary: >-
      Orthology-based long-chain acyl-CoA dehydrogenase activity (second ISO source), duplicating the
      core-function call.
    action: ACCEPT
    reason: >-
      Core molecular function of LCAD.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  qualifier: located_in
  review:
    summary: >-
      Orthology-based mitochondrial matrix localization, concordant with the core compartment.
    action: ACCEPT
    reason: >-
      The precise, core location of LCAD.
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  qualifier: located_in
  review:
    summary: >-
      Orthology-based mitochondrial membrane localization. LCAD is a soluble mitochondrial matrix
      enzyme (unlike the membrane-associated VLCAD); a membrane assignment is not supported for LCAD.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      LCAD is a soluble matrix protein; the mitochondrial-membrane call likely reflects imprecise
      orthology transfer and is superseded by the matrix localization.
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  qualifier: involved_in
  review:
    summary: >-
      Orthology-based annotation to the acyl-CoA-dehydrogenase step of beta-oxidation, duplicating the
      core process.
    action: ACCEPT
    reason: >-
      Core biological process for LCAD.
- term:
    id: GO:0042758
    label: long-chain fatty acid catabolic process
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  qualifier: involved_in
  review:
    summary: >-
      Orthology-based long-chain fatty acid catabolism, duplicating the core chain-length process.
    action: ACCEPT
    reason: >-
      Core biological process matching LCAD's long-chain specificity.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  qualifier: enables
  review:
    summary: >-
      Orthology-based self-association annotation. LCAD is a homotetramer, so self-association is real
      and required for the active enzyme, but "protein homodimerization activity" is a non-catalytic
      assembly property rather than an informative molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real, functionally required oligomerization but non-core; the core MF is the long-chain
      dehydrogenase activity (consistent with the ACADVL/ACADM GO:0042802 treatment).
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: ISO
  original_reference_id: GO_REF:0000096
  qualifier: enables
  review:
    summary: >-
      Orthology-based FAD-binding annotation, duplicating the cofactor core function.
    action: ACCEPT
    reason: >-
      Cofactor binding required for catalysis.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: >-
      Sequence-similarity-based mitochondrial matrix localization, concordant with the core
      compartment.
    action: ACCEPT
    reason: >-
      The precise, core location of LCAD.
- term:
    id: GO:0016042
    label: lipid catabolic process
  evidence_type: IMP
  original_reference_id: PMID:9861014
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype evidence: LCAD-knockout mice accumulate lipid and show impaired fatty-acid
      catabolism. A general parent of the specific fatty acid beta-oxidation process.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but general; the specific fatty acid beta-oxidation terms capture LCAD's role more
      precisely.
    supported_by:
    - reference_id: PMID:9861014
      supporting_text: "lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic"
      full_text_unavailable: false
- term:
    id: GO:0004466
    label: long-chain fatty acyl-CoA dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:9861014
  qualifier: enables
  review:
    summary: >-
      Direct-assay support for LCAD's long-chain acyl-CoA dehydrogenase activity from the knockout
      study, which established the enzyme's crucial role in fatty acid oxidation.
    action: ACCEPT
    reason: >-
      Core molecular function of LCAD, experimentally grounded.
    supported_by:
    - reference_id: PMID:9861014
      supporting_text: "long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation"
      full_text_unavailable: false
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IDA
  original_reference_id: PMID:9861014
  qualifier: involved_in
  review:
    summary: >-
      Direct-assay support for LCAD's role in the acyl-CoA-dehydrogenase step of beta-oxidation from
      the knockout study.
    action: ACCEPT
    reason: >-
      Core biological process for LCAD.
    supported_by:
    - reference_id: PMID:9861014
      supporting_text: "lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic"
      full_text_unavailable: false
- term:
    id: GO:0120162
    label: positive regulation of cold-induced thermogenesis
  evidence_type: IMP
  original_reference_id: PMID:9802886
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype evidence that LCAD is required for normal cold-induced (non-shivering)
      thermogenesis: LCAD-deficient mice have abnormal thermogenesis and cold intolerance. This is a
      genuine mouse LCAD phenotype (and one that was mis-transferred to human ACADVL).
    action: ACCEPT
    reason: >-
      A real, experimentally established whole-organism role of mouse LCAD in cold-induced
      thermogenesis via long-chain FAO-derived heat production.
    supported_by:
    - reference_id: PMID:9802886
      supporting_text: "Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation"
      full_text_unavailable: true
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:26767982
  qualifier: located_in
  review:
    summary: >-
      Direct-assay mitochondrial localization. Correct compartment, less specific than the matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment; mitochondrial matrix is the core location.
- term:
    id: GO:0009062
    label: fatty acid catabolic process
  evidence_type: IMP
  original_reference_id: PMID:21151927
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Mutant-phenotype evidence linking LCAD to fatty acid catabolism (a general parent of
      beta-oxidation), from a study of LCAD-deficient mice under cold/fasting stress.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but general; the specific fatty acid beta-oxidation terms are the core process
      annotations.
    supported_by:
    - reference_id: PMID:21151927
      supporting_text: "cold and fasting stresses, these mice"
      full_text_unavailable: false
- term:
    id: GO:0009409
    label: response to cold
  evidence_type: IMP
  original_reference_id: PMID:21151927
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Mutant-phenotype evidence that LCAD-deficient mice are compromised under cold stress, consistent
      with the requirement for long-chain FAO in cold adaptation.
    action: ACCEPT
    reason: >-
      A genuine mouse LCAD physiological role in the response to cold (a phenotype mis-transferred to
      human ACADVL).
    supported_by:
    - reference_id: PMID:21151927
      supporting_text: "cold and fasting stresses, these mice"
      full_text_unavailable: false
- term:
    id: GO:0090181
    label: regulation of cholesterol metabolic process
  evidence_type: IMP
  original_reference_id: PMID:15639194
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype evidence that LCAD deficiency alters cholesterol/lipid homeostasis (via
      PPAR-alpha-linked gene induction during fasting/cold). A downstream regulatory consequence of
      the FAO block rather than a core catalytic function.
    action: KEEP_AS_NON_CORE
    reason: >-
      A genuine but downstream/regulatory whole-organism consequence of LCAD loss; non-core relative
      to the dehydrogenase function.
    supported_by:
    - reference_id: PMID:15639194
      supporting_text: "LCAD-/-) develop hepatic steatosis upon"
      full_text_unavailable: true
- term:
    id: GO:0001659
    label: temperature homeostasis
  evidence_type: IMP
  original_reference_id: PMID:15639194
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype evidence that LCAD is required for temperature homeostasis - LCAD-deficient
      mice fail to maintain body temperature under cold exposure. A classic, genuine mouse LCAD
      phenotype (mis-transferred to human ACADVL).
    action: ACCEPT
    reason: >-
      A real, experimentally established whole-organism role of mouse LCAD in thermoregulation.
    supported_by:
    - reference_id: PMID:15639194
      supporting_text: "LCAD-/-) develop hepatic steatosis upon"
      full_text_unavailable: true
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IMP
  original_reference_id: PMID:15639194
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype evidence for LCAD's role in the acyl-CoA-dehydrogenase step of beta-oxidation,
      from the LCAD-knockout fasting/cold study.
    action: ACCEPT
    reason: >-
      Core biological process for LCAD.
    supported_by:
    - reference_id: PMID:15639194
      supporting_text: "LCAD-/-) develop hepatic steatosis upon"
      full_text_unavailable: true
- term:
    id: GO:0045717
    label: negative regulation of fatty acid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:15639194
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype evidence that LCAD loss alters fatty-acid biosynthetic gene regulation (a
      PPAR-alpha-linked adaptive response). A downstream regulatory consequence, not a core function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine but downstream/regulatory whole-organism consequence of LCAD loss; non-core.
    supported_by:
    - reference_id: PMID:15639194
      supporting_text: "LCAD-/-) develop hepatic steatosis upon"
      full_text_unavailable: true
- term:
    id: GO:0046322
    label: negative regulation of fatty acid oxidation
  evidence_type: IMP
  original_reference_id: PMID:15639194
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype-derived regulatory annotation from the LCAD-knockout study. This is a
      downstream/compensatory regulatory effect rather than a core function (LCAD itself performs, not
      negatively regulates, fatty acid oxidation).
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream regulatory consequence observed in the knockout; non-core and potentially misleading
      as a direct function, retained per the curator's experimental annotation.
    supported_by:
    - reference_id: PMID:15639194
      supporting_text: "LCAD-/-) develop hepatic steatosis upon"
      full_text_unavailable: true
- term:
    id: GO:0019254
    label: carnitine metabolic process, CoA-linked
  evidence_type: IMP
  original_reference_id: PMID:9861014
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype evidence linking LCAD to CoA-linked carnitine metabolism (abnormal
      acylcarnitine profiles in LCAD-deficient mice). Peripheral to the core dehydrogenase function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Related to LCAD's FAO role via acylcarnitine flux; non-core.
    supported_by:
    - reference_id: PMID:9861014
      supporting_text: "lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic"
      full_text_unavailable: false
- term:
    id: GO:0042413
    label: carnitine catabolic process
  evidence_type: IMP
  original_reference_id: PMID:9861014
  qualifier: involved_in
  review:
    summary: >-
      Mutant-phenotype-derived carnitine catabolism annotation from the LCAD-knockout study.
      Peripheral to the core dehydrogenase function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Related to the acylcarnitine changes in LCAD deficiency; non-core.
    supported_by:
    - reference_id: PMID:9861014
      supporting_text: "lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic"
      full_text_unavailable: false
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:18614015
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics mitochondrial localization; correct compartment, less specific than
      the matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment; mitochondrial matrix is the core location.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:14651853
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics mitochondrial localization (second dataset); correct compartment,
      less specific than the matrix.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct compartment; mitochondrial matrix is the core location.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000096
  title: Automated transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000119
  title: Automated transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:9861014
  title: Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals
    crucial roles for fatty acid oxidation.
  findings:
  - statement: LCAD-knockout mice show that long-chain acyl-CoA dehydrogenase is crucial for fatty
      acid oxidation, presenting with lipidosis, hypoglycemia, elevated serum free fatty acids and
      nonketotic dicarboxylic aciduria.
    supporting_text: "lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic"
    full_text_unavailable: false
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "The LCAD-knockout mouse paper; grounds the core long-chain acyl-CoA dehydrogenase
      activity and the FAO/lipid/carnitine phenotypes. Abstract-only in cache."
- id: PMID:9802886
  title: Abnormal nonshivering thermogenesis in mice with inherited defects of fatty
    acid oxidation.
  findings:
  - statement: Mice with inherited fatty acid oxidation defects (including LCAD deficiency) show
      abnormal non-shivering thermogenesis and cold intolerance.
    supporting_text: "Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation"
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Grounds the cold-induced thermogenesis role of mouse LCAD; a phenotype mis-transferred
      to human ACADVL. Abstract-only in cache."
- id: PMID:21151927
  title: Stressed-induced TMEM135 protein is part of a conserved genetic network involved
    in fat storage and longevity regulation in Caenorhabditis elegans.
  findings:
  - statement: LCAD-deficient mice are compromised under cold and fasting stress, consistent with a
      requirement for long-chain fatty acid oxidation in stress responses.
    supporting_text: "cold and fasting stresses, these mice"
    full_text_unavailable: false
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: "Source of the response-to-cold and fatty-acid-catabolic IMP annotations for mouse
      LCAD (studied alongside a TMEM135 network). Abstract-only in cache."
- id: PMID:15639194
  title: Differential induction of genes in liver and brown adipose tissue regulated
    by peroxisome proliferator-activated receptor-alpha during fasting and cold exposure
    in acyl-CoA dehydrogenase-deficient mice.
  findings:
  - statement: LCAD-deficient mice develop hepatic steatosis upon fasting/cold exposure with altered
      PPAR-alpha-regulated gene induction, underlying the temperature-homeostasis and lipid/cholesterol
      regulatory phenotypes.
    supporting_text: "LCAD-/-) develop hepatic steatosis upon"
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Grounds the temperature-homeostasis and lipid/cholesterol regulatory IMP annotations
      of mouse LCAD - the cluster mis-transferred to human ACADVL. Abstract-only in cache."
- id: PMID:26767982
  title: Nutritional stress exacerbates hepatic steatosis induced by deletion of the
    histidine nucleotide-binding (Hint2) mitochondrial protein.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: "Source of an IDA mitochondrion localization for LCAD; used only for the (non-core)
      mitochondrion compartment call."
- id: PMID:18614015
  title: A mitochondrial protein compendium elucidates complex I disease biology.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: "MitoCarta-type high-throughput mitochondrial proteomics; source of an HDA
      mitochondrion localization."
- id: PMID:14651853
  title: Integrated analysis of protein composition, tissue diversity, and gene regulation
    in mouse mitochondria.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: "High-throughput mouse mitochondrial proteomics; source of an HDA mitochondrion
      localization."
core_functions:
- description: >-
    Long-chain specific acyl-CoA dehydrogenase (EC 1.3.8.8): FAD-dependent alpha,beta-dehydrogenation
    of long-chain (and unsaturated/methyl-branched) acyl-CoA thioesters to (2E)-enoyl-CoA, the first
    step of each mitochondrial fatty acid beta-oxidation cycle, transferring electrons to ETF. In
    rodents this is a physiologically important long-chain dehydrogenase overlapping VLCAD/ACAD9.
  supported_by:
  - reference_id: PMID:9861014
    supporting_text: "long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation"
    full_text_unavailable: false
  molecular_function:
    id: GO:0004466
    label: long-chain fatty acyl-CoA dehydrogenase activity
  directly_involved_in:
  - id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  - id: GO:0042758
    label: long-chain fatty acid catabolic process
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
- description: >-
    FAD cofactor binding: each LCAD subunit binds one non-covalently associated FAD, the redox
    cofactor that accepts the electrons removed from the acyl-CoA substrate before passing them to ETF;
    essential for dehydrogenase activity.
  supported_by:
  - reference_id: PMID:9861014
    supporting_text: "long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation"
    full_text_unavailable: false
  molecular_function:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  directly_involved_in:
  - id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
proposed_new_terms: []
suggested_questions:
- question: >-
    Given that mouse LCAD is a functionally important long-chain dehydrogenase (overlapping VLCAD)
    whereas human LCAD (ACADL) is minor, which long-chain substrates in vivo depend specifically on
    LCAD versus VLCAD/ACAD9 in the mouse, particularly unsaturated and methyl-branched acyl-CoAs?
- question: >-
    Are the LCAD-knockout thermoregulation and lipid-regulation phenotypes direct consequences of the
    long-chain FAO block, or do they involve secondary PPAR-alpha-mediated transcriptional adaptation?
suggested_experiments:
- description: >-
    Substrate-resolved acylcarnitine and flux profiling in Acadl-/- versus Acadvl-/- mouse tissues to
    delineate the non-redundant long-chain substrate range of LCAD in the rodent.
  hypothesis: >-
    Mouse LCAD is the principal dehydrogenase for unsaturated and methyl-branched long-chain acyl-CoAs,
    a niche not fully covered by VLCAD.