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. Loss of LCAD therefore compromises thermoregulation and hepatic lipid homeostasis in the mouse, in addition to blocking long-chain fatty acid oxidation itself.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred cytoplasmic localization. LCAD is a mitochondrial matrix enzyme, so "cytoplasm" is an over-general parent rather than a wrong compartment. Reason: LCAD's experimentally supported location is GO:0005739 mitochondrion (ECO:0000314 IDA, PMID:26767982, plus five HDA rows across PMID:14651853 and PMID:18614015); the finer GO:0005759 mitochondrial matrix rows are all IEA, ISO and ISS, so "experimentally supported" belongs to the mitochondrion row rather than the matrix one. Either way GO:0005739 has GO:0005737 among its is_a/part_of ancestors (QuickGO), so the IBA parent term is imprecise but not false. Per the IBA review project's localization rule, a broad subsuming compartment is not grounds for flagging - only mutually exclusive compartments are - so this is retained as non-core rather than marked over-annotated. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002535634 SUPPORTS TRANSFER A deep acyl-CoA dehydrogenase node whose IBD seeds span bacteria, fly, rodent and human ACADM/ACAD11. Both bacterial seeds are resolved in the local PANTHER family indexes as E. coli K12 genes: P60584 as caiA (crotonobetainyl-CoA reductase) in PTHR43884-entries.csv, the node's own family, and Q47146 as fadE (acyl-coenzyme A dehydrogenase) in PTHR48083-entries.csv, a different family from the one whose IBD it seeds, so the node's own index does not contain it. In the bacterial seeds the enzyme genuinely is cytoplasmic, and in eukaryotes the mitochondrial matrix is part_of cytoplasm, so the ancestral compartment call remains true - if uninformative - for mouse Acadl rather than being a mis-transfer. MGI:MGI:87866 · mouse Acadl (the review target itself) SUPPORTS TRANSFER The target's own MGI record is among the IBD seeds, which is the expected marker that experimental grounding exists on the target itself and helped place the ancestral call; it is not circular support. The annotation is the located_in GO:0005739 mitochondrion IDA (ECO:0000314, PMID:26767982) - a descendant of this row's GO:0005737 rather than the same term, and retained here as KEEP_AS_NON_CORE. Acadl has no experimental GO:0005737 row at all; the only one is this IBA. |
| GO:0004466 long-chain fatty acyl-CoA dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Core molecular function of LCAD; concordant with the IDA/ISO evidence and the knockout phenotype. Supporting Evidence: PMID:9861014 long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred mitochondrial localization, consistent with all evidence but less specific than the mitochondrial matrix. Reason: Correct compartment; the mitochondrial matrix (GO:0005759) is the core location. |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Core biological process; LCAD performs the acyl-CoA dehydrogenase step of long-chain FAO. |
| GO:0050660 flavin adenine dinucleotide binding | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Cofactor binding required for catalysis; a genuine core molecular function of this flavoenzyme. |
| GO:0019254 carnitine metabolic process, CoA-linked | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. Reason: Related to LCAD's role in long-chain FAO (acylcarnitine flux) but not its core catalytic function; retained as non-core. |
| GO:0042758 long-chain fatty acid catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred long-chain fatty acid catabolism - the chain-length-appropriate catabolic process for LCAD. Reason: Core biological process matching LCAD's long-chain substrate specificity. |
| GO:0003995 acyl-CoA dehydrogenase activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro electronic annotation to the general acyl-CoA dehydrogenase activity. Correct but a broad parent of the specific long-chain activity (GO:0004466). Reason: Accurate parent term subsumed by the specific long-chain acyl-CoA dehydrogenase activity. |
| GO:0004466 long-chain fatty acyl-CoA dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (multi-method) assignment of the long-chain acyl-CoA dehydrogenase activity, duplicating the IBA/IDA core-function call. Reason: Core molecular function of LCAD, corroborated across electronic, phylogenetic and experimental evidence. |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic mitochondrion annotation; correct compartment, less specific than the matrix. Reason: Correct compartment; mitochondrial matrix (GO:0005759) is the core location. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic (UniProt subcellular-location) annotation to the mitochondrial matrix - the correct, specific compartment for this soluble matrix enzyme. Reason: The precise, core location of LCAD. |
| GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro electronic annotation to the parent oxidoreductase (CH-CH donor) class - the reaction chemistry of acyl-CoA dehydrogenases. Reason: Accurate parent term subsumed by the specific long-chain acyl-CoA dehydrogenase activity. |
| GO:0017099 very-long-chain fatty acyl-CoA dehydrogenase activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | 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. 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). |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation to the acyl-CoA-dehydrogenase step of beta-oxidation, duplicating the core process call. Reason: Core biological process for LCAD. |
| GO:0042758 long-chain fatty acid catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro electronic annotation to long-chain fatty acid catabolism, duplicating the core chain-length-appropriate process. Reason: Core biological process matching LCAD's long-chain specificity. |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro electronic FAD-binding annotation, duplicating the cofactor core function. Reason: Cofactor binding required for catalysis. |
| GO:0070991 medium-chain fatty acyl-CoA dehydrogenase activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | 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. Reason: LCAD's core specificity is long-chain; the medium-chain-specific term mischaracterizes it. |
| GO:0004466 long-chain fatty acyl-CoA dehydrogenase activity | ISO GO_REF:0000096 | ACCEPT | Summary: Orthology-based (from human/rat) long-chain acyl-CoA dehydrogenase activity, duplicating the core-function call. Reason: Core molecular function of LCAD. |
| GO:0004466 long-chain fatty acyl-CoA dehydrogenase activity | ISO GO_REF:0000119 | ACCEPT | Summary: Orthology-based long-chain acyl-CoA dehydrogenase activity (second ISO source), duplicating the core-function call. Reason: Core molecular function of LCAD. |
| GO:0005759 mitochondrial matrix | ISO GO_REF:0000096 | ACCEPT | Summary: Orthology-based mitochondrial matrix localization, concordant with the core compartment. Reason: The precise, core location of LCAD. |
| GO:0031966 mitochondrial membrane | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | 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. Reason: LCAD is a soluble matrix protein; the mitochondrial-membrane call likely reflects imprecise orthology transfer and is superseded by the matrix localization. |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | ISO GO_REF:0000096 | ACCEPT | Summary: Orthology-based annotation to the acyl-CoA-dehydrogenase step of beta-oxidation, duplicating the core process. Reason: Core biological process for LCAD. |
| GO:0042758 long-chain fatty acid catabolic process | ISO GO_REF:0000096 | ACCEPT | Summary: Orthology-based long-chain fatty acid catabolism, duplicating the core chain-length process. Reason: Core biological process matching LCAD's long-chain specificity. |
| GO:0042803 protein homodimerization activity | ISO GO_REF:0000096 | KEEP AS NON CORE | 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. 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). |
| GO:0050660 flavin adenine dinucleotide binding | ISO GO_REF:0000096 | ACCEPT | Summary: Orthology-based FAD-binding annotation, duplicating the cofactor core function. Reason: Cofactor binding required for catalysis. |
| GO:0005759 mitochondrial matrix | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-based mitochondrial matrix localization, concordant with the core compartment. Reason: The precise, core location of LCAD. |
| GO:0016042 lipid catabolic process | IMP PMID:9861014 Targeted disruption of mouse long-chain acyl-CoA dehydrogena... | KEEP AS NON CORE | 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. Reason: Correct but general; the specific fatty acid beta-oxidation terms capture LCAD's role more precisely. Supporting Evidence: PMID:9861014 lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic |
| GO:0004466 long-chain fatty acyl-CoA dehydrogenase activity | IDA PMID:9861014 Targeted disruption of mouse long-chain acyl-CoA dehydrogena... | ACCEPT | 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. Reason: Core molecular function of LCAD, experimentally grounded. Supporting Evidence: PMID:9861014 long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IDA PMID:9861014 Targeted disruption of mouse long-chain acyl-CoA dehydrogena... | ACCEPT | Summary: Direct-assay support for LCAD's role in the acyl-CoA-dehydrogenase step of beta-oxidation from the knockout study. Reason: Core biological process for LCAD. Supporting Evidence: PMID:9861014 lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic |
| GO:0120162 positive regulation of cold-induced thermogenesis | IMP PMID:9802886 Abnormal nonshivering thermogenesis in mice with inherited d... | ACCEPT | 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). Reason: A real, experimentally established whole-organism role of mouse LCAD in cold-induced thermogenesis via long-chain FAO-derived heat production. Supporting Evidence: PMID:9802886 Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation |
| GO:0005739 mitochondrion | IDA PMID:26767982 Nutritional stress exacerbates hepatic steatosis induced by ... | KEEP AS NON CORE | Summary: Direct-assay mitochondrial localization. Correct compartment, less specific than the matrix. Reason: Correct compartment; mitochondrial matrix is the core location. |
| GO:0009062 fatty acid catabolic process | IMP PMID:21151927 Stressed-induced TMEM135 protein is part of a conserved gene... | KEEP AS NON CORE | 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. Reason: Correct but general; the specific fatty acid beta-oxidation terms are the core process annotations. Supporting Evidence: PMID:21151927 cold and fasting stresses, these mice |
| GO:0009409 response to cold | IMP PMID:21151927 Stressed-induced TMEM135 protein is part of a conserved gene... | ACCEPT | Summary: Mutant-phenotype evidence that LCAD-deficient mice are compromised under cold stress, consistent with the requirement for long-chain FAO in cold adaptation. Reason: A genuine mouse LCAD physiological role in the response to cold (a phenotype mis-transferred to human ACADVL). Supporting Evidence: PMID:21151927 cold and fasting stresses, these mice |
| GO:0090181 regulation of cholesterol metabolic process | IMP PMID:15639194 Differential induction of genes in liver and brown adipose t... | KEEP AS NON CORE | 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. Reason: A genuine but downstream/regulatory whole-organism consequence of LCAD loss; non-core relative to the dehydrogenase function. Supporting Evidence: PMID:15639194 LCAD-/-) develop hepatic steatosis upon |
| GO:0001659 temperature homeostasis | IMP PMID:15639194 Differential induction of genes in liver and brown adipose t... | ACCEPT | 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). Reason: A real, experimentally established whole-organism role of mouse LCAD in thermoregulation. Supporting Evidence: PMID:15639194 LCAD-/-) develop hepatic steatosis upon |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IMP PMID:15639194 Differential induction of genes in liver and brown adipose t... | ACCEPT | Summary: Mutant-phenotype evidence for LCAD's role in the acyl-CoA-dehydrogenase step of beta-oxidation, from the LCAD-knockout fasting/cold study. Reason: Core biological process for LCAD. Supporting Evidence: PMID:15639194 LCAD-/-) develop hepatic steatosis upon |
| GO:0045717 negative regulation of fatty acid biosynthetic process | IMP PMID:15639194 Differential induction of genes in liver and brown adipose t... | KEEP AS NON CORE | 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. Reason: Genuine but downstream/regulatory whole-organism consequence of LCAD loss; non-core. Supporting Evidence: PMID:15639194 LCAD-/-) develop hepatic steatosis upon |
| GO:0046322 negative regulation of fatty acid oxidation | IMP PMID:15639194 Differential induction of genes in liver and brown adipose t... | KEEP AS NON CORE | 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). Reason: Downstream regulatory consequence observed in the knockout; non-core and potentially misleading as a direct function, retained per the curator's experimental annotation. Supporting Evidence: PMID:15639194 LCAD-/-) develop hepatic steatosis upon |
| GO:0019254 carnitine metabolic process, CoA-linked | IMP PMID:9861014 Targeted disruption of mouse long-chain acyl-CoA dehydrogena... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence linking LCAD to CoA-linked carnitine metabolism (abnormal acylcarnitine profiles in LCAD-deficient mice). Peripheral to the core dehydrogenase function. Reason: Related to LCAD's FAO role via acylcarnitine flux; non-core. Supporting Evidence: PMID:9861014 lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic |
| GO:0042413 carnitine catabolic process | IMP PMID:9861014 Targeted disruption of mouse long-chain acyl-CoA dehydrogena... | KEEP AS NON CORE | Summary: Mutant-phenotype-derived carnitine catabolism annotation from the LCAD-knockout study. Peripheral to the core dehydrogenase function. Reason: Related to the acylcarnitine changes in LCAD deficiency; non-core. Supporting Evidence: PMID:9861014 lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic |
| GO:0005739 mitochondrion | HDA PMID:18614015 A mitochondrial protein compendium elucidates complex I dise... | KEEP AS NON CORE | Summary: High-throughput proteomics mitochondrial localization; correct compartment, less specific than the matrix. Reason: Correct compartment; mitochondrial matrix is the core location. |
| GO:0005739 mitochondrion | HDA PMID:14651853 Integrated analysis of protein composition, tissue diversity... | KEEP AS NON CORE | Summary: High-throughput proteomics mitochondrial localization (second dataset); correct compartment, less specific than the matrix. Reason: Correct compartment; mitochondrial matrix is the core location. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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.
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