ABCB10 is a homodimeric ATP-binding cassette transporter of the mitochondrial inner membrane, delivered there by an unusually long presequence and assembling into homodimers and higher oligomers. It exports the tetrapyrrole biliverdin from the mitochondrial matrix to the cytosol, a substrate assignment established by direct transport assay and confirmed by cryo-EM structures of the apo and biliverdin-bound states. The protein was for many years assumed instead to export 5-aminolevulinic acid, the first committed heme precursor, but that model was tested directly and ruled out. Its ATPase cycle is the functional core: catalytic Walker A/B and C-loop residues are required, conserved transmembrane arginines mediate biliverdin-induced ATPase stimulation, and activity is tuned by cardiolipin and by glutathione redox status. ABCB10 is nonetheless required for hemoglobinization, but indirectly - its loss represses the heme-biosynthesis transcriptional programme through Bach1 and destabilises mitoferrin-1, reducing mitochondrial iron import - and it physically organises mitochondrial iron-heme machinery, forming a complex in which dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers. Loss of ABCB10 causes mitochondrial and lysosomal iron accumulation, elevated reactive oxygen species and failure of erythropoiesis. Its exported product also acts outside erythroid cells, where bilirubin derived from the exported biliverdin has been implicated in limiting hepatic glucose handling and beta-cell insulin secretion.
Definition: Enables the transfer of biliverdin from one side of a membrane to the other. Biliverdin is the linear tetrapyrrole produced by heme oxygenase cleavage of heme.
Justification: GO already resolves tetrapyrrole transport at substrate level on both sides of this gap: GO:0015232 heme transmembrane transporter activity for the cyclic tetrapyrrole, and bilirubin transport terms for the downstream reduced product. Biliverdin, the linear tetrapyrrole sitting between them, has no transport term at all. That is a sharper statement of the gap than 'no biliverdin term exists': the ontology covers the step before and the step after, and skips this one. ABCB10 is the characterised biliverdin exporter of the mitochondrial inner membrane, established by transport of biliverdin by purified protein reconstituted into liposomes and by cryo-EM structures of the apo and biliverdin-bound transporter, yet the most specific molecular function available for it is the family-level GO:0140359 ABC-type transporter activity. The gap matters because substrate identity is the single most consequential fact about this protein: it is what distinguishes the current model from the disproven 5-aminolevulinic acid export model, and what connects mitochondrial heme catabolism to cytosolic bilirubin signalling. The proposed parent is GO:0005310 dicarboxylic acid transmembrane transporter activity, which is how GO already places the closest existing term: GO:0015127 bilirubin transmembrane transporter activity is a direct is_a child of GO:0005310 (verified against QuickGO). Biliverdin, like bilirubin, carries two propionate side chains, so the subsumption is true rather than merely convenient.proposed_parent is an is_a assertion, so it would entail that every biliverdin transporter is a heme transporter - heme is the cyclic tetrapyrrole, biliverdin its ring-opened catabolite, and a curator importing that would reclassify ABCB10 under heme transport, reintroducing the confusion the review exists to remove. Note also that GO:0015232 and GO:0015127 are not in a chain: GO:0015232 is a direct child of GO:0022857 while GO:0015127 sits in the carboxylic-acid branch, so heme, biliverdin and bilirubin are siblings. A shared tetrapyrrole-transport grouping over all three would be a genuine improvement to the ontology, but it is a restructuring proposal rather than an available parent, and is recorded here as such.
Parent term: dicarboxylic acid transmembrane transporter activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: ATP binding, from automatic annotation of the ABC transporter nucleotide-binding domains. Correct and central: ABCB10's catalytic Walker A/B and C-loop residues are required for ATP binding and hydrolysis, and the ATPase cycle is what its function depends on. Supporting Evidence: file:human/ABCB10/ABCB10-deep-research-affinage.md Its ATPase cycle is the functional core: catalytic Walker A/B and C-loop residues are required for ATP binding and hydrolysis |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Mitochondrial inner-membrane localisation. ABCB10 is delivered to the inner membrane by an unusually long presequence and is one of the best-established residents of that membrane; this is the compartment in which its transport activity occurs. Core location. Electronic mapping from the UniProt subcellular location. Supporting Evidence: file:human/ABCB10/ABCB10-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic 'membrane', from InterPro. Not wrong, but uninformative when the specific mitochondrial inner membrane is separately annotated with better evidence (ISS, IDA and IEA). Reason: Redundant parent of the specific, well-supported mitochondrial inner-membrane location. Supporting Evidence: file:human/ABCB10/ABCB10-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000120 | ACCEPT | Summary: ATP hydrolysis activity, automatic. Correct and independently demonstrated by direct assay on purified protein (see the IDA row from PMID:33253225). The ATPase activity is not incidental: it is what is required for hemoglobinization, independently of any transport of a heme-pathway intermediate. Supporting Evidence: PMID:28808058 our findings rule out that Abcb10 transports ALA and indicate that Abcb10's ATP-hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization. |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Mitochondrial membrane, from an ARBA machine-learning model. Correct but one level less specific than the mitochondrial inner membrane annotated elsewhere; retained as non-core. Supporting Evidence: file:human/ABCB10/ABCB10-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0042802 identical protein binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Identical protein binding, from an ARBA model. Correct: ABCB10 functions as a homodimer, which is separately supported by direct assay (GO:0042803 IDA from PMID:30765471) and by the cryo-EM structures. Retained as the less informative of the two homodimerisation terms. Supporting Evidence: file:human/ABCB10/ABCB10-deep-research-affinage.md ABCB10 is a homodimeric ABC transporter of the inner mitochondrial membrane that exports the tetrapyrrole biliverdin from the matrix to the cytosol |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Transmembrane transport, from InterPro. Correct but very general for a transporter whose substrate is now identified; the specific export activity is captured by GO:0170037 and by the ABC-type transporter activity rows. Supporting Evidence: PMID:34011630 ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity. |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: ABC-type transporter activity, from InterPro. Correct family-level molecular function, and independently supported by two IDA rows. See the note on those rows about the missing biliverdin-specific term. Supporting Evidence: PMID:34011630 ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity. |
| GO:0005515 protein binding | IPI PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | MODIFY | Summary: Interaction with ferrochelatase (FECH, UniProtKB:P22830). Unlike the high-throughput protein-binding annotations seen on most genes in this campaign, this one is mechanistically central: dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers into an architecturally defined complex near the nucleotide-binding domains, physically organising mitochondrial iron-heme machinery. Bare 'protein binding' badly understates it. Note the gene already carries GO:0043190 ABC transporter complex from the same paper, so complex membership is recorded; what these rows add is the partner identity, for which protein-containing complex binding is the closest informative existing term. Reason: Uninformative term for a structurally characterised, mechanistically central interaction with ferrochelatase. Proposed replacements: protein-containing complex binding Supporting Evidence: file:human/ABCB10/ABCB10-deep-research-affinage.md forming a complex with ferrochelatase bridged to ABCB7 near the nucleotide-binding domains |
| GO:0005515 protein binding | IPI PMID:36836934 Proteomic Analysis of Ferrochelatase Interactome in Erythroi... | MODIFY | Summary: Interaction with ferrochelatase (UniProtKB:P22830) recovered independently by a dedicated proteomic analysis of the ferrochelatase interactome in erythroid and non-erythroid cells. Independent confirmation of the ABCB10-FECH interaction from the FECH side, which strengthens the case that this is a genuine complex rather than a co-purification artefact. Reason: Uninformative term for a reproducible, structurally characterised interaction. Proposed replacements: protein-containing complex binding Supporting Evidence: file:human/ABCB10/ABCB10-deep-research-affinage.md forming a complex with ferrochelatase bridged to ABCB7 near the nucleotide-binding domains |
| GO:0006783 heme biosynthetic process | IEA GO_REF:0000107 | MODIFY | Summary: The historical model for this annotation has been disproven, and the term now invites precisely the reading the field discarded. ABCB10 was long assumed to export 5-aminolevulinic acid (ALA), the first committed heme precursor, which would make it a direct participant in heme biosynthesis. PMID:28808058 tested that directly and ruled it out: inhibiting ALA dehydratase caused ALA to accumulate equally in control and Abcb10-knockdown cells, showing that reducing Abcb10 does not affect ALA export. The actual transported substrate is biliverdin, a heme catabolite rather than a precursor. ABCB10 nevertheless is required for hemoglobinization, but indirectly: its ATP-hydrolysis activity is critical, loss of it represses the heme-biosynthesis transcriptional programme through Bach1 (partially rescuable by ALAS2 or GATA1 overexpression), and it stabilises mitoferrin-1 to support mitochondrial iron import. That is regulation of the pathway, not participation in it, and GO:0070455 positive regulation of heme biosynthetic process - already annotated on this gene by ISS - says exactly that. Reason: ABCB10 does not transport a heme-pathway intermediate; its effect on heme biosynthesis is regulatory and indirect. The regulation term is already present on this gene and is what the evidence supports. Proposed replacements: positive regulation of heme biosynthetic process Supporting Evidence: PMID:28808058 demonstrating that reductions in Abcb10 do not affect ALA export from mitochondria and indicating that Abcb10 does not transport ALA. PMID:28808058 our findings rule out that Abcb10 transports ALA and indicate that Abcb10's ATP-hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization. PMID:28808058 Abcb10 silencing resulted in an alteration in the heme biosynthesis transcriptional profile due to repression by the transcriptional regulator Bach1 |
| GO:0045648 positive regulation of erythrocyte differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: Positive regulation of erythrocyte differentiation. Well supported: ABCB10 loss causes mitochondrial and lysosomal iron accumulation, elevated ROS and lethal failure of erythropoiesis, and reduced ABCB10 impairs hemoglobinization in erythroid cells. Correct core process. Supporting Evidence: PMID:22085049 Human mitochondrial ATP-binding cassette transporter ABCB10 is required for efficient red blood cell development. file:human/ABCB10/ABCB10-deep-research-affinage.md Loss of ABCB10 causes mitochondrial and lysosomal iron accumulation, elevated ROS, and lethal failure of erythropoiesis |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial inner-membrane localisation. ABCB10 is delivered to the inner membrane by an unusually long presequence and is one of the best-established residents of that membrane; this is the compartment in which its transport activity occurs. Core location. Sequence-similarity transfer, consistent with the IEA and IDA rows. Supporting Evidence: file:human/ABCB10/ABCB10-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005515 protein binding | IPI PMID:40105103 Definition of the human mitochondrial TOM interactome reveal... | MARK AS OVER ANNOTATED | Summary: Interaction with MUL1 (UniProtKB:Q969V5), a mitochondrial E3 ubiquitin ligase, from a study defining the mitochondrial TOM interactome. Plausible in context - MUL1 acts on mitochondrial membrane proteins - but the pair has no dedicated functional follow-up, and the term is uninformative. Reason: Uninformative term for an interaction with no functional characterisation for this pair. Supporting Evidence: PMID:40105103 we have defined the TOM interactome in a comprehensive manner using biochemical approaches to isolate the TOM complex in combination with quantitative mass spectrometry analyses |
| GO:0006783 heme biosynthetic process | NAS PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | MODIFY | Summary: This row is NOT the ALA-export inference the other two GO:0006783 rows rest on, and needs its own argument. It is a ComplexPortal NAS assignment from PMID:30765471, which identified a crosslinking/MS-defined complex of ferrochelatase (FECH), ABCB7 and ABCB10 and titled it "required for heme biosynthesis". That curator was asserting complex-level participation via FECH - the terminal enzyme of the pathway - not that ABCB10 itself transports a heme intermediate, so rebutting ALA transport does not engage this evidence. The term is still wrong for ABCB10, on narrower grounds. An annotation inherited from a partner's catalytic role is a complex-level attribution, and ABCB10's own demonstrated contribution to hemoglobinization is regulatory: ATP-hydrolysis-dependent relief of Bach1 repression of the heme transcriptional programme, and stabilisation of mitoferrin-1 for mitochondrial iron import. GO:0070455 positive regulation of heme biosynthetic process, already on this gene by ISS, says that without asserting that ABCB10 carries out a step. The FECH association itself is not lost - it is carried by the complex-membership annotations this review retains, which is where a complex-level fact belongs. Reason: Complex-level attribution inherited from a partner (ferrochelatase) rather than a demonstrated ABCB10 activity. ABCB10's own contribution to the pathway is regulatory and the regulation term is already present on this gene. This reasoning is deliberately different from the other two GO:0006783 rows, which rest on the disproven ALA-export model; that argument does not apply to a ComplexPortal complex-membership assignment. Proposed replacements: positive regulation of heme biosynthetic process Supporting Evidence: PMID:30765471 we identified a complex formed of ferrochelatase (FECH), ABCB7 and ABCB10 and characterized its overall architecture PMID:28808058 Abcb10 silencing resulted in an alteration in the heme biosynthesis transcriptional profile due to repression by the transcriptional regulator Bach1 |
| GO:0031966 mitochondrial membrane | IDA PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | KEEP AS NON CORE | Summary: Mitochondrial inner-membrane localisation. ABCB10 is delivered to the inner membrane by an unusually long presequence and is one of the best-established residents of that membrane; this is the compartment in which its transport activity occurs. Direct assay in the structural study of the ABCB7-FECH-ABCB10 complex. Slightly less specific than 'mitochondrial inner membrane' but from strong evidence; retained as non-core relative to the inner-membrane rows. Supporting Evidence: file:human/ABCB10/ABCB10-deep-research-affinage.md forming a complex with ferrochelatase bridged to ABCB7 near the nucleotide-binding domains |
| GO:0043190 ATP-binding cassette (ABC) transporter complex | IPI PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | ACCEPT | Summary: Membership of an ABC transporter complex, from the structural study showing dimeric ferrochelatase bridging ABCB7 and ABCB10 homodimers. This is the informative complex-level annotation for this gene and it is well earned; accept as core. Supporting Evidence: file:human/ABCB10/ABCB10-deep-research-affinage.md forming a complex with ferrochelatase bridged to ABCB7 near the nucleotide-binding domains |
| GO:0140359 ABC-type transporter activity | IDA PMID:34011630 ABCB10 exports mitochondrial biliverdin, driving metabolic m... | ACCEPT | Summary: ABC-type transporter activity, by direct assay. Correct, and now underspecified in an interesting way: the transported substrate has been identified as biliverdin, and cryo-EM structures of ABCB10 in apo and biliverdin-bound states are available. GO has GO:0015232 heme transmembrane transporter activity for the related tetrapyrrole but no term for biliverdin transport, so there is no more specific term to modify to. Accepted as correct but general, with the missing term filed under proposed_new_terms rather than forcing the annotation into an ill-fitting existing term. Supporting Evidence: PMID:34011630 ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity. file:human/ABCB10/ABCB10-deep-research-affinage.md biliverdin/bilirubin export rather than direct ALA or dALA transport is the established substrate axis |
| GO:0140359 ABC-type transporter activity | IDA PMID:37041204 Cryo-EM structures of mitochondrial ABC transporter ABCB10 i... | ACCEPT | Summary: ABC-type transporter activity, by direct assay. Correct, and now underspecified in an interesting way: the transported substrate has been identified as biliverdin, and cryo-EM structures of ABCB10 in apo and biliverdin-bound states are available. GO has GO:0015232 heme transmembrane transporter activity for the related tetrapyrrole but no term for biliverdin transport, so there is no more specific term to modify to. Accepted as correct but general, with the missing term filed under proposed_new_terms rather than forcing the annotation into an ill-fitting existing term. Supporting Evidence: PMID:34011630 ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity. file:human/ABCB10/ABCB10-deep-research-affinage.md biliverdin/bilirubin export rather than direct ALA or dALA transport is the established substrate axis |
| GO:0170037 export from the mitochondrion | IDA PMID:34011630 ABCB10 exports mitochondrial biliverdin, driving metabolic m... | ACCEPT | Summary: Export from the mitochondrion, by direct assay. This is the most accurate process term on the gene: ABCB10 exports biliverdin from the matrix to the cytosol across the inner membrane. Core process, and notably it does not commit to the disproven heme-precursor model that the heme-biosynthesis rows do. Supporting Evidence: PMID:34011630 ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity. file:human/ABCB10/ABCB10-deep-research-affinage.md biliverdin/bilirubin export rather than direct ALA or dALA transport is the established substrate axis |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: Assignment to the high-confidence human mitochondrial proteome (MitoCoP). Consistent with the extensively documented mitochondrial inner-membrane localisation; high-throughput and less specific than the IDA rows, so non-core. Supporting Evidence: file:human/ABCB10/ABCB10-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0016887 ATP hydrolysis activity | IDA PMID:33253225 Stimulation of the human mitochondrial transporter ABCB10 by... | ACCEPT | Summary: ATP hydrolysis activity by direct assay on the purified human transporter. This is the functional core of the protein: catalytic Walker A/B and C-loop residues are required, and the ATPase activity is what is needed for hemoglobinization independently of transport of any heme-pathway intermediate. Core molecular function. Supporting Evidence: file:human/ABCB10/ABCB10-deep-research-affinage.md Its ATPase cycle is the functional core: catalytic Walker A/B and C-loop residues are required for ATP binding and hydrolysis PMID:28808058 our findings rule out that Abcb10 transports ALA and indicate that Abcb10's ATP-hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization. |
| GO:0042803 protein homodimerization activity | IDA PMID:30765471 Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers i... | ACCEPT | Summary: Protein homodimerisation activity, by direct assay in the structural study. ABCB10 is a homodimeric ABC transporter - the functional unit is the dimer, which is how the two nucleotide-binding domains form composite ATP sites. Core molecular function, and more informative than the ARBA identical-protein-binding row. Supporting Evidence: file:human/ABCB10/ABCB10-deep-research-affinage.md ABCB10 is a homodimeric ABC transporter of the inner mitochondrial membrane that exports the tetrapyrrole biliverdin from the matrix to the cytosol |
| GO:0034514 mitochondrial unfolded protein response | IMP PMID:28315685 ABCB10 depletion reduces unfolded protein response in mitoch... | KEEP AS NON CORE | Summary: Mitochondrial unfolded protein response, by mutant phenotype: ABCB10 depletion reduces the UPRmt. A genuine loss-of-function observation, but mechanistically downstream and disconnected from the transport activity that defines this protein; the link may well be secondary to the iron and ROS dysregulation that follows ABCB10 loss. Retained as non-core. Supporting Evidence: PMID:28315685 ABCB10 depletion significantly decreased expression of UPRmt-related mitochondrial chaperones file:human/ABCB10/ABCB10-deep-research-affinage.md ABCB10 depletion in HepG2 cells reduces expression of mitochondrial unfolded protein response (UPRmt) markers |
| GO:0046985 positive regulation of hemoglobin biosynthetic process | IMP PMID:22085049 Human mitochondrial ATP-binding cassette transporter ABCB10 ... | ACCEPT | Summary: Positive regulation of hemoglobin biosynthetic process, by mutant phenotype. Correct and important, and it is the term that survives the collapse of the ALA-export model: ABCB10's ATP-hydrolysis activity is critical for hemoglobinization even though ABCB10 transports no heme-pathway intermediate. The mechanism is regulatory, running through Bach1-mediated repression of the heme-biosynthesis transcriptional programme and through stabilisation of mitoferrin-1. Core process. Supporting Evidence: PMID:28808058 our findings rule out that Abcb10 transports ALA and indicate that Abcb10's ATP-hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization. PMID:28808058 Abcb10 silencing resulted in an alteration in the heme biosynthesis transcriptional profile due to repression by the transcriptional regulator Bach1 |
| GO:0046985 positive regulation of hemoglobin biosynthetic process | IMP PMID:28808058 Reductions in the mitochondrial ABC transporter Abcb10 affec... | ACCEPT | Summary: Positive regulation of hemoglobin biosynthetic process, by mutant phenotype. Correct and important, and it is the term that survives the collapse of the ALA-export model: ABCB10's ATP-hydrolysis activity is critical for hemoglobinization even though ABCB10 transports no heme-pathway intermediate. The mechanism is regulatory, running through Bach1-mediated repression of the heme-biosynthesis transcriptional programme and through stabilisation of mitoferrin-1. Core process. Supporting Evidence: PMID:28808058 our findings rule out that Abcb10 transports ALA and indicate that Abcb10's ATP-hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization. PMID:28808058 Abcb10 silencing resulted in an alteration in the heme biosynthesis transcriptional profile due to repression by the transcriptional regulator Bach1 |
| GO:0048821 erythrocyte development | IMP PMID:22085049 Human mitochondrial ATP-binding cassette transporter ABCB10 ... | ACCEPT | Summary: Erythrocyte development, by mutant phenotype. ABCB10 is required for normal erythropoiesis; its loss causes iron accumulation, elevated ROS and lethal failure of erythroid development. Core process. Supporting Evidence: PMID:22085049 Human mitochondrial ATP-binding cassette transporter ABCB10 is required for efficient red blood cell development. file:human/ABCB10/ABCB10-deep-research-affinage.md Loss of ABCB10 causes mitochondrial and lysosomal iron accumulation, elevated ROS, and lethal failure of erythropoiesis |
| GO:0070455 positive regulation of heme biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: Positive regulation of heme biosynthetic process. This is the accurate term for what ABCB10 does to the heme pathway - regulate it rather than participate in it - and it is the destination proposed for the three GO:0006783 rows. Accept as a core process. Supporting Evidence: PMID:28808058 our findings rule out that Abcb10 transports ALA and indicate that Abcb10's ATP-hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization. PMID:28808058 Abcb10 silencing resulted in an alteration in the heme biosynthesis transcriptional profile due to repression by the transcriptional regulator Bach1 |
| GO:0006783 heme biosynthetic process | ISS GO_REF:0000024 | MODIFY | Summary: The historical model for this annotation has been disproven, and the term now invites precisely the reading the field discarded. ABCB10 was long assumed to export 5-aminolevulinic acid (ALA), the first committed heme precursor, which would make it a direct participant in heme biosynthesis. PMID:28808058 tested that directly and ruled it out: inhibiting ALA dehydratase caused ALA to accumulate equally in control and Abcb10-knockdown cells, showing that reducing Abcb10 does not affect ALA export. The actual transported substrate is biliverdin, a heme catabolite rather than a precursor. ABCB10 nevertheless is required for hemoglobinization, but indirectly: its ATP-hydrolysis activity is critical, loss of it represses the heme-biosynthesis transcriptional programme through Bach1 (partially rescuable by ALAS2 or GATA1 overexpression), and it stabilises mitoferrin-1 to support mitochondrial iron import. That is regulation of the pathway, not participation in it, and GO:0070455 positive regulation of heme biosynthetic process - already annotated on this gene by ISS - says exactly that. Reason: ABCB10 does not transport a heme-pathway intermediate; its effect on heme biosynthesis is regulatory and indirect. The regulation term is already present on this gene and is what the evidence supports. Proposed replacements: positive regulation of heme biosynthetic process Supporting Evidence: PMID:28808058 demonstrating that reductions in Abcb10 do not affect ALA export from mitochondria and indicating that Abcb10 does not transport ALA. PMID:28808058 our findings rule out that Abcb10 transports ALA and indicate that Abcb10's ATP-hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization. PMID:28808058 Abcb10 silencing resulted in an alteration in the heme biosynthesis transcriptional profile due to repression by the transcriptional regulator Bach1 |
| GO:0045648 positive regulation of erythrocyte differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: Positive regulation of erythrocyte differentiation. Well supported: ABCB10 loss causes mitochondrial and lysosomal iron accumulation, elevated ROS and lethal failure of erythropoiesis, and reduced ABCB10 impairs hemoglobinization in erythroid cells. Correct core process. Supporting Evidence: PMID:22085049 Human mitochondrial ATP-binding cassette transporter ABCB10 is required for efficient red blood cell development. file:human/ABCB10/ABCB10-deep-research-affinage.md Loss of ABCB10 causes mitochondrial and lysosomal iron accumulation, elevated ROS, and lethal failure of erythropoiesis |
| GO:0005739 mitochondrion | IDA PMID:22655043 Shifting the paradigm: the putative mitochondrial protein AB... | KEEP AS NON CORE | Summary: Mitochondrial localisation by direct assay. Note the citation is a paper about ABCB6 rather than ABCB10; ABCB10 appears in it as a comparator, which is a normal curation practice and not a mis-attribution. The location is correct and abundantly supported elsewhere, though less specific than the inner-membrane rows. Supporting Evidence: file:human/ABCB10/ABCB10-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005515 protein binding | IPI PMID:25063848 PAAT, a novel ATPase and trans-regulator of mitochondrial AB... | MARK AS OVER ANNOTATED | Summary: Interaction with PAAT (UniProtKB:Q9H8K7), described as a novel ATPase and trans-regulator of mitochondrial ABC transporters. Topically plausible, but the pair has had no follow-up in the decade since, it does not appear in the structural work on the ABCB7-FECH-ABCB10 complex, and the term is uninformative. Reason: Uninformative term for an interaction that has not been pursued or independently confirmed. Supporting Evidence: file:human/ABCB10/ABCB10-deep-research-affinage.md forming a complex with ferrochelatase bridged to ABCB7 near the nucleotide-binding domains |
| GO:0006839 mitochondrial transport | NAS PMID:10922475 M-ABC2, a new human mitochondrial ATP-binding cassette membr... | KEEP AS NON CORE | Summary: Mitochondrial transport, NAS from the original cloning paper that named the protein M-ABC2. Correct in the broadest sense and now much better specified: the transported substrate is biliverdin and the direction is export from the matrix, captured by GO:0170037. Retained as a non-core general parent. Supporting Evidence: PMID:34011630 ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity. |
| GO:0031966 mitochondrial membrane | IDA PMID:10922475 M-ABC2, a new human mitochondrial ATP-binding cassette membr... | KEEP AS NON CORE | Summary: Mitochondrial membrane localisation from the original cloning paper. Correct; less specific than the inner-membrane annotations and from a 2000 characterisation, so non-core. Supporting Evidence: file:human/ABCB10/ABCB10-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
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Download this section (compressed HTML)Q: Should the three GO:0006783 heme biosynthetic process annotations be re-curated as regulation? PMID:28808058 directly rules out ALA transport by ABCB10, so the gene does not carry a heme-pathway intermediate; its effect is transcriptional (via Bach1) and organisational (via mitoferrin-1 stabilisation). GO:0070455 positive regulation of heme biosynthetic process is already annotated on this gene and describes what is actually shown.
Q: What is the physiological consequence of biliverdin export, and is bilirubin the effector? The exported biliverdin is reduced to bilirubin in the cytosol, which has been implicated in limiting hepatic glucose handling and beta-cell insulin secretion. Whether that signalling role, rather than erythroid heme metabolism, is ABCB10's principal function in non-erythroid tissue is unresolved.
Q: How does an exporter of a heme catabolite end up being required for heme synthesis? The Bach1 and mitoferrin-1 routes are both documented, but whether removing biliverdin from the matrix is itself the signal - as PMID:28808058 suggests when it says the transported substrate provides a signal that optimizes hemoglobinization - has not been tested directly.
Q: Is the mitochondrial unfolded protein response phenotype a distinct function or a downstream consequence? ABCB10 depletion reduces the UPRmt, but ABCB10 loss also causes iron accumulation and elevated ROS, either of which could account for it indirectly.
Q: Does the ABCB7-ferrochelatase-ABCB10 complex have a transport function beyond the sum of its parts, for instance substrate channelling between iron import, heme synthesis and biliverdin export? The architecture is known but the functional consequence of the assembly is not.
Experiment: Compare ABCB10-null erythroid cells rescued with wild-type ABCB10 against rescue with a transport-dead but ATPase-competent variant, and against wild-type cells in which matrix biliverdin is lowered by an orthogonal route such as biliverdin reductase targeting. If matrix biliverdin clearance is the signal, the orthogonal route should rescue hemoglobinization without ABCB10.
Hypothesis: Removal of biliverdin from the matrix is itself the signal that optimises hemoglobinization.
Type: cell biology and genetics
Experiment: Use structure-guided interface mutations that disrupt the ferrochelatase bridge without destabilising either transporter, then measure mitochondrial iron import, heme synthesis flux and biliverdin export independently, to test whether the assembly does more than co-localise its components.
Hypothesis: The ABCB7-FECH-ABCB10 assembly channels substrates between iron import, heme synthesis and biliverdin export.
Type: structure-function
Experiment: Compare tissue-specific ABCB10 knockouts in liver and pancreatic beta cells with matched biliverdin reductase manipulation, measuring glucose handling and insulin secretion, to establish whether the metabolic phenotypes track the exported product rather than the transporter itself.
Hypothesis: ABCB10's non-erythroid function is bilirubin-mediated signalling rather than heme metabolism.
Type: mouse physiology
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