SLC25A6 (ADP/ATP translocase 3, ANT3) is one of the human adenine nucleotide translocase isoforms of the SLC25 mitochondrial carrier family (TC 2.A.29). It is a multi-pass integral protein of the mitochondrial inner membrane with the characteristic three-fold repeated mitochondrial carrier fold (six transmembrane helices, three Solcar repeats). Its principal function is ADP/ATP antiport: it exchanges ATP generated in the matrix for cytosolic ADP, importing ADP for phosphorylation by the F1Fo-ATP synthase and exporting newly synthesized ATP to the cytosol to fuel the cell, thereby serving as the final step that couples oxidative phosphorylation to cellular energy supply. Transport proceeds by an alternating-access mechanism in which a single nucleotide-binding site is exposed alternately to the cytosolic (c-state) and matrix (m-state) sides of the membrane, and is blocked by the inhibitors carboxyatractyloside (c-state) and bongkrekic acid (m-state). ANT3 is the ubiquitously expressed ANT isoform; its gene lies in the pseudoautosomal region 1 (PAR1) of the X and Y chromosomes and escapes X-inactivation. Like other ANT isoforms, ANT3 is associated with the mitochondrial permeability transition pore and can contribute to apoptosis, and it has been implicated in mitochondrial uncoupling/proton transport (thermogenesis), although these activities are secondary to its core role as an ADP/ATP exchanger.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005471 ATP:ADP antiporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. ANT3 is an ADP/ATP antiporter that exchanges matrix ATP for cytosolic ADP; this phylogenetic (IBA) inference across the ANT/SLC25 family is correct and central to the gene's biology. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt ADP:ATP antiporter that mediates import of ADP into the PMID:16201016 ANT3 is an inner mitochondrial membrane protein that functions as an antiporter catalyzing the exchange of ATP for ADP |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Core cellular location. ANT3 is a multi-pass protein of the mitochondrial inner membrane where it carries out ADP/ATP exchange. Correct. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005757 mitochondrial permeability transition pore complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ANT isoforms are associated with the mitochondrial permeability transition pore complex (PTPC) and ANT3 has been directly implicated in it, but whether ANT is a pore-forming subunit or a regulator is unresolved, and this is a secondary role shared across ANT paralogs rather than the core function. Retain as non-core. Supporting Evidence: PMID:16201016 the adenine nucleotide translocator 3 (ANT3) in the inner mitochondrial membrane and the voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane file:human/SLC25A6/SLC25A6-uniprot.txt It is however unclear if |
| GO:0046902 regulation of mitochondrial membrane permeability | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Consistent with ANT's role at the permeability transition pore, where it contributes to regulation of inner-membrane permeability during apoptosis. This is a plausible but non-core, family-level (IBA) process for ANT3. Retain as non-core. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt Also plays a key role in mPTP |
| GO:1990544 mitochondrial ATP transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Core biological process. The antiporter exports matrix ATP to the cytosol; this IBA process term correctly captures the ATP arm of ADP/ATP exchange. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt export of ATP out to fuel |
| GO:0005471 ATP:ADP antiporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic inference of the core antiporter activity from the ADT (adenine nucleotide translocase) domain signature. Correct; redundant with the IBA and ISS annotations to the same term. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt Belongs to the mitochondrial carrier (TC 2.A.29) family |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Correct but non-specific mitochondrial localization from ARBA machine-learning inference. The more precise inner-membrane term is annotated; keep this broad parent as non-core. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Correct core localization to the mitochondrial inner membrane, here from combined automated IEA methods. Consistent with IBA/ISS/Reactome evidence. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0016020 membrane | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Uninformative high-level 'membrane' term. ANT3 is specifically an integral inner-mitochondrial-membrane protein (a subset detected in the erythrocyte plasma membrane), so the generic parent is an over-annotation relative to the specific CC terms already present. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Correct but very general process term from InterPro2GO. ANT3 is a transmembrane transporter; the specific mitochondrial ADP/ATP transport terms are annotated, so keep this broad parent as non-core. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt ADP:ATP antiporter that mediates import of ADP into the |
| GO:0140021 mitochondrial ADP transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Core biological process. Captures the ADP-import arm of ADP/ATP exchange; InterPro2GO inference is correct. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt import of ADP into the |
| GO:1990544 mitochondrial ATP transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: Core biological process, here from InterPro2GO. Captures the ATP-export arm of ADP/ATP exchange; redundant with the IBA annotation to the same term. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt export of ATP out to fuel |
| GO:0005515 protein binding | IPI PMID:16201016 Influenza virus PB1-F2 protein induces cell death through mi... | MARK AS OVER ANNOTATED | Summary: IPI to influenza A virus PB1-F2 (UniProtKB:P0C0U1). The interaction is genuine and biologically meaningful (it underlies PTPC-dependent apoptosis), but bare 'protein binding' is uninformative as a molecular function. Retain per policy but mark as over-annotated; the functional consequence is captured by the mPTP/apoptosis terms. Supporting Evidence: PMID:16201016 the viral protein uniquely interacts with the inner mitochondrial membrane adenine nucleotide translocator 3 and the outer mitochondrial membrane voltage-dependent anion channel 1 |
| GO:0005515 protein binding | IPI PMID:21370995 Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits ... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' IPI from IntAct (partners VDAC1/P21796 and LRRK2/Q5S007). Uninformative as a molecular function and not a core activity. Retain per policy but mark as over-annotated. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' IPI from a large-scale interactome dataset (partner MTUS2/Q5JR59). Uninformative as a molecular function. Retain per policy but mark as over-annotated. |
| GO:0005515 protein binding | IPI PMID:24725412 Ribosomal protein s15 phosphorylation mediates LRRK2 neurode... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' IPI from IntAct (partner LRRK2/Q5S007) reported in a LRRK2-focused study. Uninformative as a molecular function and not a core activity. Retain per policy but mark as over-annotated. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' IPI from the BioPlex/proteome-scale interactome (multiple partners: TRIM23, AP2B1, TRAF1, KRT31, TRIP6, MTUS2, NOTCH2NLA, TEKT4, LZTS2, MID2). High-throughput and uninformative as a molecular function. Retain per policy but mark as over-annotated. |
| GO:0005515 protein binding | IPI PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to ... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' IPI from a mitochondrial interaction map (partner VDAC1/P21796). Consistent with ANT-VDAC association at the PTPC but uninformative as a molecular function. Retain per policy but mark as over-annotated. |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' IPI from an interactome-perturbation dataset (partner AP2B1/P63010). Uninformative as a molecular function. Retain per policy but mark as over-annotated. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' IPI from a dual proteome-scale interactome (partner SLC25A4/ANT1, P12235). Plausible given ANT-ANT proximity in the inner membrane but uninformative as a molecular function. Retain per policy but mark as over-annotated. |
| GO:0005515 protein binding | IPI PMID:35266954 The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its loc... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' IPI from IntAct (partner LRRK2/Q5S007) in a LRRK2/TRIM1 study. Uninformative as a molecular function. Retain per policy but mark as over-annotated. |
| GO:0005515 protein binding | IPI PMID:40355756 The solute carrier superfamily interactome. | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' IPI from the solute carrier superfamily interactome (partner SLC25A4/ANT1, P12235). Uninformative as a molecular function. Retain per policy but mark as over-annotated. |
| GO:0005471 ATP:ADP antiporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: Core molecular function transferred by sequence similarity from characterized human ANT2 (UniProtKB:P48962). Correct and redundant with the IBA/IEA annotations to the same term. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt Reaction=ADP(in) + ATP(out) = ADP(out) + ATP(in) |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Core localization transferred by similarity from bovine ANT1 (UniProtKB:P02722). Correct; consistent with all other localization evidence. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput detection in a high-confidence human mitochondrial proteome. Correct but non-specific; the inner-membrane term is the informative core location. Keep as non-core. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0016020 membrane | IDA PMID:27641616 TSPO ligands stimulate ZnPPIX transport and ROS accumulation... | MARK AS OVER ANNOTATED | Summary: Direct detection of ANT3 in erythrocyte membranes (at protein level), supporting the UniProt note that a fraction may localize to non-mitochondrial membranes. However 'membrane' is a very general term relative to the specific inner-membrane localization; this experimental annotation is retained but flagged as over-annotated (per policy, not removed). Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt Expressed in erythrocytes (at protein level) |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | MARK AS OVER ANNOTATED | Summary: Detection in a human sperm-nucleus proteome. ANT3 is a highly abundant inner mitochondrial-membrane protein and a common contaminant of nuclear/chromatin fractionation; there is no functional evidence for a nuclear role. Over-annotation. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | KEEP AS NON CORE | Summary: High-throughput detection in isolated human muscle mitochondria (phosphoproteome). Correct but non-specific; keep as non-core relative to the inner-membrane term. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-163215 | ACCEPT | Summary: Reactome TAS for the SLC25A5,6 ADP/ATP exchange reaction; correctly places ANT3 in the mitochondrial inner membrane. Consistent with the core localization. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-168878 | ACCEPT | Summary: Reactome TAS (PB1-F2 binding to ANT3 inducing apoptosis) placing ANT3 in the mitochondrial inner membrane. Correct core localization. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-180905 | ACCEPT | Summary: Reactome TAS placing ANT in the mitochondrial inner membrane. Correct core localization (redundant with other inner-membrane annotations). Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-1955380 | ACCEPT | Summary: Reactome TAS (mitochondrial protein import module) placing ANT3 in the mitochondrial inner membrane. Correct core localization. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9837978 | ACCEPT | Summary: Reactome TAS (LONP1 binds inner-membrane proteins) placing ANT3 in the mitochondrial inner membrane. Correct core localization. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9838004 | ACCEPT | Summary: Reactome TAS (LONP1 degrades inner-membrane proteins) placing ANT3 in the mitochondrial inner membrane. Correct core localization. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0005471 ATP:ADP antiporter activity | NAS PMID:2541251 DNA sequences of two expressed nuclear genes for human mitoc... | ACCEPT | Summary: Author statement (Cozens, Runswick & Walker 1989) of the core ADP/ATP translocase activity. This is the classic human ANT gene/sequence paper and asserts the transport function; correct as the core molecular function. Supporting Evidence: PMID:2541251 It carries ATP from the matrix into the intermembrane space and transports ADP back. |
| GO:0005744 TIM23 mitochondrial import inner membrane translocase complex | TAS PMID:2541251 DNA sequences of two expressed nuclear genes for human mitoc... | UNDECIDED | Summary: Legacy TAS from a 1989 gene-sequencing paper. ANT is a well-known cargo/substrate of the mitochondrial carrier (TIM22) import pathway, not a stable structural subunit of the TIM23 presequence translocase, and the cited paper does not assay translocase-complex membership. This looks like a mis-mapped part_of annotation. Because I cannot access the full text to verify what the curator saw, I mark it UNDECIDED (likely substrate, not subunit) rather than removing an existing annotation. Supporting Evidence: file:human/SLC25A6/SLC25A6-uniprot.txt DNA sequences of two expressed nuclear genes for human mitochondrial |
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Download this section (compressed HTML)Q: Does the TIM23-translocase-complex (GO:0005744) part_of annotation reflect a genuine structural subunit relationship, or is ANT3 merely a carrier-pathway (TIM22) import substrate that was mis-annotated as a translocase component?
Q: Beyond ADP/ATP exchange, does human ANT3 specifically contribute proton-transport (uncoupling/thermogenesis) activity in vivo, and should a dedicated proton-transport MF/BP annotation be added for ANT3 as has been proposed for the ANT family?
Experiment: Reconstitute purified human ANT3 into proteoliposomes and measure ADP/ATP exchange kinetics with carboxyatractyloside and bongkrekic acid controls to directly confirm the antiporter activity currently supported by orthology/ISS.
Experiment: Use isoform-selective knockout/knockdown of SLC25A6 in cells lacking ANT1/ANT2 to test its individual contribution to permeability transition pore opening and apoptosis versus the other ANT paralogs.
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