SLC25A1 (tricarboxylate transport protein, mitochondrial; also called the mitochondrial citrate carrier CIC, citrate transport protein CTP, or tricarboxylate carrier) is a member of the mitochondrial carrier (SLC25) family. It is a multi-pass protein of the mitochondrial inner membrane built from three Solcar repeats and six transmembrane helices, functioning as an electroneutral antiporter (secondary active transporter). Its primary physiological role is to export citrate (and isocitrate) from the mitochondrial matrix to the cytosol in exchange for cytosolic malate; it can also exchange citrate for phosphoenolpyruvate, cis-aconitate, and, less efficiently, trans-aconitate, maleate and succinate. By supplying cytosolic citrate, SLC25A1 feeds ATP-citrate lyase (ACLY) to generate cytosolic acetyl-CoA, the building block for fatty-acid, sterol, dolichol and ubiquinone biosynthesis; cytosolic citrate also contributes to regulation of glycolysis and protein acetylation. SLC25A1 operates as a monomer with a ping-pong (consecutive) exchange mechanism. The gene lies in the chromosome 22q11 DiGeorge/velocardiofacial critical region. Loss-of-function variants that abolish or reduce citrate transport cause the autosomal recessive neurometabolic disorder combined D-2- and L-2-hydroxyglutaric aciduria (D2L2AD) and a presynaptic congenital myasthenic syndrome (CMS23).
Definition: Enables the transfer of citrate from one side of a membrane to the other in exchange for malate transported in the opposite direction (citrate/malate antiport).
Justification: The physiologically dominant activity of SLC25A1 is electroneutral antiport of matrix citrate for cytosolic malate (the citrate-malate shuttle), but GO currently provides only citrate:succinate (GO:0015515) and citrate:2-oxoglutarate (GO:0180056) antiporter terms. A citrate:malate antiporter term would allow the correct, most specific molecular function to be annotated for the mammalian citrate carrier.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Phylogenetic (IBA) placement in the mitochondrion. SLC25A1 is indeed a mitochondrial protein, but its precise, well-supported location is the mitochondrial inner membrane (ISS/IEA). "Mitochondrion" is a correct but broad parent term that is superseded by the inner-membrane annotation. Reason: True but uninformative relative to the specific mitochondrial inner membrane location; keep the inner-membrane term as the core localization. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrion inner membrane |
| GO:0071913 citrate secondary active transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) call of the specific molecular function. This is the correct and most specific molecular function: SLC25A1 is a secondary active (antiport-driven) citrate transmembrane transporter. Independently supported by IDA (PMID:29031613). This is the core molecular function of the gene. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrial electroneutral antiporter that exports citrate |
| GO:0006843 mitochondrial citrate transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) call of the biological process. Correct and specific: SLC25A1 mediates mitochondrial citrate transmembrane transport (export of matrix citrate to the cytosol). Independently supported by IDA (PMID:29031613). This is the core biological process. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrial electroneutral antiporter that exports citrate |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell-mapping (IEA) location. SLC25A1 is a multi-pass protein of the mitochondrial inner membrane, consistent with the SLC25 carrier family. This is the core cellular location and is independently supported by ISS from the mouse ortholog (Q8JZU2). Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrion inner membrane |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO (IEA) mapping from the mitochondrial carrier domain (IPR002067) to the generic process "transmembrane transport". Correct but very broad; superseded by the specific mitochondrial citrate transmembrane transport term. Reason: Generic domain-derived parent term; retain the specific citrate-transport BP as core. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Belongs to the mitochondrial carrier (TC 2.A.29) family. |
| GO:0071422 succinate transmembrane transport | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Automatically inferred (IEA, inter-ontology logical inference) from the citrate:succinate antiporter activity (GO:0015515). Succinate is only a minor/lesser substrate of SLC25A1; the physiologically relevant counter-substrate is malate, and succinate transport is not a core function. This over-states the succinate role. Reason: Derived from the citrate:succinate antiporter term, but succinate is only transported "to a lesser extent"; not a core transport role for this carrier. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Also able to mediate the exchange of citrate for |
| GO:0055085 transmembrane transport | TAS Reactome:R-HSA-9955298 | MARK AS OVER ANNOTATED | Summary: Reactome (TAS) placement in the generic "SLC-mediated transport of organic anions" pathway. Correct but very broad; superseded by the specific mitochondrial citrate transmembrane transport term. Reason: Generic pathway-level parent process; retain the specific citrate-transport BP as core. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer from the mouse ortholog (UniProtKB:Q8JZU2) placing SLC25A1 in the mitochondrial inner membrane. Consistent with the SLC25 carrier family and the IEA SubCell location. Core cellular location. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrion inner membrane |
| GO:0015515 citrate:succinate antiporter activity | EXP PMID:29031613 Pathogenic mutations of the human mitochondrial citrate carr... | MODIFY | Summary: Experimental (EXP) annotation to the very specific citrate:succinate antiporter activity. Majd et al. did assay citrate/succinate exchange, but they showed the carrier "predominantly transports citrate, isocitrate, cis-aconitate, phosphoenolpyruvate and malate", with succinate only a lesser substrate; the primary physiological antiport is citrate/malate. Naming succinate as the counter-substrate mislabels the core activity. The most appropriate, best-supported molecular function is the more general secondary-active citrate transporter term (GO:0071913), which does not over-commit to a minor counter-substrate. Reason: Succinate is only a minor substrate; the physiologically dominant exchange is citrate for malate/isocitrate/PEP. Replace with the secondary-active citrate transporter MF, which is accurate without asserting the wrong counter-substrate. (GO currently has no citrate:malate antiporter term.) Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: citrate secondary active transmembrane transporter activity Supporting Evidence: PMID:29031613 the human citrate carrier predominantly transports citrate, isocitrate, |
| GO:0031966 mitochondrial membrane | IMP PMID:39881208 SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ... | MARK AS OVER ANNOTATED | Summary: IMP annotation (ferroptosis study) placing SLC25A1 activity at the mitochondrial membrane. Correct but broader than the specific mitochondrial inner membrane; retained as a non-core (true parent) localization. Reason: "Mitochondrial membrane" is a true but broad parent of the specific inner-membrane location; keep GO:0005743 as the core location. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrion inner membrane |
| GO:0110076 negative regulation of ferroptosis | IMP PMID:39881208 SLC25A1 and ACLY maintain cytosolic acetyl-CoA and regulate ... | KEEP AS NON CORE | Summary: IMP annotation from a CRISPR screen identifying SLC25A1 as a ferroptosis regulator. SLC25A1 drives citrate export that fuels ACLY-dependent cytosolic acetyl-CoA, which sustains FSP1 acetylation and thereby suppresses ferroptosis. This is a genuine but downstream/contextual consequence of the core citrate-export function, not a core evolved function of the carrier. Reason: Real biology in cancer cells but a downstream metabolic-signalling consequence of citrate transport; not the core molecular role of the carrier. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: PMID:39881208 identify SLC25A1 as a critical ferroptosis PMID:39881208 SLC25A1 drives citrate export from the |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | MARK AS OVER ANNOTATED | Summary: High-throughput (HTP) mitochondrial-proteome detection placing SLC25A1 in the mitochondrion. Consistent with the known localization but broad; superseded by the specific mitochondrial inner membrane location. Reason: True but uninformative parent relative to the mitochondrial inner membrane; keep GO:0005743 as core. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrion inner membrane |
| GO:0015142 tricarboxylic acid transmembrane transporter activity | TAS Reactome:R-HSA-372449 | KEEP AS NON CORE | Summary: Reactome (TAS) annotation to tricarboxylic acid transmembrane transporter activity, from the hypothetical PEP/citrate exchange reaction. This is a correct broader parent of the specific citrate transporter activity; kept as a non-core (true parent) molecular function. Reason: Correct but broader parent of the specific citrate secondary-active transporter activity (GO:0071913), which is retained as core. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Also able to mediate the exchange of citrate for |
| GO:0015142 tricarboxylic acid transmembrane transporter activity | TAS Reactome:R-HSA-75849 | KEEP AS NON CORE | Summary: Reactome (TAS) annotation to tricarboxylic acid transmembrane transporter activity, from the SLC25A1 citrate/malate exchange reaction. Correct broader parent of the specific citrate transporter activity; kept as a non-core (true parent) molecular function. Reason: Correct but broader parent of the specific citrate secondary-active transporter activity (GO:0071913), which is retained as core. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrial electroneutral antiporter that exports citrate |
| GO:0006843 mitochondrial citrate transmembrane transport | IDA PMID:29031613 Pathogenic mutations of the human mitochondrial citrate carr... | ACCEPT | Summary: Direct experimental (IDA) demonstration of mitochondrial citrate transmembrane transport: Majd et al. reconstituted the carrier and measured citrate transport, showing pathogenic variants abolish or severely reduce it. This is the core biological process for SLC25A1. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:29031613 mutations abolish transport of citrate completely, whereas the other three |
| GO:0015142 tricarboxylic acid transmembrane transporter activity | IDA PMID:29031613 Pathogenic mutations of the human mitochondrial citrate carr... | KEEP AS NON CORE | Summary: Direct experimental (IDA) annotation to tricarboxylic acid transmembrane transporter activity. Correct: SLC25A1 transports the tricarboxylates citrate, isocitrate and cis-aconitate. This is a true broader parent of the specific citrate secondary-active transporter activity; kept as non-core. Reason: Correct but broader parent of GO:0071913 (retained as core); the carrier does transport multiple tricarboxylates, so this term is accurate at a higher level. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Supporting Evidence: PMID:29031613 the human citrate carrier predominantly transports citrate, isocitrate, |
| GO:0071913 citrate secondary active transmembrane transporter activity | IDA PMID:29031613 Pathogenic mutations of the human mitochondrial citrate carr... | ACCEPT | Summary: Direct experimental (IDA) demonstration that SLC25A1 is a citrate secondary active transmembrane transporter (electroneutral antiport with a Km for citrate of 7.5 uM). This is the most specific, best-supported molecular function and the core function of the gene. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt KM=7.5 uM for citrate |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | MARK AS OVER ANNOTATED | Summary: High-throughput (HDA) proteomic detection of SLC25A1 in a human sperm-nucleus preparation. SLC25A1 is a mitochondrial inner-membrane citrate carrier with no known nuclear function; this is most consistent with a proteomic contaminant/co-fractionation and is an over-annotation. Reason: Mass-spec detection in a sperm-nucleus fraction; not the site of function for an inner-membrane carrier. No supporting biology for a nuclear role. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: COMPARTMENT OR COMPLEX MISMATCH Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrion inner membrane |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: High-throughput (HDA) proteomic detection of SLC25A1 in urinary exosomes. This is a large-scale exosome-catalogue detection, not evidence of a functional extracellular location for a mitochondrial inner-membrane carrier; an over-annotation. Reason: Bulk exosome proteomics detection; not the functional compartment of an inner-membrane citrate carrier. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: COMPARTMENT OR COMPLEX MISMATCH Supporting Evidence: file:human/SLC25A1/SLC25A1-uniprot.txt Mitochondrion inner membrane |
| GO:0015137 citrate transmembrane transporter activity | TAS PMID:8666394 Localization of the human mitochondrial citrate transporter ... | KEEP AS NON CORE | Summary: TAS annotation to citrate transmembrane transporter activity from the original gene-mapping paper, which identified the cloned cDNA as the human mitochondrial citrate transporter. This is a correct broader parent of the specific citrate secondary-active transporter activity; kept as non-core. Reason: Correct but broader parent of GO:0071913 (retained as core); accurately reflects the citrate transporter identity established at cloning. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Supporting Evidence: PMID:8666394 human mitochondrial citrate transporter protein. |
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Download this section (compressed HTML)Q: Under physiological conditions, what is the predominant counter-substrate exchanged for exported citrate in different human tissues (malate vs phosphoenolpyruvate vs isocitrate)?
Experiment: Reconstitute purified human SLC25A1 in proteoliposomes and quantify exchange rates and apparent affinities for citrate against each candidate counter-substrate (malate, isocitrate, PEP, cis-aconitate, succinate) to rank physiological relevance and confirm the primary citrate/malate antiport.
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