SLC25A3 is the mitochondrial phosphate carrier (PiC; also PHC, PTP), a member of the SLC25 mitochondrial carrier family (TC 2.A.29). It is a nuclear-encoded, multi-pass integral protein of the mitochondrial inner membrane built from the characteristic tripartite (three-repeat) Solcar fold with six transmembrane helices, and is synthesized with an N-terminal transit peptide that is cleaved on mitochondrial import. Its principal function is to import inorganic phosphate (Pi) from the intermembrane space into the mitochondrial matrix by proton- coupled symport (phosphate/H+ symport, equivalently described as Pi/OH- exchange). The imported phosphate is the substrate used by F1Fo-ATP synthase (Complex V) to phosphorylate ADP to ATP, making PiC an essential component of oxidative phosphorylation. It functions as a transporter, not an enzyme. A secondary, more recently characterized activity is import of copper ions (as anionic Cu(I) complexes) to supply the matrix copper pool required for cytochrome c oxidase (Complex IV) biogenesis. Two tissue-differentially expressed alternative-splicing isoforms (A and B) differ in part of the first transmembrane region. Loss-of-function variants cause mitochondrial phosphate carrier deficiency, an autosomal-recessive disorder of oxidative phosphorylation with lactic acidosis, hypertrophic cardiomyopathy and hypotonia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005315 phosphate transmembrane transporter activity | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) inference of phosphate transmembrane transporter activity, propagated across the SLC25 phosphate-carrier clade (yeast Pic2/ Mir1, Drosophila, plant orthologs). This is correct and captures the substrate specificity, but is a more general parent of the specific proton-coupled mechanism. The physiological activity of SLC25A3 is a phosphate:proton symport (GO:0015317), which is the core molecular function. Kept as a correct, non-core parent term. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt Mediates proton-coupled symport of phosphate ions necessary for |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that PiC is active in the mitochondrial inner membrane. This is the correct, core subcellular location for this SLC25 carrier, corroborated by UniProt (Mitochondrion inner membrane; Multi-pass membrane protein) and by experimental localization data. Accept. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0035435 phosphate ion transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference of the phosphate ion transmembrane transport process. This is the core biological process for the phosphate carrier and is directly supported by the UniProt function description. Accept. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt Mediates proton-coupled symport of phosphate ions necessary for |
| GO:0005315 phosphate transmembrane transporter activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO electronic annotation (IPR044677, SLC25A3/Pic2/Mir1-like) of phosphate transmembrane transporter activity. Correct substrate-level MF, consistent with the IBA annotation, but a general parent of the specific phosphate:proton symporter activity. Kept as non-core. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt Mediates proton-coupled symport of phosphate ions necessary for |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation to mitochondrion. Correct but less specific than the curated mitochondrial inner-membrane location. Keep as a correct, non-core (less granular) location. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation from the UniProt Subcellular Location mapping (SL-0168), consistent with the curated inner-membrane localization. Accept. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0016020 membrane | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Generic "membrane" from ARBA. Uninformative parent of the specific mitochondrial inner-membrane location. Correct (it is a polytopic membrane protein) but too general to convey the functional location. Marked as over-annotated. Reason: Root-level "membrane" is uninformative; superseded by the specific mitochondrial inner-membrane annotation. |
| GO:1902600 proton transmembrane transport | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Proton transmembrane transport, inferred by inter-ontology link (GOC) from the phosphate:proton symporter activity. This reflects the co-transported H+ of the phosphate/H+ symport rather than an independent proton-pumping function. Correct but secondary; kept as non-core. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt Mediates proton-coupled symport of phosphate ions necessary for |
| GO:1990547 mitochondrial phosphate ion transmembrane transport | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation of mitochondrial phosphate ion transmembrane transport. This is the specific, organelle-resolved core biological process for PiC (import of Pi across the mitochondrial inner membrane) and is directly supported by UniProt. Accept. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt Mediates proton-coupled symport of phosphate ions necessary for |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Direct immunofluorescence localization (HPA) to mitochondrion. Correct core compartment, though less granular than the inner-membrane term. Keep as a correct, non-core location. |
| GO:0005743 mitochondrial inner membrane | EXP PMID:40652815 Human cytomegalovirus protein UL13 targets to mitochondria t... | ACCEPT | Summary: Experimental inner-membrane localization from the HCMV UL13 cuproptosis study, which explicitly describes SLC25A3 as the inner mitochondrial membrane copper transporter and shows UL13 associating with it there. This is the correct core location. Accept. Supporting Evidence: PMID:40652815 the inner mitochondrial membrane copper transporter SLC25A3, |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput mitochondrial-proteome (MitoCoP) localization to mitochondrion. Corroborates the mitochondrial location but is less specific than the inner-membrane term. Keep as non-core. |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity (ISS) transfer of the inner-membrane location from the bovine ortholog (UniProtKB:P12234). Consistent with the curated core location. Accept. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane |
| GO:0015317 phosphate:proton symporter activity | ISS GO_REF:0000024 | ACCEPT | Summary: Core molecular function. Sequence-similarity (ISS) transfer from the bovine phosphate carrier (UniProtKB:P12234-1) of phosphate:proton symporter activity. This matches the UniProt-curated catalytic (transport) reaction phosphate(in) + H(+)(in) = phosphate(out) + H(+)(out) and the FUNCTION description of proton-coupled phosphate symport. It is the most specific, mechanistically accurate MF for PiC (a transporter, not an enzyme). Accept. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt phosphate(in) + H(+)(in) = phosphate(out) + H(+)(out) file:human/SLC25A3/SLC25A3-uniprot.txt Mediates proton-coupled symport of phosphate ions necessary for |
| GO:0044877 protein-containing complex binding | IDA PMID:23209302 KIF14 negatively regulates Rap1a-Radil signaling during brea... | MARK AS OVER ANNOTATED | Summary: Bare "protein-containing complex binding" (IDA, assigned by MGI). The cited cached publication is the KIF14/Radil breast-cancer signaling paper; its full text does not mention SLC25A3, the phosphate carrier, or Q00325, so the supporting evidence for this human annotation is not verifiable from the cache (the MGI IDA presumably derives from a mouse Slc25a3 context). Per policy, an experimental IDA is not removed. The term is uninformative as a molecular function and cannot be confirmed for SLC25A3 here, so it is marked as over-annotated rather than accepted. Reason: Bare complex-binding term conveys no specific molecular function, and the cited cached publication does not visibly support it for SLC25A3. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: Generic "membrane" from a high-throughput NK-cell membrane proteome. An integral inner-mitochondrial-membrane carrier is expected in bulk membrane preparations, but the term is uninformative and the study provides no SLC25A3-specific location beyond generic membrane. Marked as over-annotated. Reason: Root-level "membrane" from a bulk membrane proteome; uninformative and superseded by the specific mitochondrial inner-membrane location. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: Detection in a urinary-exosome proteome (high-throughput MS). Mitochondrial inner-membrane proteins are frequent contaminants of exosome/vesicle preparations, and there is no evidence that this integral inner-membrane carrier functions in extracellular exosomes. Not a credible physiological location. Marked as over-annotated (HDA, not removed). Reason: Exosome detection in a large-scale proteome most likely reflects mitochondrial carry-over; inconsistent with the carrier's inner-membrane topology and function. |
| GO:0005739 mitochondrion | TAS PMID:8168843 Chromosomal localization of genes required for the terminal ... | KEEP AS NON CORE | Summary: Traceable-author statement (chromosomal-mapping paper) placing the phosphate carrier (PHC) in the mitochondrion, where it transports phosphate into the matrix as one of the three nuclear-encoded components of the terminal steps of oxidative phosphorylation. Consistent with the core compartment (less granular than inner membrane). Keep as non-core. Supporting Evidence: PMID:8168843 The terminal steps of oxidative phosphorylation include transport of phosphate |
| GO:0005743 mitochondrial inner membrane | TAS PMID:8144629 The sequences of human and bovine genes of the phosphate car... | ACCEPT | Summary: TAS from the human/bovine phosphate-carrier gene-sequencing paper, whose abstract describes the phosphate carrier of the inner membranes of mitochondria. Consistent with the core inner-membrane location. Accept. Supporting Evidence: PMID:8144629 phosphate carrier from the |
| GO:0005886 plasma membrane | TAS PMID:8144629 The sequences of human and bovine genes of the phosphate car... | MARK AS OVER ANNOTATED | Summary: Plasma-membrane annotation attributed to the phosphate-carrier gene paper, whose abstract in fact concerns the carrier of the inner membranes of mitochondria, not the plasma membrane. SLC25A3 is an integral inner- mitochondrial-membrane carrier; plasma-membrane localization is inconsistent with all other evidence and its multi-pass mitochondrial topology, and is very likely an early mis-annotation. Marked as over-annotated (TAS, not removed). Reason: Contradicted by the established inner-mitochondrial-membrane localization; the cited paper describes inner-membrane, not plasma-membrane, transport. |
| GO:0015317 phosphate:proton symporter activity | TAS PMID:8144629 The sequences of human and bovine genes of the phosphate car... | ACCEPT | Summary: TAS for phosphate:proton symporter activity, matching the core molecular function. The cited paper characterizes the human/bovine mitochondrial phosphate carrier, whose proton-coupled phosphate symport is the defining activity. Accept. Supporting Evidence: file:human/SLC25A3/SLC25A3-uniprot.txt phosphate(in) + H(+)(in) = phosphate(out) + H(+)(out) |
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