SLC25A46 is a divergent, "modified" member of the SLC25 mitochondrial carrier family that has been recruited to the outer mitochondrial membrane and has lost the classical solute/metabolite-carrier (transport) function of the family; the charged carrier-signature residues that form the transport pore are not conserved. It is the mammalian counterpart of yeast Ugo1 and is a multi-pass integral protein of the mitochondrial outer membrane. Rather than transporting metabolites, it regulates mitochondrial membrane dynamics, acting in a pro-fission / anti-fusion manner: its loss causes mitochondrial hyperfusion and its overexpression causes fragmentation. It functions as a scaffold/adaptor that physically links the outer-membrane fusion machinery (MFN2, OPA1) to the inner-membrane MICOS (mitochondrial contact site and cristae organizing system) complex, and interacts with the ER membrane protein complex (EMC), thereby helping to organize cristae architecture and to distribute mitochondrial phospholipids via ER-mitochondria contact sites. Downstream consequences of its loss include disrupted cristae, impaired respiration with a specific complex IV assembly defect, and altered phospholipid composition. In humans, biallelic loss-of-function variants cause a neurodegenerative spectrum spanning Charcot-Marie-Tooth type 2 with optic atrophy, Leigh syndrome, and lethal congenital pontocerebellar hypoplasia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000266 mitochondrial fission | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) propagation of the well-supported experimental role of SLC25A46 in mitochondrial fission. This is the core biological process of the gene and is corroborated by multiple experimental annotations. Supporting Evidence: PMID:26168012 SLC25A46 acts in a pro-fission manner |
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic propagation of the outer-mitochondrial-membrane localization. SLC25A46 is an integral OMM protein (unlike the inner-membrane SLC25 carriers), confirmed experimentally by proteinase-K protection and TOM20 colocalization. Correct and specific; accept. Supporting Evidence: PMID:26168012 SLC25A46 is an integral outer membrane protein |
| GO:0061564 axon development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation reflecting the neuronal phenotype seen when SLC25A46 is lost (shortened motor-neuron axons and retinal-ganglion-cell axon defects in zebrafish knockdowns). This is an organismal/tissue-level consequence of a defect in mitochondrial dynamics rather than the cell-autonomous molecular function of the protein, so it is retained as non-core. Supporting Evidence: PMID:26168012 significantly shorter axon tracts, many of which failed to innervate the rostral myotome |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (ARBA/InterPro/UniProt-SubCell) assignment of OMM localization. Fully consistent with the experimental IDA/IMP annotations and with UniProt. Accept. Supporting Evidence: file:human/SLC25A46/SLC25A46-uniprot.txt Mitochondrion outer membrane |
| GO:0007005 mitochondrion organization | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation to the very general parent term "mitochondrion organization". SLC25A46 genuinely controls mitochondrial organization, but the more specific experimental terms (mitochondrial fission, cristae formation) capture the function better. Kept as non-core because it is correct but uninformatively general. Supporting Evidence: file:human/SLC25A46/SLC25A46-uniprot.txt that controls mitochondrial organization |
| GO:0090149 mitochondrial membrane fission | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation to mitochondrial membrane fission, a child that contributes to mitochondrial fission. This is accurate and appropriately specific for a pro-fission OMM protein; accept. Supporting Evidence: PMID:26168012 SLC25A46 acts in a pro-fission manner |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: High-throughput binary-interactome (IPI) annotation to the uninformative term "protein binding". Per curation guidelines this term does not describe an actual molecular function. The annotation is not removed (experimental IPI), but it is marked as over-annotated; the informative interaction-based MF for this gene is captured by protein-containing complex binding (GO:0044877). Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: High-throughput binary-interactome (HuRI/IPI) annotation to bare "protein binding". Uninformative per guidelines; retained (experimental IPI) but marked as over-annotated. The meaningful adaptor/complex-binding function is captured by GO:0044877. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence localization to mitochondrion. Correct but less specific than the experimentally established outer-mitochondrial-membrane localization. Kept as non-core. Supporting Evidence: PMID:26168012 SLC25A46 is an integral outer membrane protein |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput mitochondrial-proteome localization to mitochondrion. Consistent with the mitochondrial localization but non-specific; kept as non-core relative to the OMM annotation. |
| GO:0000266 mitochondrial fission | IMP PMID:27390132 SLC25A46 is required for mitochondrial lipid homeostasis and... | ACCEPT | Summary: IMP (patient mutation / siRNA) annotation: loss of SLC25A46 causes mitochondrial hyperfusion and its restoration rescues the network, placing it upstream of fission. Core process; accept. Supporting Evidence: PMID:27390132 SLC25A46 functions upstream of the MICOS complex and is required for the maintenance of mitochondrial cristae architecture |
| GO:0005741 mitochondrial outer membrane | IMP PMID:27390132 SLC25A46 is required for mitochondrial lipid homeostasis and... | ACCEPT | Summary: Experimental (carbonate extraction / proteinase-K protection) demonstration that SLC25A46 is an integral outer mitochondrial membrane protein. Accept. Supporting Evidence: PMID:27390132 SLC25A46 behaves as an outer membrane protein |
| GO:0008535 respiratory chain complex IV assembly | IMP PMID:27390132 SLC25A46 is required for mitochondrial lipid homeostasis and... | KEEP AS NON CORE | Summary: Subject fibroblasts with the T142I SLC25A46 mutation show a specific complex IV (COX) assembly defect. This is a real but secondary/downstream consequence of disrupted cristae architecture and membrane dynamics rather than a direct function of SLC25A46 in COX assembly, so it is kept as non-core. Supporting Evidence: PMID:27390132 assembly defect in complex IV in subject fibroblasts |
| GO:0042407 cristae formation | IMP PMID:27390132 SLC25A46 is required for mitochondrial lipid homeostasis and... | ACCEPT | Summary: Loss of SLC25A46 disrupts the MICOS complex and produces markedly shortened cristae, and the protein is required for maintenance of cristae architecture. This is a core structural role; accept. Supporting Evidence: PMID:27390132 SLC25A46 functions upstream of the MICOS complex and is required for the maintenance of mitochondrial cristae architecture |
| GO:0055091 phospholipid homeostasis | IMP PMID:27390132 SLC25A46 is required for mitochondrial lipid homeostasis and... | KEEP AS NON CORE | Summary: Subject mitochondria show altered phospholipid composition, consistent with a role in ER-mitochondria lipid transfer via the EMC. This is a genuine but downstream lipid-distribution consequence of SLC25A46 function at ER-mito contact sites rather than its primary molecular activity; kept as non-core. Supporting Evidence: PMID:27390132 phospholipid composition is altered in subject mitochondria |
| GO:0065003 protein-containing complex assembly | IMP PMID:27390132 SLC25A46 is required for mitochondrial lipid homeostasis and... | KEEP AS NON CORE | Summary: IMP annotation reflecting that SLC25A46 loss perturbs assembly of complexes it associates with (MICOS; and indirectly OXPHOS complex IV). General and largely a downstream/indirect effect; the specific, better-supported roles are cristae formation and complex-binding. Kept as non-core. Supporting Evidence: PMID:27390132 The MICOS complex is disrupted in subject |
| GO:0044877 protein-containing complex binding | IDA PMID:27390132 SLC25A46 is required for mitochondrial lipid homeostasis and... | ACCEPT | Summary: IDA (co-immunoprecipitation / cross-linking) demonstration that SLC25A46 binds the fusion machinery (MFN2, OPA1) and core MICOS components (MIC60/IMMT, MIC19), as well as the EMC. This complex-binding/adaptor activity is the honest, informative molecular function of this transport-dead carrier and is the preferred MF over bare "protein binding". Accept as core. Supporting Evidence: PMID:27390132 components of the MICOS complex (MIC60, MIC19) |
| GO:0000266 mitochondrial fission | IDA PMID:26168012 Mutations in SLC25A46, encoding a UGO1-like protein, cause a... | ACCEPT | Summary: Direct assay: SLC25A46 overexpression fragments the mitochondrial network and knockdown causes hyperfusion, establishing a pro-fission role. Core process; accept. Supporting Evidence: PMID:26168012 SLC25A46, unlike ANT2, leads to mitochondrial fragmentation in cell lines |
| GO:0000266 mitochondrial fission | IMP PMID:27543974 Loss of function of SLC25A46 causes lethal congenital pontoc... | ACCEPT | Summary: IMP: mutant/knockdown SLC25A46 yields abnormally elongated mitochondria rescued by wild-type but not mutant mRNA; overexpression fragments the network, confirming the pro-fission function. Core process; accept. Supporting Evidence: PMID:27543974 SLC25A46 is a pro-fission mitochondrial outer membrane protein important in the regulation of mitochondrial dynamics |
| GO:0005741 mitochondrial outer membrane | IMP PMID:27543974 Loss of function of SLC25A46 causes lethal congenital pontoc... | ACCEPT | Summary: Functional study confirming mitochondrial (outer-membrane) localization of SLC25A46. Consistent with the other localization evidence; accept. Supporting Evidence: PMID:27543974 SLC25A46 is a pro-fission mitochondrial outer membrane protein important in the regulation of mitochondrial dynamics |
| GO:0005515 protein binding | IPI PMID:26168012 Mutations in SLC25A46, encoding a UGO1-like protein, cause a... | MODIFY | Summary: IPI annotation (SLC25A46 vs IMMT/mitofilin, Q16891). The interaction itself is real and functionally central, but the term "protein binding" is uninformative. Rather than remove an experimental IPI, this is modified to the more specific, evidenced molecular function protein-containing complex binding (SLC25A46 binds the MICOS core organizer mitofilin/MIC60). Proposed replacements: protein-containing complex binding Supporting Evidence: PMID:26168012 Mitofilin was among the top hits in this assay |
| GO:0005741 mitochondrial outer membrane | IDA PMID:26168012 Mutations in SLC25A46, encoding a UGO1-like protein, cause a... | ACCEPT | Summary: Direct immunocytochemistry (TOM20 colocalization) plus proteinase-K protection establishing integral outer-mitochondrial-membrane localization. Core location; accept. Supporting Evidence: PMID:26168012 co-localizes more with the MOM marker (TOM20) |
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Download this section (compressed HTML)Q: Does SLC25A46 have any residual transport activity (e.g. as a channel or lipid conduit) at the outer membrane, or is it entirely transport-dead and purely a structural/adaptor protein?
Q: Is the pro-fission role exerted directly by scaffolding the fission machinery, or indirectly through effects on cristae/lipid homeostasis at ER-mitochondria contacts?
Experiment: Reconstitute purified SLC25A46 in proteoliposomes and assay for solute/lipid transport to formally confirm loss of carrier activity.
Experiment: Structure-guided mutagenesis of the SLC25A46-MICOS and SLC25A46-EMC interfaces to separate its cristae/lipid role from its fission role and test each in the mitochondrial-network phenotype.
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