SLC25A46 (Q96AG3) — review notes
Summary of gene function
SLC25A46 is a divergent, "modified" member of the SLC25 mitochondrial carrier
family that has been recruited to the outer mitochondrial membrane (OMM) and
has lost the classical solute/metabolite-carrier (transport) function of the
family. It is the mammalian counterpart of yeast Ugo1 and regulates
mitochondrial membrane dynamics — acting in a pro-fission / anti-fusion
manner — and controls cristae architecture (via the MICOS complex) and
mitochondrial phospholipid distribution (via ER–mitochondria contact / EMC
machinery). Loss of function causes an autosomal-recessive neurodegenerative
spectrum: Charcot–Marie–Tooth type 2 with optic atrophy (HMSN6B / "optic atrophy
spectrum disorder"), Leigh syndrome, and lethal congenital pontocerebellar
hypoplasia (PCH1E).
Key evidence (with provenance)
It is a modified/degenerate carrier that has lost transport function
- SLC25A46 is a member of the SLC25 (mitochondrial solute carrier) family but the
carrier consensus residues are absent, so it is not a conventional transporter:
PMID:27390132 and
PMID:27390132.
- UniProt classifies it as a member of the mitochondrial carrier (TC 2.A.29) family
by similarity only, while naming it a "Mitochondrial outer membrane protein":
[file:human/SLC25A46/SLC25A46-uniprot.txt "Belongs to the mitochondrial carrier (TC 2.A.29) family."].
- Carrier homologs recruited to the OMM (Ugo1, MTCH1, MTCH2) perform functions
"unrelated to metabolite transport": PMID:26168012;
SLC25A46 is "a highly derived carrier protein": PMID:26168012.
- Implication: SLC25 family / InterPro transmembrane-transporter MF propagations to
SLC25A46 would be over-annotations. (GOA currently carries no transporter-activity
MF annotation for SLC25A46 — the only MF terms present are protein binding /
protein-containing complex binding.)
Subcellular location = OUTER mitochondrial membrane
Molecular role = protein–protein / complex interactions, not catalysis
- Interacts with mitofilin/IMMT (MIC60): PMID:26168012.
- Interacts with the fusion machinery (MFN2, OPA1) and MICOS core components:
PMID:27390132;
PMID:27390132.
Note: in the Abrams paper SLC25A46 did NOT co-IP MFN2/OPA1 in that assay
PMID:26168012;
the Janer paper (cross-linking IP) detected the MFN2/OPA1/MICOS interactions.
- Interacts with the ER membrane protein complex (EMC), linking to ER→mito lipid transfer:
PMID:27390132.
- So the honest MF is an adaptor / protein-containing-complex-binding role
(GO:0044877), NOT transporter activity. Bare "protein binding" (GO:0005515) IPI
annotations are uninformative; the specific complex-binding term is preferred.
Core biological process = pro-fission regulation of mitochondrial dynamics
Downstream consequences: cristae, respiration, phospholipids
- Loss disrupts MICOS → shortened cristae; secondary complex IV (COX) assembly defect:
PMID:27390132.
- Altered mitochondrial phospholipid composition (ER–mito lipid transfer role):
PMID:27390132;
PMID:27390132.
- These (complex IV assembly, phospholipid homeostasis) are best treated as
DOWNSTREAM/secondary effects of the primary membrane-dynamics defect, not the
core molecular function. IMP annotations to them (respiratory chain complex IV
assembly; phospholipid homeostasis) are kept but as non-core.
Disease
- HMSN6B (CMT2 + optic atrophy), MIM 616505 [file:human/SLC25A46/SLC25A46-uniprot.txt
"Neuropathy, hereditary motor and sensory, 6B, with optic"].
- PCH1E (lethal congenital pontocerebellar hypoplasia), MIM 619303
[PMID:27543974 title]; severity inversely correlates with mutant-protein stability.
- Leigh syndrome (T142I) [PMID:27390132 title].
Annotation-review decisions (rationale highlights)
- Transporter MF: none present in GOA → nothing to remove; but flagged in notes
that any SLC25-family transporter MF would be an over-annotation (transport-dead).
- protein binding (GO:0005515) IPI (IntAct/interactome, and PMID:26168012 vs IMMT):
never REMOVE per policy; the numerous binary-interactome IPIs (PMID:25416956,
PMID:32296183) are MARK_AS_OVER_ANNOTATED (bare, uninformative "protein binding");
the mitofilin/IMMT IPI (PMID:26168012) is MODIFY → protein-containing complex
binding (functionally meaningful adaptor interaction).
- protein-containing complex binding (GO:0044877) IDA (PMID:27390132): ACCEPT —
the defining, informative MF (binds MFN2/OPA1/MICOS/EMC).
- mitochondrial fission (GO:0000266) (IDA PMID:26168012, IMP PMID:27390132/27543974,
IBA): ACCEPT as core BP.
- cristae formation (GO:0042407) IMP: ACCEPT (core downstream architecture role).
- mitochondrial outer membrane (GO:0005741) (IDA/IMP/IBA/IEA): ACCEPT.
- mitochondrion (GO:0005739) (IDA HPA; HTP): KEEP_AS_NON_CORE (correct but less
specific than OMM).
- mitochondrial membrane fission (GO:0090149) IEA: ACCEPT (accurate, more specific
membrane-level fission term; consistent with mitochondrial fission).
- mitochondrion organization (GO:0007005) IEA (ARBA): KEEP_AS_NON_CORE (correct but
very general parent of the specific fission/cristae terms).
- respiratory chain complex IV assembly (GO:0008535) IMP, phospholipid
homeostasis (GO:0055091) IMP, protein-containing complex assembly (GO:0065003)
IMP: KEEP_AS_NON_CORE — real but downstream/secondary consequences of the membrane
dynamics defect, not the primary function.
- axon development (GO:0061564) IBA: KEEP_AS_NON_CORE — organismal/neuronal
phenotype (motor-neuron/RGC axon defects on knockdown) rather than the cell-level
molecular role; reflects tissue vulnerability to loss of mitochondrial dynamics.