SLC25A46

SLC25A46 is a modified solute-carrier-family protein embedded in the outer mitochondrial membrane that regulates the balance between mitochondrial fusion and fission and maintains cristae architecture (PMID:26168012, PMID:27390132, PMID:36977595). It localizes to discrete puncta at mitochondrial branch points and tubule tips that demarcate essentially all fission and fusion events, where it co-localizes with DRP1 and OPA1 and physically engages the fusion machinery (PMID:36977595). SLC25A46 binds the outer-membrane fusogens MFN1/MFN2 via their cytosolic face and the inner-membrane GTPase OPA1 through OPA1's bundle signaling element, and it interacts with the MICOS subunit MIC60 (PMID:27390132, PMID:30178502, PMID:39222684, PMID:38234813); loss of SLC25A46 stabilizes and increases oligomerization of MFN1/MFN2, shifting the network toward hyperfusion, while disrupting MICOS integrity and shortening cristae (PMID:28057766, PMID:27390132). Through associations with ER membrane components and lipid-transfer proteins at interorganellar contact sites, SLC25A46 also governs mitochondrial phospholipid composition and ER-mitochondria coupling (PMID:27390132, PMID:36977595). Disease-causing missense mutants act through two mechanisms—destabilization, with rapid clearance via MULAN/MARCH5-mediated ubiquitylation and P97/proteasome degradation independent of mitophagy and apoptosis, or selective disruption of partner interactions such as the SLC25A46-MIC60 interface (PMID:28057766, PMID:30178502). Across zebrafish, mouse, Drosophila, and C. elegans models, SLC25A46 loss perturbs mitochondrial dynamics, metabolism, and neuronal integrity, and patient mutations underlie a neurodegenerative phenotype spectrum (PMID:26168012, PMID:27543974, PMID:28376083, PMID:40444356).

1. 2015 High

   Established SLC25A46 as an outer-membrane protein whose loss promotes mitochondrial hyperfusion, reframing a 'solute carrier' as a dynamics regulator and linking it to a human neuropathy.

   Evidence Co-IP, subcellular fractionation, zebrafish loss-of-function, and whole-exome sequencing of patient families

   PMID:26168012

   Open questions at the time

   • Did not define which dynamics machinery SLC25A46 acts through
   • Mechanism linking MIC60 binding to cristae control unresolved
2. 2016 High

   Mapped SLC25A46's interaction network to MFN2, OPA1 and MICOS and connected its loss to cristae collapse, respiratory failure, altered ER morphology and shifted phospholipid composition, implicating it in mitochondria-ER lipid handling.

   Evidence Co-IP, patient-fibroblast respiration and EM cristae analysis, ER imaging, and lipidomics

   PMID:27390132

   Open questions at the time

   • Did not establish whether SLC25A46 directly transfers lipids
   • Direction of MFN/OPA1 regulation not mechanistically resolved
3. 2016 Medium

   Demonstrated a pro-fission activity via overexpression-induced fragmentation and zebrafish rescue, and tied clinical severity to mutant protein stability.

   Evidence Zebrafish morpholino knockdown with mRNA rescue and overexpression morphology assays

   PMID:27543974

   Open questions at the time

   • Single lab
   • Did not reconcile pro-fission overexpression with hyperfusion-on-loss phenotype mechanistically
4. 2017 High

   Provided the biochemical mechanism for hyperfusion—SLC25A46 loss stabilizes and oligomerizes MFN1/MFN2—and defined how unstable disease mutants are eliminated through MULAN/MARCH5 ubiquitylation and P97/proteasome degradation.

   Evidence Co-IP, ubiquitylation assays, BN-PAGE oligomerization assays, and E3-ligase epistasis in cultured cells

   PMID:28057766

   Open questions at the time

   • How SLC25A46 restrains mitofusin oligomerization molecularly is unknown
   • Did not establish whether degradation pathway operates on wild-type protein turnover
5. 2017 Medium

   Confirmed in vivo that SLC25A46 loss causes fusion/fission imbalance, disrupted cristae and metabolic disturbance in a mammalian organism.

   Evidence Slc25a46 knockout mouse with EM, biochemical, metabolic and proteomic analyses

   PMID:28376083

   Open questions at the time

   • Single lab
   • Did not isolate primary lesion versus secondary metabolic consequences
6. 2018 Medium

   Resolved that pathogenic variants act by two distinct mechanisms—destabilization versus disruption of partner interactions—by showing a specific mutation abolishes the SLC25A46-MIC60 interaction.

   Evidence Co-IP of interaction disruption, protein stability assays across mutations, and 3D homology modeling

   PMID:30178502

   Open questions at the time

   • Structural model not experimentally validated
   • Functional consequence of selectively losing MIC60 binding not isolated from stability effects
7. 2018 Medium

   Extended the dynamics phenotype to a neuronal in vivo context, linking SLC25A46 loss to synaptic mitochondrial hyperfusion, ROS accumulation and ATP deficits at the NMJ.

   Evidence Drosophila pan-neuronal RNAi with immunocytochemistry, NMJ morphology, ROS and ATP measurements

   PMID:29604258

   Open questions at the time

   • Reported plasma-membrane localization not mechanistically explained
   • Single lab
8. 2023 High

   Demonstrated that SLC25A46 marks the physical sites of fission and fusion events and that knockout produces fragmentation while pathogenic variants produce hyperfusion, refining the loss-of-function model and confirming presence at interorganellar contact sites.

   Evidence KO human fibroblast lines with live imaging, DRP1/OPA1 co-localization, Co-IP, BioID proximity mapping, lipidomics and EM

   PMID:36977595

   Open questions at the time

   • Why knockout and pathogenic variants give opposite morphologies is not fully resolved
   • Function of contact-site lipid-transfer interactors not defined
9. 2023 Medium

   Revealed a post-translational regulatory layer in which SLC25A46 is phosphorylated at T44/T45 and dephosphorylated by glucose-induced Ca2+, coupling its dynamics function to β-cell insulin secretion and lipotoxic stress sensitivity.

   Evidence Phosphoproteomic MS, overexpression and inactivation in INS-1E cells, morphology, insulin secretion and apoptosis assays

   PMID:36942724

   Open questions at the time

   • Kinase/phosphatase acting on T44/T45 not identified
   • Single lab and single cell type
10. 2024 High

    Defined the structural interfaces of the key interactions—OPA1's bundle signaling element and the cytosolic face of MFN2 binding SLC25A46—and showed they are required for network maintenance.

    Evidence Crosslinking MS, AlphaFold2 modeling, and mutagenesis-based interface validation with morphology assays

    PMID:38234813 PMID:39222684

    Open questions at the time

    • No experimental high-resolution structure of the complexes
    • Single lab
11. 2025 High

    Placed SLC25A46 genetically in the fusion pathway by showing it acts through the mitofusin ortholog FZO-1 and that loss of the fission factor drp-1 suppresses its phenotype.

    Evidence C. elegans forward-genetics suppressor screen, FZO-1 overexpression rescue, and drp-1 epistasis with disease-mutation worm models

    PMID:40444356

    Open questions at the time

    • Whether SLC25A46 acts upstream of or parallel to the fission machinery is not distinguished
    • Direct biochemical step regulated remains undefined

• How a single outer-membrane protein mechanistically coordinates MFN oligomerization, OPA1 activity, MICOS-dependent cristae shape and lipid transfer at one focal site—and why loss versus mutation drive opposite morphologies—remains the central open question.
• No reconstituted biochemical assay of any catalytic or transport activity
• No high-resolution structure of SLC25A46 or its complexes
• Physiological transport substrate, if any, unidentified