{"gene":"SLC25A46","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2015,"finding":"SLC25A46 is a modified carrier protein recruited to the outer mitochondrial membrane (not inner membrane), where it interacts with the inner membrane remodeling protein mitofilin (Fcj1/MIC60). Loss of function in cultured cells and zebrafish leads to increased mitochondrial connectivity (hyperfusion), while severely affecting neuronal development.","method":"Co-immunoprecipitation, zebrafish loss-of-function, subcellular fractionation/localization, whole-exome sequencing of patient families","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for interaction, zebrafish KD with defined phenotype, localization confirmed by fractionation, replicated across multiple labs subsequently","pmids":["26168012"],"is_preprint":false},{"year":2016,"finding":"SLC25A46 is an integral outer mitochondrial membrane protein that interacts with MFN2, OPA1, and the MICOS complex. Loss of SLC25A46 (via destabilizing missense mutation) causes mitochondrial hyperfusion, disruption of the MICOS complex resulting in markedly shortened cristae, altered ER morphology, impaired cellular respiration, and premature cellular senescence. SLC25A46 also interacts with the ER membrane protein complex (EMC), and its loss alters mitochondrial phospholipid composition, implicating it in a mitochondrial/ER lipid transfer pathway.","method":"Co-immunoprecipitation, patient fibroblast functional studies (respiration assays, electron microscopy of cristae), ER morphology imaging, phospholipid composition analysis, Western blot","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, EM ultrastructure, respiration assay, lipidomics) in patient cells, replicated by subsequent studies","pmids":["27390132"],"is_preprint":false},{"year":2016,"finding":"SLC25A46 has pro-fission properties: knockdown in zebrafish causes abnormally elongated (hyperfused) mitochondria rescuable by wild-type but not mutant SLC25A46 mRNA co-injection, and overexpression of wild-type protein leads to mitochondrial fragmentation. Clinical severity inversely correlates with relative stability of the mutant protein.","method":"Zebrafish knockdown (morpholino), mRNA rescue experiments, overexpression studies, cellular mitochondrial morphology imaging","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish KD with rescue experiment and OE phenotype, single lab","pmids":["27543974"],"is_preprint":false},{"year":2017,"finding":"Decreased expression of SLC25A46 results in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of the disease-causing SLC25A46 L341P mutant, leading to its degradation via P97 and the proteasome, independently of mitophagy and apoptosis pathways. A subset of SLC25A46 interacts with mitochondrial dynamics components and the MICOS complex.","method":"Co-immunoprecipitation, ubiquitylation assays, proteasome inhibition experiments, MFN1/2 oligomerization assays (Blue Native PAGE), knockdown/overexpression in cultured cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitylation assay, BN-PAGE for oligomerization, genetic epistasis with E3 ligases), single lab but rigorous","pmids":["28057766"],"is_preprint":false},{"year":2017,"finding":"Knockout of Slc25a46 in mice causes fusion/fission imbalance and abnormal mitochondrial architecture (disrupted cristae) that disturbs mitochondrial metabolism, demonstrating SLC25A46's role in mitochondrial dynamics and metabolic function in vivo.","method":"Mouse knockout model, electron microscopy, biochemical and metabolic analyses, proteomic analyses","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple readouts (EM, biochemistry, proteomics), single lab","pmids":["28376083"],"is_preprint":false},{"year":2018,"finding":"SLC25A46 forms molecular complexes with proteins involved in mitochondrial dynamics and cristae remodeling. A specific patient mutation directly disrupts the SLC25A46 interaction with MIC60 (MICOS subunit). 3D homology modeling reveals that approximately half of reported pathogenic substitutions fall outside canonical carrier motifs, suggesting two distinct molecular mechanisms: protein destabilization and altered molecular interactions.","method":"Co-immunoprecipitation (SLC25A46–MIC60 interaction), protein stability assays, 3D structural modeling of mutations","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for interaction disruption, stability assays across seven mutations, structural modeling; single lab","pmids":["30178502"],"is_preprint":false},{"year":2018,"finding":"In Drosophila, neuron-specific knockdown of dSLC25A46 (CG5755) causes mitochondrial hyperfusion at NMJ synapses, accumulation of reactive oxygen species, reduction of ATP, and defects in neuromuscular junction morphology. Immunocytochemical analysis revealed dSLC25A46 localizes not only to mitochondria but also to the plasma membrane.","method":"Drosophila pan-neuron knockdown (RNAi), immunocytochemistry, NMJ morphology analysis, ROS measurement, ATP measurement","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Drosophila KD with multiple cellular phenotype readouts; single lab","pmids":["29604258"],"is_preprint":false},{"year":2023,"finding":"SLC25A46 localizes to discrete puncta at mitochondrial branch points and tips of mitochondrial tubules, co-localizing with DRP1 and OPA1, and virtually all fission/fusion events are demarcated by an SLC25A46 focus. SLC25A46 knockout causes mitochondrial fragmentation (not hyperfusion as seen with pathogenic variants), while pathogenic variants cause hyperfusion. SLC25A46 co-immunoprecipitates with fusion machinery, and loss of function alters oligomerization state of OPA1 and MFN2. Proximity interaction mapping identified ER membrane components, lipid transfer proteins, and outer membrane proteins, indicating presence at interorganellar contact sites. Loss of SLC25A46 leads to altered mitochondrial lipid composition.","method":"SLC25A46 KO cell line in human fibroblasts, live imaging with co-localization of DRP1/OPA1, co-immunoprecipitation, BioID proximity mapping, lipid composition analysis, EM ultrastructure","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cell line with multiple orthogonal methods (live imaging, Co-IP, proximity proteomics, lipidomics, EM), rigorous study","pmids":["36977595"],"is_preprint":false},{"year":2023,"finding":"In pancreatic β-cells (INS-1E), SLC25A46 is phosphorylated on threonine residues T44/T45 under resting glucose conditions and is dephosphorylated in response to glucose-induced Ca2+ signals, revealing a post-translational regulatory mechanism. Overexpression of SLC25A46 causes complete mitochondrial fragmentation with lowered glucose-induced insulin secretion; loss of SLC25A46 causes mitochondrial hyperfusion and exacerbated sensitivity to lipotoxic stress/palmitate-induced apoptosis.","method":"Phosphoproteomic mass spectrometry, SLC25A46 overexpression and gene inactivation in INS-1E cells, mitochondrial morphology imaging, insulin secretion assay, apoptosis assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomic identification of modification site, KO and OE with defined phenotypes, single lab","pmids":["36942724"],"is_preprint":false},{"year":2024,"finding":"Crosslinking mass spectrometry and AlphaFold2 modeling identified that the bundle signaling element (BSE) of OPA1 interacts with SLC25A46, and that MFN2 interacts with SLC25A46 via its cytosolic face. Validation of these interfaces confirmed they play a role in mitochondrial network maintenance.","method":"Crosslinking mass spectrometry, AlphaFold2 structural modeling, mutagenesis/interface validation, mitochondrial morphology assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crosslinking MS with structural modeling and mutagenesis validation; single lab but multiple orthogonal methods","pmids":["39222684","38234813"],"is_preprint":false},{"year":2022,"finding":"Proteomic interactome mapping in transgenic mice expressing SLC25A46-FLAG identified 371 novel putative interactors and confirmed 17 known ones, including MICOS complex subunits, OPA1, VDACs, ADP/ATP translocases SLC25A4 and SLC25A5, OXPHOS complex subunits, F1Fo-ATP synthase components, and mitochondria-ER contact site proteins.","method":"Co-immunoprecipitation followed by mass spectrometry (proteomic interactome), transgenic mice expressing SLC25A46-FLAG in multiple tissues","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS interactome across multiple tissues in transgenic mice; single lab, confirmatory for known interactors","pmids":["34983179"],"is_preprint":false},{"year":2025,"finding":"In C. elegans, slc-25A46 is an essential factor for mitochondrial fusion acting through the mitofusin ortholog FZO-1. Forward genetics suppressor screening identified loss-of-function mutations in drp-1 (mitochondrial fission factor) as suppressors of slc-25A46 mutant phenotype, placing SLC-25A46 genetically upstream of or parallel to the fission/fusion balance. Overexpressing FZO-1 mitigated mitochondrial defects in slc-25a46 mutants. Disease-model worms carrying human SLC25A46 disease-associated mutations exhibited mitochondrial fragmentation and accelerated neurodegeneration.","method":"Forward genetics (suppressor mutagenesis screen), C. elegans loss-of-function mutants, FZO-1 overexpression rescue, genetic epistasis (drp-1 double mutant)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — genetic epistasis by suppressor screen, rescue experiment, multiple alleles; single lab but rigorous forward genetics","pmids":["40444356"],"is_preprint":false},{"year":2019,"finding":"In Drosophila, HDAC1 ortholog Rpd3 acts as an epigenetic regulator of dSLC25A46 genomic regions via histone H4K8 acetylation. Functional reduction of Rpd3 rescued locomotor deficits and neuromuscular junction morphology defects caused by dSLC25A46 knockdown, placing HDAC1-mediated epigenetic regulation as a modifier of SLC25A46-related mitochondrial disease phenotypes.","method":"Drosophila genetic interaction (Rpd3 reduction in dSLC25A46 knockdown background), ChIP data analysis, histone acetylation assays, NMJ morphology and locomotion phenotype readouts","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vivo Drosophila genetic interaction with phenotype rescue and histone modification evidence; single lab","pmids":["31614134"],"is_preprint":false}],"current_model":"SLC25A46 is a modified solute carrier family protein embedded in the outer mitochondrial membrane that functions as a regulator of mitochondrial fusion/fission balance by interacting with the outer membrane fusogen MFN1/2 (via its cytosolic face) and the inner membrane GTPase OPA1 (via OPA1's bundle signaling element), as well as with the MICOS complex subunit MIC60; loss of SLC25A46 shifts the balance toward hyperfusion (by stabilizing MFN1/2 oligomers) or fragmentation depending on context, disrupts cristae ultrastructure, alters mitochondrial lipid composition at ER-mitochondria contact sites, and its disease-causing mutant forms are rapidly degraded via MULAN/MARCH5-mediated ubiquitylation and proteasomal degradation through P97, independently of mitophagy or apoptosis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2015,"claim":"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","pmids":["26168012"],"confidence":"High","gaps":["Did not define which dynamics machinery SLC25A46 acts through","Mechanism linking MIC60 binding to cristae control unresolved"]},{"year":2016,"claim":"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","pmids":["27390132"],"confidence":"High","gaps":["Did not establish whether SLC25A46 directly transfers lipids","Direction of MFN/OPA1 regulation not mechanistically resolved"]},{"year":2016,"claim":"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","pmids":["27543974"],"confidence":"Medium","gaps":["Single lab","Did not reconcile pro-fission overexpression with hyperfusion-on-loss phenotype mechanistically"]},{"year":2017,"claim":"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","pmids":["28057766"],"confidence":"High","gaps":["How SLC25A46 restrains mitofusin oligomerization molecularly is unknown","Did not establish whether degradation pathway operates on wild-type protein turnover"]},{"year":2017,"claim":"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","pmids":["28376083"],"confidence":"Medium","gaps":["Single lab","Did not isolate primary lesion versus secondary metabolic consequences"]},{"year":2018,"claim":"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","pmids":["30178502"],"confidence":"Medium","gaps":["Structural model not experimentally validated","Functional consequence of selectively losing MIC60 binding not isolated from stability effects"]},{"year":2018,"claim":"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","pmids":["29604258"],"confidence":"Medium","gaps":["Reported plasma-membrane localization not mechanistically explained","Single lab"]},{"year":2023,"claim":"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","pmids":["36977595"],"confidence":"High","gaps":["Why knockout and pathogenic variants give opposite morphologies is not fully resolved","Function of contact-site lipid-transfer interactors not defined"]},{"year":2023,"claim":"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","pmids":["36942724"],"confidence":"Medium","gaps":["Kinase/phosphatase acting on T44/T45 not identified","Single lab and single cell type"]},{"year":2024,"claim":"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","pmids":["39222684","38234813"],"confidence":"High","gaps":["No experimental high-resolution structure of the complexes","Single lab"]},{"year":2025,"claim":"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","pmids":["40444356"],"confidence":"High","gaps":["Whether SLC25A46 acts upstream of or parallel to the fission machinery is not distinguished","Direct biochemical step regulated remains undefined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,4,7]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,4,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,4,8]}],"complexes":["MICOS complex (interactor)"],"partners":["MFN1","MFN2","OPA1","MIC60","DRP1","MULAN","MARCH5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96AG3","full_name":"Mitochondrial outer membrane protein SLC25A46","aliases":["Solute carrier family 25 member 46"],"length_aa":418,"mass_kda":46.2,"function":"Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization (PubMed:26168012, PubMed:27390132, PubMed:27543974). May regulate the assembly of the MICOS (mitochondrial contact site and cristae organizing system) complex which is essential to the biogenesis and dynamics of mitochondrial cristae, the inwards folds of the inner mitochondrial membrane (PubMed:27390132). Through its interaction with the EMC (endoplasmic reticulum membrane protein complex), could regulate mitochondrial lipid homeostasis and thereby mitochondrial fission (PubMed:27390132)","subcellular_location":"Mitochondrion outer membrane","url":"https://www.uniprot.org/uniprotkb/Q96AG3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC25A46","classification":"Not Classified","n_dependent_lines":38,"n_total_lines":1208,"dependency_fraction":0.03145695364238411},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC25A46","total_profiled":1310},"omim":[{"mim_id":"619303","title":"PONTOCEREBELLAR HYPOPLASIA, TYPE 1E; PCH1E","url":"https://www.omim.org/entry/619303"},{"mim_id":"616505","title":"NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIB, WITH OPTIC ATROPHY; HMSN6B","url":"https://www.omim.org/entry/616505"},{"mim_id":"610826","title":"SOLUTE CARRIER FAMILY 25, MEMBER 46; SLC25A46","url":"https://www.omim.org/entry/610826"},{"mim_id":"607596","title":"PONTOCEREBELLAR HYPOPLASIA, TYPE 1A; PCH1A","url":"https://www.omim.org/entry/607596"},{"mim_id":"601152","title":"NEUROPATHY, HEREDITARY MOTOR AND SENSORY, TYPE VIA, WITH OPTIC ATROPHY; HMSN6A","url":"https://www.omim.org/entry/601152"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC25A46"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96AG3","domains":[{"cath_id":"1.50.40","chopping":"108-416","consensus_level":"medium","plddt":87.0736,"start":108,"end":416}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AG3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AG3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AG3-F1-predicted_aligned_error_v6.png","plddt_mean":73.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC25A46","jax_strain_url":"https://www.jax.org/strain/search?query=SLC25A46"},"sequence":{"accession":"Q96AG3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96AG3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96AG3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AG3"}},"corpus_meta":[{"pmid":"26168012","id":"PMC_26168012","title":"Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26168012","citation_count":174,"is_preprint":false},{"pmid":"27390132","id":"PMC_27390132","title":"SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome.","date":"2016","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27390132","citation_count":168,"is_preprint":false},{"pmid":"27543974","id":"PMC_27543974","title":"Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia.","date":"2016","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/27543974","citation_count":78,"is_preprint":false},{"pmid":"28057766","id":"PMC_28057766","title":"Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.","date":"2017","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/28057766","citation_count":68,"is_preprint":false},{"pmid":"32208444","id":"PMC_32208444","title":"Genetic compensation in a stable slc25a46 mutant zebrafish: A case for using F0 CRISPR mutagenesis to study phenotypes caused by inherited disease.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32208444","citation_count":48,"is_preprint":false},{"pmid":"26951855","id":"PMC_26951855","title":"Novel pathogenic SLC25A46 splice-site mutation causes an optic atrophy spectrum disorder.","date":"2016","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26951855","citation_count":37,"is_preprint":false},{"pmid":"28376086","id":"PMC_28376086","title":"Novel insights into SLC25A46-related pathologies in a genetic mouse model.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28376086","citation_count":36,"is_preprint":false},{"pmid":"30178502","id":"PMC_30178502","title":"Insights into the genotype-phenotype correlation and molecular function of SLC25A46.","date":"2018","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/30178502","citation_count":30,"is_preprint":false},{"pmid":"28558379","id":"PMC_28558379","title":"SLC25A46 Mutations Associated with Autosomal Recessive Cerebellar Ataxia in North African Families.","date":"2017","source":"Neuro-degenerative diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28558379","citation_count":28,"is_preprint":false},{"pmid":"29604258","id":"PMC_29604258","title":"Novel Drosophila model for mitochondrial diseases by targeting of a solute carrier protein SLC25A46.","date":"2018","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/29604258","citation_count":24,"is_preprint":false},{"pmid":"31943007","id":"PMC_31943007","title":"Systemic administration of AAV-Slc25a46 mitigates mitochondrial neuropathy in Slc25a46-/- mice.","date":"2020","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31943007","citation_count":23,"is_preprint":false},{"pmid":"32259769","id":"PMC_32259769","title":"SLC25A46 mutations in patients with Parkinson's Disease and optic atrophy.","date":"2020","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/32259769","citation_count":23,"is_preprint":false},{"pmid":"36977595","id":"PMC_36977595","title":"The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/36977595","citation_count":22,"is_preprint":false},{"pmid":"28376083","id":"PMC_28376083","title":"Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28376083","citation_count":21,"is_preprint":false},{"pmid":"39222684","id":"PMC_39222684","title":"Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39222684","citation_count":9,"is_preprint":false},{"pmid":"31614134","id":"PMC_31614134","title":"Reduction of Rpd3 suppresses defects in locomotive ability and neuronal morphology induced by the knockdown of Drosophila SLC25A46 via an epigenetic pathway.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31614134","citation_count":9,"is_preprint":false},{"pmid":"33277645","id":"PMC_33277645","title":"A Slc25a46 Mouse Model Simulating Age-Associated Motor Deficit, Redox Imbalance, and Mitochondria Dysfunction.","date":"2021","source":"The journals of gerontology. Series A, Biological sciences and medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33277645","citation_count":7,"is_preprint":false},{"pmid":"34983179","id":"PMC_34983179","title":"Proteomic Identification of the SLC25A46 Interactome in Transgenic Mice Expressing SLC25A46-FLAG.","date":"2022","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/34983179","citation_count":7,"is_preprint":false},{"pmid":"34672083","id":"PMC_34672083","title":"Haematococcus Pluvialis Extends Yeast Lifespan and Improves Slc25a46 Gene Knockout-Associated Mice Phenotypic Defects.","date":"2021","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/34672083","citation_count":6,"is_preprint":false},{"pmid":"34945750","id":"PMC_34945750","title":"Reanalysis of Exome Data Identifies Novel SLC25A46 Variants Associated with Leigh Syndrome.","date":"2021","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34945750","citation_count":6,"is_preprint":false},{"pmid":"36578309","id":"PMC_36578309","title":"Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy.","date":"2022","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36578309","citation_count":5,"is_preprint":false},{"pmid":"36942724","id":"PMC_36942724","title":"SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin-secreting cells.","date":"2023","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/36942724","citation_count":3,"is_preprint":false},{"pmid":"35012485","id":"PMC_35012485","title":"Diagnosis of SLC25A46-related pontocerebellar hypoplasia in two siblings with fulminant neonatal course: role of postmortem CT and whole genomic analysis: a case report.","date":"2022","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35012485","citation_count":3,"is_preprint":false},{"pmid":"40444356","id":"PMC_40444356","title":"SLC-25A46 regulates mitochondrial fusion through the mitofusin protein FZO-1 and is essential for maintaining neuronal morphology.","date":"2025","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/40444356","citation_count":2,"is_preprint":false},{"pmid":"38234813","id":"PMC_38234813","title":"Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38234813","citation_count":1,"is_preprint":false},{"pmid":"41385895","id":"PMC_41385895","title":"Assessment of SLC25A46 variants in idiopathic Parkinson's disease.","date":"2025","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/41385895","citation_count":1,"is_preprint":false},{"pmid":"38021708","id":"PMC_38021708","title":"Anesthetic Management for a Child With a Newly Identified Mitochondrial Disease SLC25A46 Mutation: A Case Report.","date":"2023","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/38021708","citation_count":0,"is_preprint":false},{"pmid":"41646756","id":"PMC_41646756","title":"Lack of genetic evidence for a role of SLC25A46 in alpha-synucleinopathies.","date":"2026","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41646756","citation_count":0,"is_preprint":false},{"pmid":"41640504","id":"PMC_41640504","title":"An Apparently Isolated Optic Neuropathy Associated with Biallelic Variants in SLC25A46 Gene Encoding the Mitochondrial Ugo1-Like Protein.","date":"2025","source":"Neuro-ophthalmology (Aeolus Press)","url":"https://pubmed.ncbi.nlm.nih.gov/41640504","citation_count":0,"is_preprint":false},{"pmid":"38464896","id":"PMC_38464896","title":"A novel homozygous variant in SLC25A46 gene associated with pontocerebellar hypoplasia type 1E: a case report.","date":"2024","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/38464896","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15298,"output_tokens":3695,"usd":0.05066,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11528,"output_tokens":3741,"usd":0.075582,"stage2_stop_reason":"end_turn"},"total_usd":0.126242,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC25A46 is a modified carrier protein recruited to the outer mitochondrial membrane (not inner membrane), where it interacts with the inner membrane remodeling protein mitofilin (Fcj1/MIC60). Loss of function in cultured cells and zebrafish leads to increased mitochondrial connectivity (hyperfusion), while severely affecting neuronal development.\",\n      \"method\": \"Co-immunoprecipitation, zebrafish loss-of-function, subcellular fractionation/localization, whole-exome sequencing of patient families\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for interaction, zebrafish KD with defined phenotype, localization confirmed by fractionation, replicated across multiple labs subsequently\",\n      \"pmids\": [\"26168012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLC25A46 is an integral outer mitochondrial membrane protein that interacts with MFN2, OPA1, and the MICOS complex. Loss of SLC25A46 (via destabilizing missense mutation) causes mitochondrial hyperfusion, disruption of the MICOS complex resulting in markedly shortened cristae, altered ER morphology, impaired cellular respiration, and premature cellular senescence. SLC25A46 also interacts with the ER membrane protein complex (EMC), and its loss alters mitochondrial phospholipid composition, implicating it in a mitochondrial/ER lipid transfer pathway.\",\n      \"method\": \"Co-immunoprecipitation, patient fibroblast functional studies (respiration assays, electron microscopy of cristae), ER morphology imaging, phospholipid composition analysis, Western blot\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, EM ultrastructure, respiration assay, lipidomics) in patient cells, replicated by subsequent studies\",\n      \"pmids\": [\"27390132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SLC25A46 has pro-fission properties: knockdown in zebrafish causes abnormally elongated (hyperfused) mitochondria rescuable by wild-type but not mutant SLC25A46 mRNA co-injection, and overexpression of wild-type protein leads to mitochondrial fragmentation. Clinical severity inversely correlates with relative stability of the mutant protein.\",\n      \"method\": \"Zebrafish knockdown (morpholino), mRNA rescue experiments, overexpression studies, cellular mitochondrial morphology imaging\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish KD with rescue experiment and OE phenotype, single lab\",\n      \"pmids\": [\"27543974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Decreased expression of SLC25A46 results in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of the disease-causing SLC25A46 L341P mutant, leading to its degradation via P97 and the proteasome, independently of mitophagy and apoptosis pathways. A subset of SLC25A46 interacts with mitochondrial dynamics components and the MICOS complex.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assays, proteasome inhibition experiments, MFN1/2 oligomerization assays (Blue Native PAGE), knockdown/overexpression in cultured cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitylation assay, BN-PAGE for oligomerization, genetic epistasis with E3 ligases), single lab but rigorous\",\n      \"pmids\": [\"28057766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockout of Slc25a46 in mice causes fusion/fission imbalance and abnormal mitochondrial architecture (disrupted cristae) that disturbs mitochondrial metabolism, demonstrating SLC25A46's role in mitochondrial dynamics and metabolic function in vivo.\",\n      \"method\": \"Mouse knockout model, electron microscopy, biochemical and metabolic analyses, proteomic analyses\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple readouts (EM, biochemistry, proteomics), single lab\",\n      \"pmids\": [\"28376083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC25A46 forms molecular complexes with proteins involved in mitochondrial dynamics and cristae remodeling. A specific patient mutation directly disrupts the SLC25A46 interaction with MIC60 (MICOS subunit). 3D homology modeling reveals that approximately half of reported pathogenic substitutions fall outside canonical carrier motifs, suggesting two distinct molecular mechanisms: protein destabilization and altered molecular interactions.\",\n      \"method\": \"Co-immunoprecipitation (SLC25A46–MIC60 interaction), protein stability assays, 3D structural modeling of mutations\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for interaction disruption, stability assays across seven mutations, structural modeling; single lab\",\n      \"pmids\": [\"30178502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Drosophila, neuron-specific knockdown of dSLC25A46 (CG5755) causes mitochondrial hyperfusion at NMJ synapses, accumulation of reactive oxygen species, reduction of ATP, and defects in neuromuscular junction morphology. Immunocytochemical analysis revealed dSLC25A46 localizes not only to mitochondria but also to the plasma membrane.\",\n      \"method\": \"Drosophila pan-neuron knockdown (RNAi), immunocytochemistry, NMJ morphology analysis, ROS measurement, ATP measurement\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Drosophila KD with multiple cellular phenotype readouts; single lab\",\n      \"pmids\": [\"29604258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC25A46 localizes to discrete puncta at mitochondrial branch points and tips of mitochondrial tubules, co-localizing with DRP1 and OPA1, and virtually all fission/fusion events are demarcated by an SLC25A46 focus. SLC25A46 knockout causes mitochondrial fragmentation (not hyperfusion as seen with pathogenic variants), while pathogenic variants cause hyperfusion. SLC25A46 co-immunoprecipitates with fusion machinery, and loss of function alters oligomerization state of OPA1 and MFN2. Proximity interaction mapping identified ER membrane components, lipid transfer proteins, and outer membrane proteins, indicating presence at interorganellar contact sites. Loss of SLC25A46 leads to altered mitochondrial lipid composition.\",\n      \"method\": \"SLC25A46 KO cell line in human fibroblasts, live imaging with co-localization of DRP1/OPA1, co-immunoprecipitation, BioID proximity mapping, lipid composition analysis, EM ultrastructure\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cell line with multiple orthogonal methods (live imaging, Co-IP, proximity proteomics, lipidomics, EM), rigorous study\",\n      \"pmids\": [\"36977595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In pancreatic β-cells (INS-1E), SLC25A46 is phosphorylated on threonine residues T44/T45 under resting glucose conditions and is dephosphorylated in response to glucose-induced Ca2+ signals, revealing a post-translational regulatory mechanism. Overexpression of SLC25A46 causes complete mitochondrial fragmentation with lowered glucose-induced insulin secretion; loss of SLC25A46 causes mitochondrial hyperfusion and exacerbated sensitivity to lipotoxic stress/palmitate-induced apoptosis.\",\n      \"method\": \"Phosphoproteomic mass spectrometry, SLC25A46 overexpression and gene inactivation in INS-1E cells, mitochondrial morphology imaging, insulin secretion assay, apoptosis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomic identification of modification site, KO and OE with defined phenotypes, single lab\",\n      \"pmids\": [\"36942724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Crosslinking mass spectrometry and AlphaFold2 modeling identified that the bundle signaling element (BSE) of OPA1 interacts with SLC25A46, and that MFN2 interacts with SLC25A46 via its cytosolic face. Validation of these interfaces confirmed they play a role in mitochondrial network maintenance.\",\n      \"method\": \"Crosslinking mass spectrometry, AlphaFold2 structural modeling, mutagenesis/interface validation, mitochondrial morphology assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crosslinking MS with structural modeling and mutagenesis validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39222684\", \"38234813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Proteomic interactome mapping in transgenic mice expressing SLC25A46-FLAG identified 371 novel putative interactors and confirmed 17 known ones, including MICOS complex subunits, OPA1, VDACs, ADP/ATP translocases SLC25A4 and SLC25A5, OXPHOS complex subunits, F1Fo-ATP synthase components, and mitochondria-ER contact site proteins.\",\n      \"method\": \"Co-immunoprecipitation followed by mass spectrometry (proteomic interactome), transgenic mice expressing SLC25A46-FLAG in multiple tissues\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS interactome across multiple tissues in transgenic mice; single lab, confirmatory for known interactors\",\n      \"pmids\": [\"34983179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, slc-25A46 is an essential factor for mitochondrial fusion acting through the mitofusin ortholog FZO-1. Forward genetics suppressor screening identified loss-of-function mutations in drp-1 (mitochondrial fission factor) as suppressors of slc-25A46 mutant phenotype, placing SLC-25A46 genetically upstream of or parallel to the fission/fusion balance. Overexpressing FZO-1 mitigated mitochondrial defects in slc-25a46 mutants. Disease-model worms carrying human SLC25A46 disease-associated mutations exhibited mitochondrial fragmentation and accelerated neurodegeneration.\",\n      \"method\": \"Forward genetics (suppressor mutagenesis screen), C. elegans loss-of-function mutants, FZO-1 overexpression rescue, genetic epistasis (drp-1 double mutant)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — genetic epistasis by suppressor screen, rescue experiment, multiple alleles; single lab but rigorous forward genetics\",\n      \"pmids\": [\"40444356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila, HDAC1 ortholog Rpd3 acts as an epigenetic regulator of dSLC25A46 genomic regions via histone H4K8 acetylation. Functional reduction of Rpd3 rescued locomotor deficits and neuromuscular junction morphology defects caused by dSLC25A46 knockdown, placing HDAC1-mediated epigenetic regulation as a modifier of SLC25A46-related mitochondrial disease phenotypes.\",\n      \"method\": \"Drosophila genetic interaction (Rpd3 reduction in dSLC25A46 knockdown background), ChIP data analysis, histone acetylation assays, NMJ morphology and locomotion phenotype readouts\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vivo Drosophila genetic interaction with phenotype rescue and histone modification evidence; single lab\",\n      \"pmids\": [\"31614134\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC25A46 is a modified solute carrier family protein embedded in the outer mitochondrial membrane that functions as a regulator of mitochondrial fusion/fission balance by interacting with the outer membrane fusogen MFN1/2 (via its cytosolic face) and the inner membrane GTPase OPA1 (via OPA1's bundle signaling element), as well as with the MICOS complex subunit MIC60; loss of SLC25A46 shifts the balance toward hyperfusion (by stabilizing MFN1/2 oligomers) or fragmentation depending on context, disrupts cristae ultrastructure, alters mitochondrial lipid composition at ER-mitochondria contact sites, and its disease-causing mutant forms are rapidly degraded via MULAN/MARCH5-mediated ubiquitylation and proteasomal degradation through P97, independently of mitophagy or apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1, #7]. 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 [#7]. 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 [#1, #5, #9]; loss of SLC25A46 stabilizes and increases oligomerization of MFN1/MFN2, shifting the network toward hyperfusion, while disrupting MICOS integrity and shortening cristae [#3, #1]. Through associations with ER membrane components and lipid-transfer proteins at interorganellar contact sites, SLC25A46 also governs mitochondrial phospholipid composition and ER-mitochondria coupling [#1, #7]. 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 [#3, #5]. 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 [#0, #2, #4, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, zebrafish loss-of-function, and whole-exome sequencing of patient families\",\n      \"pmids\": [\"26168012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which dynamics machinery SLC25A46 acts through\", \"Mechanism linking MIC60 binding to cristae control unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, patient-fibroblast respiration and EM cristae analysis, ER imaging, and lipidomics\",\n      \"pmids\": [\"27390132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether SLC25A46 directly transfers lipids\", \"Direction of MFN/OPA1 regulation not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a pro-fission activity via overexpression-induced fragmentation and zebrafish rescue, and tied clinical severity to mutant protein stability.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with mRNA rescue and overexpression morphology assays\",\n      \"pmids\": [\"27543974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not reconcile pro-fission overexpression with hyperfusion-on-loss phenotype mechanistically\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, ubiquitylation assays, BN-PAGE oligomerization assays, and E3-ligase epistasis in cultured cells\",\n      \"pmids\": [\"28057766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SLC25A46 restrains mitofusin oligomerization molecularly is unknown\", \"Did not establish whether degradation pathway operates on wild-type protein turnover\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed in vivo that SLC25A46 loss causes fusion/fission imbalance, disrupted cristae and metabolic disturbance in a mammalian organism.\",\n      \"evidence\": \"Slc25a46 knockout mouse with EM, biochemical, metabolic and proteomic analyses\",\n      \"pmids\": [\"28376083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not isolate primary lesion versus secondary metabolic consequences\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of interaction disruption, protein stability assays across mutations, and 3D homology modeling\",\n      \"pmids\": [\"30178502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model not experimentally validated\", \"Functional consequence of selectively losing MIC60 binding not isolated from stability effects\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Drosophila pan-neuronal RNAi with immunocytochemistry, NMJ morphology, ROS and ATP measurements\",\n      \"pmids\": [\"29604258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reported plasma-membrane localization not mechanistically explained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"KO human fibroblast lines with live imaging, DRP1/OPA1 co-localization, Co-IP, BioID proximity mapping, lipidomics and EM\",\n      \"pmids\": [\"36977595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why knockout and pathogenic variants give opposite morphologies is not fully resolved\", \"Function of contact-site lipid-transfer interactors not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phosphoproteomic MS, overexpression and inactivation in INS-1E cells, morphology, insulin secretion and apoptosis assays\",\n      \"pmids\": [\"36942724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase/phosphatase acting on T44/T45 not identified\", \"Single lab and single cell type\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Crosslinking MS, AlphaFold2 modeling, and mutagenesis-based interface validation with morphology assays\",\n      \"pmids\": [\"39222684\", \"38234813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental high-resolution structure of the complexes\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"C. elegans forward-genetics suppressor screen, FZO-1 overexpression rescue, and drp-1 epistasis with disease-mutation worm models\",\n      \"pmids\": [\"40444356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SLC25A46 acts upstream of or parallel to the fission machinery is not distinguished\", \"Direct biochemical step regulated remains undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 4, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 4, 8]}\n    ],\n    \"complexes\": [\"MICOS complex (interactor)\"],\n    \"partners\": [\"MFN1\", \"MFN2\", \"OPA1\", \"MIC60\", \"DRP1\", \"MULAN\", \"MARCH5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}