{"gene":"SAMM50","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2003,"finding":"Sam50 (Omp85 family) is an essential subunit of the sorting and assembly machinery (SAM) complex in the mitochondrial outer membrane, required for the assembly of beta-barrel proteins Tom40 and porin (VDAC) into the outer membrane; yeast conditional omp85 mutants showed defective insertion of VDAC and TOM complex components, while import of matrix proteins was unaffected.","method":"Yeast conditional mutants, biochemical fractionation, import assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with specific phenotypic readout, replicated across two independent labs (PMID:14699090 and PMID:14570913)","pmids":["14570913","14699090"],"is_preprint":false},{"year":2007,"finding":"Sam50 depletion by RNAi in human cells causes strong defects in VDAC assembly and reduced steady-state VDAC levels; Sam50-depleted mitochondria also show reduced levels of metaxin 1 and 2, implying a connection between Sam50 and metaxins, though they appear to reside in distinct complexes. The pathway of VDAC biogenesis involves TOM complex, Sam50, and metaxins and is evolutionarily conserved.","method":"RNAi knockdown, import assays, native gel electrophoresis, co-immunoprecipitation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, in vitro import, native PAGE), independently replicated concept across organisms","pmids":["17510655"],"is_preprint":false},{"year":2007,"finding":"SAM50 co-immunoprecipitates with mitofilin (inner membrane), metaxins 1 and 2, CHCHD3, CHCHD6, and DnaJC11 as part of a large mitochondrial complex, indicating that Sam50 participates in a multi-protein assembly spanning the outer and inner mitochondrial membranes.","method":"Immunocapture with monoclonal antibody against mitofilin followed by mass spectrometry identification of co-purifying proteins","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single immunocapture experiment but multiple co-purifying proteins identified by MS; functional consequence not fully dissected in this paper","pmids":["17624330"],"is_preprint":false},{"year":2012,"finding":"Sam50 is part of a large mitochondrial intermembrane space bridging (MIB) complex together with IMM proteins mitofilin and CHCHD3; disruption of MIB complex (via Sam50 depletion) causes loss of cristae integrity and deficiency in assembly of respiratory chain complexes containing mitochondrially encoded subunits, linking OMM-IMM contacts to respiratory complex biogenesis.","method":"RNAi knockdown, co-immunoprecipitation, blue native PAGE, electron microscopy, BN-PAGE respiratory complex assembly assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, co-IP, EM, BN-PAGE), clean functional phenotypes linking Sam50 to cristae and respiratory complex assembly","pmids":["22252321"],"is_preprint":false},{"year":2015,"finding":"Mitofilin and CHCHD6 directly interact with Sam50; immunoprecipitation experiments identified a complex containing Mitofilin, Sam50, CHCHD3, and CHCHD6. Knockout of Mitofilin (but not CHCHD6) disrupted binding partners controlling cristae morphology. Direct binding of Mitofilin and CHCHD6 to Sam50 was demonstrated, and MICOS-Sam50 interaction is required for cristae organization and mitochondrial membrane potential.","method":"TALEN-mediated knockdown/knockout, immunoprecipitation, transmission electron microscopy, mitochondrial membrane potential measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction demonstrated, functional consequences measured, single lab with multiple orthogonal methods","pmids":["26530328"],"is_preprint":false},{"year":2017,"finding":"Granzyme B (and granzyme A and caspase-3) enter mitochondria through a pathway that requires Sam50 (the central SAM subunit) for outer membrane transit, independently of the TOM complex. Depletion of Sam50 reduces granzyme-mediated ROS production and cell death; mutation of GB residues K243/R244 also reduces mitochondrial entry.","method":"RNAi knockdown of Sam50, in vitro import assays, cell death/ROS measurement, site-directed mutagenesis of granzyme B","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with defined functional phenotype and mutagenesis, single lab","pmids":["28338658"],"is_preprint":false},{"year":2018,"finding":"SAMM50 is N-myristoylated at its N-terminus, and this lipid modification is required for proper mitochondrial targeting of SAMM50; the non-myristoylated G2A mutant fails to localize to mitochondria. N-myristoylation of MIC19 is also required for its interaction with SAMM50.","method":"In vitro and in vivo metabolic labeling, immunofluorescence, subcellular fractionation, immunoprecipitation with G2A mutant","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolic labeling plus mutagenesis plus localization, single lab with multiple methods","pmids":["30427857"],"is_preprint":false},{"year":2019,"finding":"Sam50 directly interacts with Mic19 (a MICOS component) and Mic60 to form the Sam50-Mic19-Mic60 axis, which connects the SAM and MICOS complexes into the MIB supercomplex. This axis mediates OMM-IMM contacts and is required for normal cristae junction formation and cristae distribution. OMA1-mediated cleavage of Mic19 disrupts this axis and leads to MIB disassembly. Sam50 displays punctate distribution at the OMM and acts as an anchoring point for cristae junction formation.","method":"Co-immunoprecipitation, super-resolution microscopy, OMA1 protease cleavage assays, MICOS/SAM complex disruption experiments, ATP measurement","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, super-resolution localization, functional rescue, protease assays), single lab but comprehensive study","pmids":["31097788"],"is_preprint":false},{"year":2021,"finding":"SAMM50 acts as a mitophagy receptor by directly interacting with ATG8 family proteins via a canonical LIR (LC3-interacting region) motif and with p62/SQSTM1, mediating basal piecemeal mitophagy of SAM and MICOS complex components. Upon metabolic switch to oxidative phosphorylation, SAMM50 cooperates with p62 to mediate efficient mitophagy of these components.","method":"Co-immunoprecipitation, LIR motif mutation, autophagy flux assays, mitophagy reporter assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction demonstrated with canonical motif mutagenesis, multiple functional readouts of mitophagy, replicated in companion commentary (PMID:34275433)","pmids":["34037656","34275433"],"is_preprint":false},{"year":2022,"finding":"Sam50 interacts with MICOS complex and ATAD3 to form the Sam50-MICOS-ATAD3-mtDNA axis, maintaining mtDNA stability. Sam50 cooperates with Mic60 to bind cardiolipin, maintaining mitochondrial membrane integrity. Sam50 depletion causes cardiolipin externalization, triggering Bax mitochondrial recruitment, mtDNA aggregation and release, and subsequent cGAS-STING pathway activation and liver inflammation.","method":"Co-immunoprecipitation, cardiolipin binding assays, liver-specific Sam50 knockout mice, ACETAMINOPHEN model, cGAS-STING pathway activation measurement, electron microscopy","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO, multiple orthogonal biochemical assays, mechanistic pathway elucidation with rescue experiments","pmids":["35313046"],"is_preprint":false},{"year":2016,"finding":"SAMM50 overexpression causes Drp1-dependent mitochondrial fragmentation in HeLa cells, reversible by co-expression with MFN2. SAMM50 interacts physically with Drp1 both in vivo (co-IP) and in vitro (pulldown). SAMM50 knockdown leads to decreased mitochondrial Drp1 levels, decreased OPA1, and a swollen mitochondrial phenotype; mitochondrial inheritance is impaired in SAMM50-silenced cells.","method":"Co-immunoprecipitation, GST-pulldown in vitro, confocal microscopy, RNAi knockdown, overexpression","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays in vivo and in vitro, functional phenotype with specific readouts, single lab","pmids":["27059175"],"is_preprint":false},{"year":2017,"finding":"Nanoscale electron tomography mapping of tagged Sam50, Mic19, and Mic60 in mitochondria revealed that Sam50 is not uniformly distributed in the outer mitochondrial membrane and incompletely overlaps with Mic19- and Mic60-positive domains, particularly at crista junctions, suggesting spatially organized interactions.","method":"miniSOG and APEX2 genetic tagging, electron tomography","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct nanoscale localization with functional genetic tags, single lab, localization study without complete functional consequence dissection","pmids":["28808085"],"is_preprint":false},{"year":2021,"finding":"SAMM50 deficiency in vitro results in increased lipid accumulation due to decreased fatty acid oxidation; overexpression of SAMM50 enhances fatty acid oxidation and mitigates intracellular lipid accumulation.","method":"In vitro cell culture, SAMM50 overexpression and knockdown, fatty acid oxidation assays, lipid accumulation staining","journal":"FEBS open bio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, in vitro cell-based assays only, limited mechanistic resolution beyond phenotypic description","pmids":["33728819"],"is_preprint":false},{"year":2021,"finding":"Samm50 interacts with Pink1 and stimulates accumulation of Parkin on mitochondria to initiate mitophagy; Samm50 overexpression reduces mitophagy and promotes cardiac hypertrophy, while Samm50 knockdown increases mitophagy and protects against hypertrophy. The protective effect of Samm50 deficiency against hypertrophy is abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown.","method":"Co-immunoprecipitation, lentiviral overexpression and knockdown, immunofluorescence, qPCR, pharmacological inhibition of mitophagy, genetic epistasis with Pink1 knockdown","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genetic epistasis with Pink1 KD, multiple readouts, single lab","pmids":["34631840"],"is_preprint":false},{"year":2024,"finding":"Sam50 interacts with serine hydroxymethyltransferase 2 (Shmt2); this interaction was identified by co-immunoprecipitation/mass spectrometry. Shmt2 acts downstream of Sam50 to hinder Bax translocation from cytoplasm to mitochondria and subsequent caspase-3 activation. Inhibition of Shmt2 abolished the cardioprotective effect of Sam50 overexpression.","method":"Co-immunoprecipitation/mass spectrometry, overexpression and knockdown, Bax localization assays, caspase-3 activity measurement, cardiac MI model in vivo","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/MS partner identification plus functional epistasis with Shmt2 inhibition, single lab","pmids":["38723737"],"is_preprint":false},{"year":2011,"finding":"Neisserial Omp85, but not other bacterial beta-barrel proteins, can be selectively imported and integrated into the outer mitochondrial membrane of human cells; this occurs via the TOM and SAM complexes. Omp85 alone enables integration of other bacterial beta-barrel proteins in human mitochondria but cannot substitute for the function of Sam50, demonstrating that Sam50 has species-specific functions not replaceable by its bacterial homolog.","method":"In vitro import assays in isolated human mitochondria, RNAi depletion of SAM/TOM components, native PAGE","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro import reconstitution with RNAi epistasis, single lab","pmids":["21652692"],"is_preprint":false},{"year":2026,"finding":"Sam50 folds through parallel pathways with at least two transition states; the folding nucleus is at the N-terminus while the C-terminal region is kinetically trapped. The POTRA domain is dispensable for Sam50 channel function. Destabilizing hotspot residues in Sam50 are linked to its gating function, and 165 Ala substitution scan correlated per-residue stability with SAM-assisted assembly.","method":"Single-molecule electrophysiology, in vivo function assays, alanine scanning mutagenesis (165 substitutions), stability measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — comprehensive mutagenesis (165 variants), electrophysiology, in vivo functional assays, and stability measurements in a single rigorous study","pmids":["41927578"],"is_preprint":false},{"year":2025,"finding":"The SAMM50 rs3761472 SNP (encoding a D110G substitution) impairs mitochondrial integrity by downregulating key regulators of mitochondrial architecture, dynamics, and quality control; Samm50-KI mice show reduced ATP production, elevated oxidative stress and inflammation, insulin resistance, glucose intolerance, and pronounced hepatic lipid accumulation on a high-fat diet.","method":"CRISPR/Cas9 knock-in mice with D110G substitution, high-fat diet feeding, mitochondrial function assays, metabolic phenotyping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with multiple phenotypic readouts, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.06.04.657815"],"is_preprint":true}],"current_model":"SAMM50/Sam50 is an essential 16-stranded beta-barrel protein of the mitochondrial outer membrane that serves as the central channel-forming subunit of the SAM (sorting and assembly machinery) complex, responsible for inserting beta-barrel proteins (including VDAC/porin and Tom40) into the outer membrane; it physically bridges the outer and inner mitochondrial membranes by forming the Sam50-Mic19-Mic60 axis within the MIB supercomplex, which is required for cristae junction formation, respiratory complex assembly, and mtDNA stability (maintained through cooperation with MICOS and ATAD3); Sam50 also binds cardiolipin to maintain membrane integrity, acts as a mitophagy receptor via a LIR motif interacting with ATG8 proteins and p62/SQSTM1 for piecemeal degradation of SAM/MICOS components, facilitates non-canonical mitochondrial entry of cytotoxic proteases (granzymes) via its beta-barrel channel, interacts with Drp1 to regulate mitochondrial fission dynamics, and requires N-myristoylation for its proper mitochondrial targeting."},"narrative":{"mechanistic_narrative":"SAMM50/Sam50 is the essential beta-barrel core of the mitochondrial outer-membrane sorting and assembly machinery (SAM) complex, where it drives the membrane insertion of beta-barrel substrates including Tom40 and porin/VDAC, with matrix protein import remaining unaffected by its loss [PMID:14570913, PMID:14699090, PMID:17510655]. Its barrel architecture folds through parallel pathways nucleated at the N-terminus, and its channel gating—rather than the POTRA domain—is the functionally critical feature for SAM-assisted assembly [PMID:41927578]. Beyond substrate insertion, Sam50 physically bridges the outer and inner membranes by forming a Sam50-Mic19-Mic60 axis that joins the SAM and MICOS complexes into the larger MIB supercomplex, an interaction required for cristae junction formation, cristae integrity, and the assembly of respiratory chain complexes containing mitochondrially encoded subunits [PMID:22252321, PMID:31097788]. Sam50 cooperates with Mic60 to bind cardiolipin and, together with MICOS and ATAD3, maintains mtDNA stability; its loss causes cardiolipin externalization, Bax recruitment, mtDNA release, and cGAS-STING-driven inflammation in liver [PMID:35313046]. Sam50 additionally functions as a mitophagy receptor through a canonical LIR motif that engages ATG8-family proteins and p62/SQSTM1 to mediate piecemeal degradation of SAM and MICOS components [PMID:34037656, PMID:34275433], and it interacts with Drp1 to influence mitochondrial fission and inheritance [PMID:27059175]. Its beta-barrel channel provides a TOM-independent route for cytotoxic granzymes to enter mitochondria during cell death [PMID:28338658], and proper mitochondrial targeting of Sam50 requires N-myristoylation of its N-terminus [PMID:30427857]. A naturally occurring D110G variant impairs mitochondrial architecture and provokes metabolic dysfunction in vivo, linking SAMM50 to mitochondrial integrity in disease contexts [PMID:bio_10.1101_2025.06.04.657815].","teleology":[{"year":2003,"claim":"Established that Sam50 is the essential machinery component for inserting beta-barrel proteins into the mitochondrial outer membrane, defining a dedicated assembly pathway distinct from matrix protein import.","evidence":"Yeast conditional omp85 mutants with biochemical fractionation and import assays","pmids":["14570913","14699090"],"confidence":"High","gaps":["Did not resolve the structural basis of substrate recognition","Human relevance not yet tested"]},{"year":2007,"claim":"Extended the beta-barrel assembly role to human cells and placed Sam50 in a biogenesis pathway with TOM and metaxins, while revealing it also co-purifies with inner-membrane MICOS proteins, hinting at a trans-membrane bridging role.","evidence":"RNAi knockdown with native PAGE and co-IP in human cells; mitofilin immunocapture with mass spectrometry","pmids":["17510655","17624330"],"confidence":"Medium","gaps":["Whether MICOS co-purification reflects direct binding was unresolved","Functional consequence of the large assembly not dissected"]},{"year":2012,"claim":"Showed that Sam50-anchored OMM-IMM contacts (the MIB complex) are required for cristae integrity and respiratory complex assembly, connecting outer-membrane machinery to inner-membrane organization.","evidence":"RNAi knockdown, co-IP, blue native PAGE, electron microscopy","pmids":["22252321"],"confidence":"High","gaps":["Did not identify which direct interactions hold the bridge together","Mechanism linking contacts to respiratory assembly unclear"]},{"year":2015,"claim":"Demonstrated direct binding of Mitofilin and CHCHD6 to Sam50 and showed the MICOS-Sam50 interaction controls cristae morphology and membrane potential.","evidence":"TALEN knockout, immunoprecipitation, transmission EM, membrane potential measurement","pmids":["26530328"],"confidence":"Medium","gaps":["Single-lab interaction mapping","Stoichiometry of the bridging complex not defined"]},{"year":2016,"claim":"Identified Sam50 as a physical Drp1 partner that influences fission machinery levels and mitochondrial inheritance, broadening its role into fission dynamics.","evidence":"Reciprocal co-IP and GST-pulldown, confocal microscopy, RNAi and overexpression","pmids":["27059175"],"confidence":"Medium","gaps":["Mechanism by which Sam50 regulates Drp1 recruitment unknown","Single lab"]},{"year":2017,"claim":"Resolved the spatial organization of Sam50, showing punctate, non-uniform distribution that partially overlaps MICOS domains at crista junctions, and demonstrated its barrel mediates TOM-independent granzyme entry into mitochondria.","evidence":"miniSOG/APEX2 electron tomography; RNAi with import and ROS/cell-death assays plus granzyme B mutagenesis","pmids":["28808085","28338658"],"confidence":"Medium","gaps":["How granzyme cargo is selected by the channel unresolved","Functional consequence of spatial domains not fully dissected"]},{"year":2018,"claim":"Established N-myristoylation as a requirement for Sam50 mitochondrial targeting and for MIC19-Sam50 interaction.","evidence":"Metabolic labeling, G2A mutagenesis, immunofluorescence, subcellular fractionation, co-IP","pmids":["30427857"],"confidence":"Medium","gaps":["Enzyme catalyzing the modification not identified","Single lab"]},{"year":2019,"claim":"Defined the Sam50-Mic19-Mic60 axis as the molecular bridge uniting SAM and MICOS into the MIB supercomplex, with OMA1 cleavage of Mic19 acting as a regulatory switch for bridge integrity.","evidence":"Co-IP, super-resolution microscopy, OMA1 protease cleavage assays, ATP measurement","pmids":["31097788"],"confidence":"High","gaps":["Structural detail of the axis lacking","Trigger for OMA1-mediated regulation in vivo unclear"]},{"year":2021,"claim":"Identified Sam50 as a LIR-motif mitophagy receptor mediating piecemeal degradation of SAM/MICOS components, and connected it to PINK1/Parkin-dependent mitophagy and lipid metabolism.","evidence":"Co-IP with LIR mutation and mitophagy flux assays; PINK1 co-IP with genetic epistasis; fatty acid oxidation and lipid accumulation assays","pmids":["34037656","34275433","34631840","33728819"],"confidence":"High","gaps":["How piecemeal cargo selection is restricted to SAM/MICOS unclear","Lipid metabolism link is low-confidence and phenotypic only"]},{"year":2022,"claim":"Established the Sam50-MICOS-ATAD3-mtDNA axis and cardiolipin binding as guardians of mtDNA stability and membrane integrity, with loss driving Bax recruitment, mtDNA release, and cGAS-STING inflammation.","evidence":"Liver-specific Sam50 knockout mice, cardiolipin binding assays, acetaminophen model, cGAS-STING measurement, EM","pmids":["35313046"],"confidence":"High","gaps":["Direct lipid-binding residues not mapped","Whether cardiolipin externalization is cause or consequence not fully resolved"]},{"year":2024,"claim":"Identified Shmt2 as a downstream Sam50 effector that limits Bax translocation and caspase-3 activation, extending Sam50's cardioprotective signaling.","evidence":"Co-IP/MS, overexpression and knockdown, Bax localization and caspase-3 assays, cardiac MI model","pmids":["38723737"],"confidence":"Medium","gaps":["Direct vs indirect Sam50-Shmt2 interaction not confirmed","Single lab"]},{"year":2026,"claim":"Provided the biophysical folding and gating logic of the Sam50 barrel, showing N-terminal folding nucleation, a dispensable POTRA domain, and gating-linked stability hotspots that govern SAM-assisted assembly.","evidence":"Single-molecule electrophysiology, in vivo function assays, 165-variant alanine scanning, stability measurements","pmids":["41927578"],"confidence":"High","gaps":["High-resolution structure of the assembled SAM with substrate not provided","Link between gating and substrate insertion mechanism incomplete"]},{"year":2025,"claim":"Linked a natural SAMM50 D110G variant to impaired mitochondrial architecture and metabolic disease phenotypes in vivo.","evidence":"CRISPR/Cas9 D110G knock-in mice, high-fat diet, mitochondrial function and metabolic phenotyping (preprint)","pmids":["bio_10.1101_2025.06.04.657815"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Molecular mechanism of how D110G perturbs barrel function not defined"]},{"year":null,"claim":"How Sam50's multiple roles—barrel assembly, MIB bridging, mitophagy receptor, fission regulation, and cardiolipin/mtDNA maintenance—are coordinated or switched within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of Sam50 in distinct functional states","Regulatory logic partitioning its functions is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,16]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[5,16]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]}],"complexes":["SAM complex","MIB supercomplex","MICOS complex"],"partners":["MIC60","MIC19","CHCHD6","MTX1","MTX2","DNM1L","ATAD3A","SHMT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y512","full_name":"Sorting and assembly machinery component 50 homolog","aliases":["Transformation-related gene 3 protein","TRG-3"],"length_aa":469,"mass_kda":52.0,"function":"Plays a crucial role in the maintenance of the structure of mitochondrial cristae and the proper assembly of the mitochondrial respiratory chain complexes (PubMed:22252321, PubMed:25781180). Required for the assembly of TOMM40 into the TOM complex (PubMed:15644312)","subcellular_location":"Mitochondrion outer membrane; Cytoplasm; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9Y512/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SAMM50","classification":"Common Essential","n_dependent_lines":765,"n_total_lines":1208,"dependency_fraction":0.6332781456953642},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DNAJC11","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/SAMM50","total_profiled":1310},"omim":[{"mim_id":"616574","title":"MITOCHONDRIAL CONTACT SITE AND CRISTAE ORGANIZING SYSTEM, 10-KD SUBUNIT; MICOS10","url":"https://www.omim.org/entry/616574"},{"mim_id":"615634","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 6; CHCHD6","url":"https://www.omim.org/entry/615634"},{"mim_id":"615623","title":"CYTOCHROME C OXIDASE ASSEMBLY FACTOR 7; COA7","url":"https://www.omim.org/entry/615623"},{"mim_id":"613748","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 3; CHCHD3","url":"https://www.omim.org/entry/613748"},{"mim_id":"612364","title":"ALANINE AMINOTRANSFERASE, PLASMA LEVEL OF, QUANTITATIVE TRAIT LOCUS 2","url":"https://www.omim.org/entry/612364"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":225.2}],"url":"https://www.proteinatlas.org/search/SAMM50"},"hgnc":{"alias_symbol":["CGI-51","TRG-3","YNL026W","OMP85","TOB55","SAM50"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y512","domains":[{"cath_id":"3.10.20.310","chopping":"47-125","consensus_level":"high","plddt":89.5571,"start":47,"end":125},{"cath_id":"2.40.160.50","chopping":"181-466","consensus_level":"medium","plddt":91.3677,"start":181,"end":466}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y512","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y512-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y512-F1-predicted_aligned_error_v6.png","plddt_mean":85.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SAMM50","jax_strain_url":"https://www.jax.org/strain/search?query=SAMM50"},"sequence":{"accession":"Q9Y512","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y512.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y512/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y512"}},"corpus_meta":[{"pmid":"14699090","id":"PMC_14699090","title":"The Omp85 family of proteins is essential for outer membrane biogenesis in mitochondria and bacteria.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14699090","citation_count":314,"is_preprint":false},{"pmid":"17090219","id":"PMC_17090219","title":"Assembly factor Omp85 recognizes its outer membrane protein substrates by a species-specific C-terminal motif.","date":"2006","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/17090219","citation_count":280,"is_preprint":false},{"pmid":"14570913","id":"PMC_14570913","title":"An essential role of Sam50 in the protein sorting and assembly machinery of the mitochondrial outer membrane.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14570913","citation_count":273,"is_preprint":false},{"pmid":"17702945","id":"PMC_17702945","title":"Structure of the membrane protein FhaC: a member of the Omp85-TpsB transporter 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\"finding\": \"Sam50 (Omp85 family) is an essential subunit of the sorting and assembly machinery (SAM) complex in the mitochondrial outer membrane, required for the assembly of beta-barrel proteins Tom40 and porin (VDAC) into the outer membrane; yeast conditional omp85 mutants showed defective insertion of VDAC and TOM complex components, while import of matrix proteins was unaffected.\",\n      \"method\": \"Yeast conditional mutants, biochemical fractionation, import assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with specific phenotypic readout, replicated across two independent labs (PMID:14699090 and PMID:14570913)\",\n      \"pmids\": [\"14570913\", \"14699090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Sam50 depletion by RNAi in human cells causes strong defects in VDAC assembly and reduced steady-state VDAC levels; Sam50-depleted mitochondria also show reduced levels of metaxin 1 and 2, implying a connection between Sam50 and metaxins, though they appear to reside in distinct complexes. The pathway of VDAC biogenesis involves TOM complex, Sam50, and metaxins and is evolutionarily conserved.\",\n      \"method\": \"RNAi knockdown, import assays, native gel electrophoresis, co-immunoprecipitation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, in vitro import, native PAGE), independently replicated concept across organisms\",\n      \"pmids\": [\"17510655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SAM50 co-immunoprecipitates with mitofilin (inner membrane), metaxins 1 and 2, CHCHD3, CHCHD6, and DnaJC11 as part of a large mitochondrial complex, indicating that Sam50 participates in a multi-protein assembly spanning the outer and inner mitochondrial membranes.\",\n      \"method\": \"Immunocapture with monoclonal antibody against mitofilin followed by mass spectrometry identification of co-purifying proteins\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single immunocapture experiment but multiple co-purifying proteins identified by MS; functional consequence not fully dissected in this paper\",\n      \"pmids\": [\"17624330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sam50 is part of a large mitochondrial intermembrane space bridging (MIB) complex together with IMM proteins mitofilin and CHCHD3; disruption of MIB complex (via Sam50 depletion) causes loss of cristae integrity and deficiency in assembly of respiratory chain complexes containing mitochondrially encoded subunits, linking OMM-IMM contacts to respiratory complex biogenesis.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, blue native PAGE, electron microscopy, BN-PAGE respiratory complex assembly assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, co-IP, EM, BN-PAGE), clean functional phenotypes linking Sam50 to cristae and respiratory complex assembly\",\n      \"pmids\": [\"22252321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mitofilin and CHCHD6 directly interact with Sam50; immunoprecipitation experiments identified a complex containing Mitofilin, Sam50, CHCHD3, and CHCHD6. Knockout of Mitofilin (but not CHCHD6) disrupted binding partners controlling cristae morphology. Direct binding of Mitofilin and CHCHD6 to Sam50 was demonstrated, and MICOS-Sam50 interaction is required for cristae organization and mitochondrial membrane potential.\",\n      \"method\": \"TALEN-mediated knockdown/knockout, immunoprecipitation, transmission electron microscopy, mitochondrial membrane potential measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction demonstrated, functional consequences measured, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26530328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Granzyme B (and granzyme A and caspase-3) enter mitochondria through a pathway that requires Sam50 (the central SAM subunit) for outer membrane transit, independently of the TOM complex. Depletion of Sam50 reduces granzyme-mediated ROS production and cell death; mutation of GB residues K243/R244 also reduces mitochondrial entry.\",\n      \"method\": \"RNAi knockdown of Sam50, in vitro import assays, cell death/ROS measurement, site-directed mutagenesis of granzyme B\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with defined functional phenotype and mutagenesis, single lab\",\n      \"pmids\": [\"28338658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SAMM50 is N-myristoylated at its N-terminus, and this lipid modification is required for proper mitochondrial targeting of SAMM50; the non-myristoylated G2A mutant fails to localize to mitochondria. N-myristoylation of MIC19 is also required for its interaction with SAMM50.\",\n      \"method\": \"In vitro and in vivo metabolic labeling, immunofluorescence, subcellular fractionation, immunoprecipitation with G2A mutant\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolic labeling plus mutagenesis plus localization, single lab with multiple methods\",\n      \"pmids\": [\"30427857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sam50 directly interacts with Mic19 (a MICOS component) and Mic60 to form the Sam50-Mic19-Mic60 axis, which connects the SAM and MICOS complexes into the MIB supercomplex. This axis mediates OMM-IMM contacts and is required for normal cristae junction formation and cristae distribution. OMA1-mediated cleavage of Mic19 disrupts this axis and leads to MIB disassembly. Sam50 displays punctate distribution at the OMM and acts as an anchoring point for cristae junction formation.\",\n      \"method\": \"Co-immunoprecipitation, super-resolution microscopy, OMA1 protease cleavage assays, MICOS/SAM complex disruption experiments, ATP measurement\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, super-resolution localization, functional rescue, protease assays), single lab but comprehensive study\",\n      \"pmids\": [\"31097788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SAMM50 acts as a mitophagy receptor by directly interacting with ATG8 family proteins via a canonical LIR (LC3-interacting region) motif and with p62/SQSTM1, mediating basal piecemeal mitophagy of SAM and MICOS complex components. Upon metabolic switch to oxidative phosphorylation, SAMM50 cooperates with p62 to mediate efficient mitophagy of these components.\",\n      \"method\": \"Co-immunoprecipitation, LIR motif mutation, autophagy flux assays, mitophagy reporter assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction demonstrated with canonical motif mutagenesis, multiple functional readouts of mitophagy, replicated in companion commentary (PMID:34275433)\",\n      \"pmids\": [\"34037656\", \"34275433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sam50 interacts with MICOS complex and ATAD3 to form the Sam50-MICOS-ATAD3-mtDNA axis, maintaining mtDNA stability. Sam50 cooperates with Mic60 to bind cardiolipin, maintaining mitochondrial membrane integrity. Sam50 depletion causes cardiolipin externalization, triggering Bax mitochondrial recruitment, mtDNA aggregation and release, and subsequent cGAS-STING pathway activation and liver inflammation.\",\n      \"method\": \"Co-immunoprecipitation, cardiolipin binding assays, liver-specific Sam50 knockout mice, ACETAMINOPHEN model, cGAS-STING pathway activation measurement, electron microscopy\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO, multiple orthogonal biochemical assays, mechanistic pathway elucidation with rescue experiments\",\n      \"pmids\": [\"35313046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SAMM50 overexpression causes Drp1-dependent mitochondrial fragmentation in HeLa cells, reversible by co-expression with MFN2. SAMM50 interacts physically with Drp1 both in vivo (co-IP) and in vitro (pulldown). SAMM50 knockdown leads to decreased mitochondrial Drp1 levels, decreased OPA1, and a swollen mitochondrial phenotype; mitochondrial inheritance is impaired in SAMM50-silenced cells.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown in vitro, confocal microscopy, RNAi knockdown, overexpression\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays in vivo and in vitro, functional phenotype with specific readouts, single lab\",\n      \"pmids\": [\"27059175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nanoscale electron tomography mapping of tagged Sam50, Mic19, and Mic60 in mitochondria revealed that Sam50 is not uniformly distributed in the outer mitochondrial membrane and incompletely overlaps with Mic19- and Mic60-positive domains, particularly at crista junctions, suggesting spatially organized interactions.\",\n      \"method\": \"miniSOG and APEX2 genetic tagging, electron tomography\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct nanoscale localization with functional genetic tags, single lab, localization study without complete functional consequence dissection\",\n      \"pmids\": [\"28808085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SAMM50 deficiency in vitro results in increased lipid accumulation due to decreased fatty acid oxidation; overexpression of SAMM50 enhances fatty acid oxidation and mitigates intracellular lipid accumulation.\",\n      \"method\": \"In vitro cell culture, SAMM50 overexpression and knockdown, fatty acid oxidation assays, lipid accumulation staining\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, in vitro cell-based assays only, limited mechanistic resolution beyond phenotypic description\",\n      \"pmids\": [\"33728819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Samm50 interacts with Pink1 and stimulates accumulation of Parkin on mitochondria to initiate mitophagy; Samm50 overexpression reduces mitophagy and promotes cardiac hypertrophy, while Samm50 knockdown increases mitophagy and protects against hypertrophy. The protective effect of Samm50 deficiency against hypertrophy is abolished by inhibiting mitophagy through Vps34 inhibitor or Pink1 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, lentiviral overexpression and knockdown, immunofluorescence, qPCR, pharmacological inhibition of mitophagy, genetic epistasis with Pink1 knockdown\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genetic epistasis with Pink1 KD, multiple readouts, single lab\",\n      \"pmids\": [\"34631840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sam50 interacts with serine hydroxymethyltransferase 2 (Shmt2); this interaction was identified by co-immunoprecipitation/mass spectrometry. Shmt2 acts downstream of Sam50 to hinder Bax translocation from cytoplasm to mitochondria and subsequent caspase-3 activation. Inhibition of Shmt2 abolished the cardioprotective effect of Sam50 overexpression.\",\n      \"method\": \"Co-immunoprecipitation/mass spectrometry, overexpression and knockdown, Bax localization assays, caspase-3 activity measurement, cardiac MI model in vivo\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/MS partner identification plus functional epistasis with Shmt2 inhibition, single lab\",\n      \"pmids\": [\"38723737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Neisserial Omp85, but not other bacterial beta-barrel proteins, can be selectively imported and integrated into the outer mitochondrial membrane of human cells; this occurs via the TOM and SAM complexes. Omp85 alone enables integration of other bacterial beta-barrel proteins in human mitochondria but cannot substitute for the function of Sam50, demonstrating that Sam50 has species-specific functions not replaceable by its bacterial homolog.\",\n      \"method\": \"In vitro import assays in isolated human mitochondria, RNAi depletion of SAM/TOM components, native PAGE\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro import reconstitution with RNAi epistasis, single lab\",\n      \"pmids\": [\"21652692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Sam50 folds through parallel pathways with at least two transition states; the folding nucleus is at the N-terminus while the C-terminal region is kinetically trapped. The POTRA domain is dispensable for Sam50 channel function. Destabilizing hotspot residues in Sam50 are linked to its gating function, and 165 Ala substitution scan correlated per-residue stability with SAM-assisted assembly.\",\n      \"method\": \"Single-molecule electrophysiology, in vivo function assays, alanine scanning mutagenesis (165 substitutions), stability measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — comprehensive mutagenesis (165 variants), electrophysiology, in vivo functional assays, and stability measurements in a single rigorous study\",\n      \"pmids\": [\"41927578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The SAMM50 rs3761472 SNP (encoding a D110G substitution) impairs mitochondrial integrity by downregulating key regulators of mitochondrial architecture, dynamics, and quality control; Samm50-KI mice show reduced ATP production, elevated oxidative stress and inflammation, insulin resistance, glucose intolerance, and pronounced hepatic lipid accumulation on a high-fat diet.\",\n      \"method\": \"CRISPR/Cas9 knock-in mice with D110G substitution, high-fat diet feeding, mitochondrial function assays, metabolic phenotyping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with multiple phenotypic readouts, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.04.657815\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SAMM50/Sam50 is an essential 16-stranded beta-barrel protein of the mitochondrial outer membrane that serves as the central channel-forming subunit of the SAM (sorting and assembly machinery) complex, responsible for inserting beta-barrel proteins (including VDAC/porin and Tom40) into the outer membrane; it physically bridges the outer and inner mitochondrial membranes by forming the Sam50-Mic19-Mic60 axis within the MIB supercomplex, which is required for cristae junction formation, respiratory complex assembly, and mtDNA stability (maintained through cooperation with MICOS and ATAD3); Sam50 also binds cardiolipin to maintain membrane integrity, acts as a mitophagy receptor via a LIR motif interacting with ATG8 proteins and p62/SQSTM1 for piecemeal degradation of SAM/MICOS components, facilitates non-canonical mitochondrial entry of cytotoxic proteases (granzymes) via its beta-barrel channel, interacts with Drp1 to regulate mitochondrial fission dynamics, and requires N-myristoylation for its proper mitochondrial targeting.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SAMM50/Sam50 is the essential beta-barrel core of the mitochondrial outer-membrane sorting and assembly machinery (SAM) complex, where it drives the membrane insertion of beta-barrel substrates including Tom40 and porin/VDAC, with matrix protein import remaining unaffected by its loss [#0, #1]. Its barrel architecture folds through parallel pathways nucleated at the N-terminus, and its channel gating—rather than the POTRA domain—is the functionally critical feature for SAM-assisted assembly [#16]. Beyond substrate insertion, Sam50 physically bridges the outer and inner membranes by forming a Sam50-Mic19-Mic60 axis that joins the SAM and MICOS complexes into the larger MIB supercomplex, an interaction required for cristae junction formation, cristae integrity, and the assembly of respiratory chain complexes containing mitochondrially encoded subunits [#3, #7]. Sam50 cooperates with Mic60 to bind cardiolipin and, together with MICOS and ATAD3, maintains mtDNA stability; its loss causes cardiolipin externalization, Bax recruitment, mtDNA release, and cGAS-STING-driven inflammation in liver [#9]. Sam50 additionally functions as a mitophagy receptor through a canonical LIR motif that engages ATG8-family proteins and p62/SQSTM1 to mediate piecemeal degradation of SAM and MICOS components [#8], and it interacts with Drp1 to influence mitochondrial fission and inheritance [#10]. Its beta-barrel channel provides a TOM-independent route for cytotoxic granzymes to enter mitochondria during cell death [#5], and proper mitochondrial targeting of Sam50 requires N-myristoylation of its N-terminus [#6]. A naturally occurring D110G variant impairs mitochondrial architecture and provokes metabolic dysfunction in vivo, linking SAMM50 to mitochondrial integrity in disease contexts [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that Sam50 is the essential machinery component for inserting beta-barrel proteins into the mitochondrial outer membrane, defining a dedicated assembly pathway distinct from matrix protein import.\",\n      \"evidence\": \"Yeast conditional omp85 mutants with biochemical fractionation and import assays\",\n      \"pmids\": [\"14570913\", \"14699090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of substrate recognition\", \"Human relevance not yet tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended the beta-barrel assembly role to human cells and placed Sam50 in a biogenesis pathway with TOM and metaxins, while revealing it also co-purifies with inner-membrane MICOS proteins, hinting at a trans-membrane bridging role.\",\n      \"evidence\": \"RNAi knockdown with native PAGE and co-IP in human cells; mitofilin immunocapture with mass spectrometry\",\n      \"pmids\": [\"17510655\", \"17624330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MICOS co-purification reflects direct binding was unresolved\", \"Functional consequence of the large assembly not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed that Sam50-anchored OMM-IMM contacts (the MIB complex) are required for cristae integrity and respiratory complex assembly, connecting outer-membrane machinery to inner-membrane organization.\",\n      \"evidence\": \"RNAi knockdown, co-IP, blue native PAGE, electron microscopy\",\n      \"pmids\": [\"22252321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify which direct interactions hold the bridge together\", \"Mechanism linking contacts to respiratory assembly unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated direct binding of Mitofilin and CHCHD6 to Sam50 and showed the MICOS-Sam50 interaction controls cristae morphology and membrane potential.\",\n      \"evidence\": \"TALEN knockout, immunoprecipitation, transmission EM, membrane potential measurement\",\n      \"pmids\": [\"26530328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab interaction mapping\", \"Stoichiometry of the bridging complex not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified Sam50 as a physical Drp1 partner that influences fission machinery levels and mitochondrial inheritance, broadening its role into fission dynamics.\",\n      \"evidence\": \"Reciprocal co-IP and GST-pulldown, confocal microscopy, RNAi and overexpression\",\n      \"pmids\": [\"27059175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Sam50 regulates Drp1 recruitment unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the spatial organization of Sam50, showing punctate, non-uniform distribution that partially overlaps MICOS domains at crista junctions, and demonstrated its barrel mediates TOM-independent granzyme entry into mitochondria.\",\n      \"evidence\": \"miniSOG/APEX2 electron tomography; RNAi with import and ROS/cell-death assays plus granzyme B mutagenesis\",\n      \"pmids\": [\"28808085\", \"28338658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How granzyme cargo is selected by the channel unresolved\", \"Functional consequence of spatial domains not fully dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established N-myristoylation as a requirement for Sam50 mitochondrial targeting and for MIC19-Sam50 interaction.\",\n      \"evidence\": \"Metabolic labeling, G2A mutagenesis, immunofluorescence, subcellular fractionation, co-IP\",\n      \"pmids\": [\"30427857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme catalyzing the modification not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the Sam50-Mic19-Mic60 axis as the molecular bridge uniting SAM and MICOS into the MIB supercomplex, with OMA1 cleavage of Mic19 acting as a regulatory switch for bridge integrity.\",\n      \"evidence\": \"Co-IP, super-resolution microscopy, OMA1 protease cleavage assays, ATP measurement\",\n      \"pmids\": [\"31097788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the axis lacking\", \"Trigger for OMA1-mediated regulation in vivo unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified Sam50 as a LIR-motif mitophagy receptor mediating piecemeal degradation of SAM/MICOS components, and connected it to PINK1/Parkin-dependent mitophagy and lipid metabolism.\",\n      \"evidence\": \"Co-IP with LIR mutation and mitophagy flux assays; PINK1 co-IP with genetic epistasis; fatty acid oxidation and lipid accumulation assays\",\n      \"pmids\": [\"34037656\", \"34275433\", \"34631840\", \"33728819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How piecemeal cargo selection is restricted to SAM/MICOS unclear\", \"Lipid metabolism link is low-confidence and phenotypic only\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the Sam50-MICOS-ATAD3-mtDNA axis and cardiolipin binding as guardians of mtDNA stability and membrane integrity, with loss driving Bax recruitment, mtDNA release, and cGAS-STING inflammation.\",\n      \"evidence\": \"Liver-specific Sam50 knockout mice, cardiolipin binding assays, acetaminophen model, cGAS-STING measurement, EM\",\n      \"pmids\": [\"35313046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lipid-binding residues not mapped\", \"Whether cardiolipin externalization is cause or consequence not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified Shmt2 as a downstream Sam50 effector that limits Bax translocation and caspase-3 activation, extending Sam50's cardioprotective signaling.\",\n      \"evidence\": \"Co-IP/MS, overexpression and knockdown, Bax localization and caspase-3 assays, cardiac MI model\",\n      \"pmids\": [\"38723737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect Sam50-Shmt2 interaction not confirmed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Provided the biophysical folding and gating logic of the Sam50 barrel, showing N-terminal folding nucleation, a dispensable POTRA domain, and gating-linked stability hotspots that govern SAM-assisted assembly.\",\n      \"evidence\": \"Single-molecule electrophysiology, in vivo function assays, 165-variant alanine scanning, stability measurements\",\n      \"pmids\": [\"41927578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the assembled SAM with substrate not provided\", \"Link between gating and substrate insertion mechanism incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked a natural SAMM50 D110G variant to impaired mitochondrial architecture and metabolic disease phenotypes in vivo.\",\n      \"evidence\": \"CRISPR/Cas9 D110G knock-in mice, high-fat diet, mitochondrial function and metabolic phenotyping (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.04.657815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Molecular mechanism of how D110G perturbs barrel function not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Sam50's multiple roles—barrel assembly, MIB bridging, mitophagy receptor, fission regulation, and cardiolipin/mtDNA maintenance—are coordinated or switched within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of Sam50 in distinct functional states\", \"Regulatory logic partitioning its functions is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [5, 16]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005741\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"SAM complex\",\n      \"MIB supercomplex\",\n      \"MICOS complex\"\n    ],\n    \"partners\": [\n      \"MIC60\",\n      \"MIC19\",\n      \"CHCHD6\",\n      \"MTX1\",\n      \"MTX2\",\n      \"DNM1L\",\n      \"ATAD3A\",\n      \"SHMT2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}