{"gene":"OXA1L","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1994,"finding":"OXA1 (yeast) is required at a post-translational step in cytochrome oxidase biogenesis, likely at the level of assembly; null mutation causes complete respiratory deficiency and absence of cytochrome aa3. The human homolog (OXA1L) complements the yeast oxa1 mutant, restoring cytochrome oxidase assembly and oxygen consumption, indicating conserved function.","method":"Yeast genetics (oxa1 null mutant and disruption allele), cytochrome spectroscopy, functional complementation with human cDNA","journal":"Journal of molecular biology / Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent complementation and genetic disruption in two papers from different labs, multiple orthogonal phenotypic readouts","pmids":["8196054","7991568"],"is_preprint":false},{"year":1996,"finding":"Yeast Oxa1p is necessary for the correct assembly of both cytochrome c oxidase (complex IV) and the F1Fo-ATP synthase (complex V), as shown by absence of heme aa3 and dramatic decrease in oligomycin-sensitive ATPase activity in oxa1 deletion strains; analysis on non-denaturing gels confirmed failure to assemble both complexes.","method":"Yeast deletion mutant, cytochrome spectroscopy, enzymatic activity measurements, blue native PAGE","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods on clean deletion mutant, consistent with prior genetic findings","pmids":["8612730"],"is_preprint":false},{"year":2003,"finding":"The matrix-exposed C-terminal region of yeast Oxa1 forms an alpha-helical domain that physically binds mitochondrial ribosomes (large subunit), and deletion of this domain strongly diminishes co-translational membrane insertion of the mitochondrially encoded Cox2 subunit.","method":"Biochemical ribosome-binding assay, deletion mutant analysis, in organello translation, mitochondria isolation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated in two independent labs (Szyrach et al. and Jia et al.) using complementary biochemical and genetic methods","pmids":["14657018","14657017"],"is_preprint":false},{"year":2003,"finding":"Yeast Oxa1 physically associates with the large mitochondrial ribosomal subunit; the C-terminal region of Oxa1 supports this interaction. Oxa1 cross-links to Mrp20, a large ribosomal subunit protein homologous to bacterial L23 located adjacent to the peptide exit tunnel.","method":"Co-immunoprecipitation, chemical cross-linking, sucrose gradient sedimentation, truncation analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical evidence (co-IP + crosslinking) identifying specific ribosomal contact protein, replicated across two concurrent EMBO papers","pmids":["14657017","14657018"],"is_preprint":false},{"year":2002,"finding":"Oxa1 from Neurospora crassa forms a homo-oligomeric complex of ~170–180 kDa (likely a homotetramer of 43-kDa monomers), representing the core of the OXA translocase; cells with severely reduced Oxa1 are deficient in complex I and complex IV subunits.","method":"Neurospora crassa genetic depletion, native gel electrophoresis, molecular weight estimation of isolated complex","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, isolated native complex with mass estimation, functional phenotype confirmed by yeast complementation","pmids":["11823466"],"is_preprint":false},{"year":2007,"finding":"Human OXA1L localizes exclusively to mitochondria as an integral inner membrane protein of ~42 kDa, present in a 600–700 kDa complex. shRNA-mediated knockdown in HEK293 cells markedly decreases steady-state levels and activity of F1Fo-ATP synthase and moderately reduces NADH:ubiquinone oxidoreductase (complex I), but does not significantly affect cytochrome c oxidase or the bc1 complex.","method":"shRNA knockdown in HEK293 cells, blue native PAGE, enzymatic activity assays, mitochondrial fractionation, immunoblotting","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean shRNA knockdown with multiple activity readouts and native gel complex analysis in human cells, single lab but multiple orthogonal methods","pmids":["17936786"],"is_preprint":false},{"year":2007,"finding":"Yeast Oxa1 directly and physically interacts with newly synthesized mitochondrially encoded Atp9 protein in a post-translational manner (unlike the co-translational interaction with COX subunits), and this interaction does not require the C-terminal matrix-localized region of Oxa1. In the absence of Oxa1, Atp9 assembles into an intermediate complex with F1 subunits but fails to associate with Atp6 of the Fo sector.","method":"Co-immunoprecipitation, in organello radiolabeling, blue native PAGE, deletion mutant analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct physical interaction by co-IP with defined mutant analysis and assembly intermediate characterization; single lab but multiple orthogonal methods","pmids":["17344477"],"is_preprint":false},{"year":2009,"finding":"Cryo-EM structures of both E. coli YidC and S. cerevisiae Oxa1 bound to ribosome nascent chain complexes show that YidC and Oxa1 form dimers localized above the ribosomal tunnel exit, with the ribosome specifically stabilizing the dimeric state. Conserved transmembrane helices of Oxa1 localize to the dimer interface (by cysteine crosslinking), and both Oxa1 and YidC dimers contact the ribosome at ribosomal protein L23 and conserved rRNA helices 59 and 24.","method":"Cryo-electron microscopy, cysteine crosslinking","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure validated by crosslinking mutagenesis, published in high-impact journal","pmids":["19450532"],"is_preprint":false},{"year":2009,"finding":"Chemical crosslinking maps the Saccharomyces cerevisiae Oxa1-ribosome interface and identifies MrpL40 (the yeast L24 homolog) as a ribosomal protein in close physical proximity to Oxa1 at the polypeptide exit site of the large ribosomal subunit.","method":"Chemical crosslinking, co-immunoprecipitation, mass spectrometry-based identification","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — crosslinking identifies specific ribosomal contact, single lab","pmids":["19783770"],"is_preprint":false},{"year":2009,"finding":"Mammalian OXA1L has a five-transmembrane topology in the mitochondrial inner membrane with N terminus and loop L2 exposed to the intermembrane space, and C-terminal region and loops L1/L3 exposed to the matrix. A conserved GLPWWG hexapeptide near the N terminus of TM1 is essential for correct topogenesis (export of N-terminal segment and L2 into the IMS). All five TMs cooperate for efficient membrane integration.","method":"Systematic deletion and mutation constructs in HeLa cells, protease protection assays, fluorescence microscopy, mitochondrial fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis in mammalian cells, multiple constructs, multiple orthogonal topology-mapping methods","pmids":["19349278"],"is_preprint":false},{"year":2010,"finding":"The C-terminal tail of human OXA1L (Oxa1L-CTT, ~100 aa) binds mammalian mitochondrial ribosomes with Kd of 0.3–0.8 μM and a stoichiometry of 2; this binding is enthalpy-driven. Oxa1L-CTT cross-links to mammalian mitochondrial ribosomal proteins MRPL13, MRPL20, MRPL28, MRPL48, MRPL49, and MRPL51, but does NOT cross-link to proteins decorating the canonical exit tunnel (L22, L23, L24, L29), indicating a distinct ribosome-binding interface compared to yeast Oxa1.","method":"Isothermal titration calorimetry, chemical crosslinking, mass spectrometry identification of crosslinked partners","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ITC provides thermodynamic parameters, crosslinking identifies specific ribosomal contacts; multiple methods in single rigorous study","pmids":["20601428"],"is_preprint":false},{"year":2010,"finding":"Oxa1L-CTT forms oligomers cooperatively (submicromolar Kd); a region near position 39 (within a long helix) mediates contacts during oligomer formation. Fluorescence correlation spectroscopy and anisotropy show that regions around positions 39, 67, and 94 of the CTT make extensive contacts with the ribosome, and the CTT undergoes conformational changes and induced oligomerization upon ribosome binding.","method":"Fluorescence anisotropy, fluorescence lifetime measurements, fluorescence correlation spectroscopy, cysteine-specific fluorescent labeling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biophysical methods, single lab, provides structural detail on CTT-ribosome interface","pmids":["20739282"],"is_preprint":false},{"year":2012,"finding":"Purified and reconstituted yeast Oxa1 forms a cation-selective membrane pore that specifically responds to mitochondrial export signals, with a restriction zone diameter of 0.6–2 nm sufficient for polypeptide translocation. Single-channel analyses suggest four cooperative hydrophilic pores per active unit; pore properties are regulated by membrane potential and substrate.","method":"Protein purification, lipid bilayer reconstitution, electrophysiology (single-channel analysis)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with electrophysiology, single lab but rigorous biophysical characterization","pmids":["22829595"],"is_preprint":false},{"year":2012,"finding":"Insertion of flexible linkers (100 or 200 aa) between the Oxa1 insertase domain and ribosome-binding region causes length-dependent decrease in respiratory activity and decreased cytochrome c oxidase levels, specifically impairing assembly (rather than membrane insertion per se) of COX subunits. This implicates the close proximity of Oxa1 to ribosomes in coordinating assembly factor access during co-translational biogenesis.","method":"Yeast genetic engineering, mitochondria isolation, in organello translation, blue native PAGE, respiratory growth assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean domain-swap genetic approach with functional readouts, single lab","pmids":["22904327"],"is_preprint":false},{"year":2012,"finding":"The inner-membrane distribution of Oxa1 between the inner boundary membrane (IBM) and cristae membrane (CM) is dynamic: under fermentable conditions Oxa1 is enriched in the IBM; under respiratory conditions it shifts to the CM. Enrichment in the CM requires both mitochondrial translation and the ribosome-binding domain of Oxa1. Overexpression of a nuclear-encoded Oxa1 substrate (Mdl1) shifts Oxa1 toward the IBM. Deletion of the ribosome receptor domain prevents CM enrichment.","method":"Stimulated emission depletion (STED) super-resolution microscopy, subcellular fractionation, yeast genetic mutants","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — super-resolution imaging with rigorous genetic controls linking localization to substrate availability and domain function, single lab","pmids":["22513091"],"is_preprint":false},{"year":2012,"finding":"Oxa1 is required for efficient import of mitochondrial carrier proteins (e.g., Aac2/ATP-ADP carrier) into the inner membrane; temperature-sensitive oxa1 mutant mitochondria show severely reduced import rates of Aac2 and other carrier family members, while matrix protein import is unaffected. This extends the Oxa1 substrate spectrum beyond bacterial-homolog mitochondrial proteins to eukaryote-specific carriers.","method":"Temperature-sensitive oxa1 mutant, in vitro mitochondrial import assay, enzymatic activity measurement, immunoblotting","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel temperature-sensitive allele allows acute depletion; in vitro import assay provides direct evidence; single lab","pmids":["22846909"],"is_preprint":false},{"year":2018,"finding":"In human patients with biallelic OXA1L variants (c.500_507dup and c.620G>T), there is deficiency of oxidative phosphorylation complexes I, IV, and V. Expression of wild-type human OXA1L in patient fibroblasts rescued the complex IV and V defects. Immunoprecipitation of OXA1L revealed enrichment of mtDNA-encoded subunits of complexes I, IV, and V as interacting partners. OXA1L depletion in Drosophila recapitulated complex I, IV, and V defects.","method":"Whole exome sequencing, complementation in patient fibroblasts, co-immunoprecipitation of OXA1L with respiratory complex subunits, BN-PAGE, Drosophila RNAi model","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (patient cells, rescue experiment, Co-IP, Drosophila model), single lab with comprehensive mechanistic data","pmids":["30201738"],"is_preprint":false},{"year":2024,"finding":"TMEM126A is identified as an OXA1L-interacting protein; it associates with mitochondrial ribosomes and translation products. Loss of TMEM126A destabilizes mitochondrial translation products, triggering iAAA protease-dependent degradation at the inner membrane. Upon TMEM126A loss, OXA1L insertase complexes with blocked cargo undergo proteolytic clearance by the iAAA protease, revealing TMEM126A as a quality control co-factor that cooperates with OXA1L in co-translational protein insertion.","method":"Co-immunoprecipitation/affinity purification, mitochondrial ribosome profiling, proteomics, iAAA protease inhibitor/mutant analysis, TMEM126A knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — identifies new binding partner with multiple orthogonal methods (co-IP, ribosome association, protease epistasis), published in high-impact journal","pmids":["38199007"],"is_preprint":false},{"year":2023,"finding":"NMR characterization of yeast Oxa1 C-terminal domain (CTD) reveals it forms a transient α-helical structure within residues P342–Q385. Two conserved ribosome contact sites are identified: a very N-terminal site (V321–I327) and a central stretch (I348–Q370) that undergoes transient-to-stable conformational transition upon ribosome binding.","method":"NMR spectroscopy (solution NMR), binding to E. coli 70S ribosomes","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR provides structural detail but uses heterologous E. coli ribosome; single lab, no mutagenesis validation of identified sites","pmids":["37834108"],"is_preprint":false},{"year":2025,"finding":"OXA1L deficiency in patient-specific hiPSC-derived myotubes and OXA1L-knockout immortalized skeletal muscle cells causes combined mitochondrial respiratory chain defects and OXPHOS impairment. Rescue with wild-type OXA1L (but not truncated mutant) restores respiratory chain function. Skeletal muscle conditional Oxa1l-knockout mice exhibit OXPHOS deficiencies and muscle morphofunctional abnormalities. Mechanistically, OXPHOS impairment leads to elevated ROS, which activates NF-κB signaling, triggering apoptosis.","method":"hiPSC differentiation to myotubes, CRISPR/Cas9 knockout in IHSMC, conditional mouse knockout, OXPHOS activity assays, ROS measurement, NF-κB pathway analysis","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems and rescue experiment; NF-κB pathway placement is correlative (ROS measurement + pathway markers) rather than direct epistasis; single lab","pmids":["40551575"],"is_preprint":false},{"year":2005,"finding":"Oxa1 biogenesis involves initial accumulation at Tim23 (the inner membrane protein translocase) immediately after mitochondrial import; presequence cleavage requires mtHsp70, but subsequent membrane insertion of mature Oxa1 is essentially mtHsp70-independent, indicating that membrane integration occurs downstream of Tim23 docking and is distinct from matrix import.","method":"In vitro mitochondrial import assay, crosslinking to Tim23, mtHsp70 mutant analysis, protease protection","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution with defined pathway intermediates; single lab","pmids":["16253275"],"is_preprint":false},{"year":2000,"finding":"In yeast, Fo-ATPase subunits (Atp4p, Atp6p, Atp17p) are specifically degraded in the absence of Oxa1p by the iAAA protease Yme1p; deletion of YME1 in oxa1Δ cells stabilizes these subunits and restores oligomycin-sensitive ATPase activity, demonstrating that Yme1p-mediated proteolysis is responsible for F0 subunit degradation when Oxa1p is absent and that Oxa1p is not strictly essential for export of these ATPase subunits.","method":"Yeast double-mutant analysis, enzymatic assays, cytochrome spectroscopy, immunoblotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis (double mutant) with biochemical readouts; single lab","pmids":["10816574"],"is_preprint":false},{"year":2003,"finding":"The dependence of intermembrane space domain translocation on Oxa1 correlates with the net charge of the translocated domain (negatively charged domains require Oxa1), not with its position within the protein sequence, as demonstrated using fusion proteins in a yeast mitochondrial genome deletion mutant.","method":"Yeast genetic analysis, fusion protein constructs, in organello translation, alkaline extraction","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical dissection of substrate determinants; single lab","pmids":["14593095"],"is_preprint":false},{"year":1997,"finding":"The human OXA1L gene spans 5 kb, is composed of 10 exons and 9 introns, and encodes a protein with a 24-amino acid N-terminal mitochondrial presequence, confirming its mitochondrial targeting.","method":"Long PCR amplification, genomic sequencing, exon-intron structure determination","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — sequencing and structural genomics of a single gene; confirms presequence but no functional experiment","pmids":["9247084"],"is_preprint":false}],"current_model":"OXA1L is a conserved integral protein of the mitochondrial inner membrane that functions as an insertase/translocase mediating co-translational and post-translational insertion of mtDNA-encoded subunits of respiratory chain complexes I, IV, and V and select nuclear-encoded inner membrane proteins (including carrier proteins) from the matrix into the inner membrane; its matrix-exposed C-terminal tail directly binds the large subunit of mitochondrial ribosomes (contacts MRPL13, MRPL20, MRPL28, MRPL48, MRPL49, MRPL51 in humans), tethering the ribosome to the insertase for co-translational insertion, while the five-TM hydrophobic core forms a cation-selective pore capable of accommodating translocating polypeptides; OXA1L cooperates with TMEM126A for quality-controlled protein insertion, with blocked cargo cleared by the iAAA protease, and its depletion causes combined OXPHOS deficiency (complexes I, IV, V), elevated ROS, NF-κB activation, and mitochondrial myopathy or encephalopathy in humans."},"narrative":{"mechanistic_narrative":"OXA1L is a conserved integral protein of the mitochondrial inner membrane that functions as an insertase/translocase mediating membrane insertion and assembly of respiratory chain complexes, a role established by the ability of human OXA1L to complement a respiratory-deficient yeast oxa1 null mutant [PMID:8196054, PMID:7991568]. It is required for the correct assembly of cytochrome c oxidase and the F1Fo-ATP synthase [PMID:8612730], and in human cells its depletion reduces complex V and complex I [PMID:17936786] while biallelic patient variants produce combined deficiency of complexes I, IV, and V that is rescued by wild-type protein [PMID:30201738]. The protein adopts a five-transmembrane topology with N terminus and loop L2 facing the intermembrane space and the C terminus and loops L1/L3 in the matrix, with a conserved GLPWWG hexapeptide near TM1 governing topogenesis [PMID:19349278]; its reconstituted hydrophobic core forms a cation-selective, substrate-responsive membrane pore wide enough to translocate polypeptides [PMID:22829595]. The matrix-exposed C-terminal tail directly and cooperatively binds the large subunit of the mitochondrial ribosome — in mammals contacting MRPL13, MRPL20, MRPL28, MRPL48, MRPL49, and MRPL51 [PMID:20601428] and in yeast docking at the polypeptide exit site near Mrp20/MrpL40 [PMID:14657017, PMID:14657018, PMID:19783770] — thereby tethering the translating ribosome to the insertase for co-translational insertion of mtDNA-encoded subunits [PMID:14657018, PMID:14657017]; close ribosome proximity is further required to coordinate downstream assembly [PMID:22904327]. OXA1L additionally inserts nuclear-encoded inner-membrane carrier proteins such as the ADP/ATP carrier [PMID:22846909] and cooperates with TMEM126A in quality-controlled insertion, with stalled cargo cleared by the iAAA protease [PMID:38199007, PMID:10816574]. Biallelic OXA1L mutations cause a human combined OXPHOS deficiency disorder presenting as mitochondrial myopathy/encephalopathy [PMID:30201738], and OXA1L loss in muscle models drives OXPHOS impairment, elevated ROS, NF-κB activation, and apoptosis [PMID:40551575].","teleology":[{"year":1994,"claim":"Established that OXA1 is required for cytochrome oxidase biogenesis and that this function is evolutionarily conserved to humans, defining OXA1L as the human ortholog.","evidence":"Yeast oxa1 null/disruption mutants with cytochrome spectroscopy and functional complementation by human OXA1L cDNA","pmids":["8196054","7991568"],"confidence":"High","gaps":["Did not define whether the role was in insertion, translocation, or assembly","No biochemical mechanism for how the human protein substitutes"]},{"year":1996,"claim":"Broadened the substrate scope beyond complex IV by showing Oxa1 is also required for assembly of the F1Fo-ATP synthase.","evidence":"Yeast deletion mutant analyzed by cytochrome spectroscopy, ATPase activity, and blue native PAGE","pmids":["8612730"],"confidence":"High","gaps":["Did not distinguish a direct insertase role from an indirect assembly defect"]},{"year":2002,"claim":"Defined the physical core of the translocase by showing Oxa1 forms a homo-oligomeric complex whose loss depletes complex I and IV subunits.","evidence":"Neurospora crassa depletion with native gel electrophoresis and mass estimation","pmids":["11823466"],"confidence":"Medium","gaps":["Oligomeric state inferred from native mass estimation only","No structural validation of the homotetramer"]},{"year":2003,"claim":"Identified the mechanism coupling insertion to translation: the matrix C-terminal domain binds the large ribosomal subunit at the peptide exit tunnel to enable co-translational insertion.","evidence":"Ribosome-binding assays, crosslinking to Mrp20/L23 homolog, truncation analysis, and in organello translation in yeast","pmids":["14657018","14657017"],"confidence":"High","gaps":["Did not resolve the structure of the ribosome-insertase interface","Substrate handoff from tunnel to membrane pore not visualized"]},{"year":2003,"claim":"Connected Oxa1 substrate dependence to a physical property by showing translocation requirement correlates with the net negative charge of the IMS-exposed domain.","evidence":"Yeast fusion-protein constructs in a mitochondrial genome deletion mutant with in organello translation and alkaline extraction","pmids":["14593095"],"confidence":"Medium","gaps":["Charge-recognition mechanism at the pore not defined","Single-substrate-family scope"]},{"year":2005,"claim":"Placed Oxa1 membrane integration downstream of the TIM23 import pathway, separating its insertion step from matrix import.","evidence":"In vitro import assays, crosslinking to Tim23, and mtHsp70 mutant analysis","pmids":["16253275"],"confidence":"Medium","gaps":["How mature Oxa1 transfers from Tim23 to the membrane not defined","In vitro reconstitution from one lab"]},{"year":2007,"claim":"Demonstrated the human ortholog's relevance by showing OXA1L knockdown preferentially impairs human ATP synthase and complex I, and revealed post-translational substrate engagement with Atp9.","evidence":"shRNA knockdown in HEK293 with BN-PAGE and activity assays; co-IP of newly synthesized Atp9 in yeast with deletion analysis","pmids":["17936786","17344477"],"confidence":"High","gaps":["Human substrate spectrum incompletely mapped","Reason for differing complex sensitivities between human and yeast unclear"]},{"year":2009,"claim":"Provided structural and topological frameworks: Oxa1 forms ribosome-stabilized dimers above the exit tunnel, and mammalian OXA1L has a defined five-TM topology requiring a conserved GLPWWG motif.","evidence":"Cryo-EM of ribosome-nascent-chain complexes with cysteine crosslinking; systematic mutagenesis and protease-protection topology mapping in human cells; additional crosslinking to MrpL40","pmids":["19450532","19349278","19783770"],"confidence":"High","gaps":["Pore-lining residues and gating not resolved structurally","No high-resolution structure of the mammalian protein"]},{"year":2010,"claim":"Quantified the mammalian OXA1L C-terminal-tail/ribosome interaction and revealed a distinct ribosomal interface (MRPL13/20/28/48/49/51) different from yeast.","evidence":"Isothermal titration calorimetry, crosslinking with mass spectrometry, and biophysical anisotropy/FCS analysis of the CTT","pmids":["20601428","20739282"],"confidence":"High","gaps":["Functional consequence of distinct mammalian interface not tested by mutagenesis","Structure of the bound CTT not solved"]},{"year":2012,"claim":"Established the pore function biophysically and tied ribosome proximity, substrate availability, and submembrane localization to insertase activity and carrier import.","evidence":"Reconstituted electrophysiology of purified Oxa1; linker-insertion genetics; STED imaging of IBM/CM distribution; temperature-sensitive import assays for carrier proteins","pmids":["22829595","22904327","22513091","22846909"],"confidence":"High","gaps":["Direct visualization of a polypeptide traversing the pore lacking","Mechanism of carrier-protein recognition by Oxa1 undefined"]},{"year":2018,"claim":"Established OXA1L as a human disease gene, linking biallelic variants to combined complex I/IV/V deficiency rescuable by wild-type protein.","evidence":"Whole exome sequencing, fibroblast complementation, co-IP of OXA1L with mtDNA-encoded subunits, BN-PAGE, and Drosophila RNAi","pmids":["30201738"],"confidence":"High","gaps":["Genotype-phenotype correlation across patients limited","Tissue-specific vulnerability not explained"]},{"year":2023,"claim":"Refined the ribosome-binding region of the yeast CTD at residue resolution, identifying conserved contact stretches that undergo conformational transition on binding.","evidence":"Solution NMR of the yeast Oxa1 CTD bound to E. coli 70S ribosomes","pmids":["37834108"],"confidence":"Medium","gaps":["Used heterologous bacterial ribosome rather than mitoribosome","Identified contact sites not validated by mutagenesis"]},{"year":2024,"claim":"Identified TMEM126A as a quality-control co-factor, integrating OXA1L insertion with iAAA-protease-mediated clearance of stalled cargo.","evidence":"Affinity purification, mitochondrial ribosome profiling, proteomics, and iAAA protease epistasis with TMEM126A knockdown","pmids":["38199007"],"confidence":"High","gaps":["Structural basis of OXA1L-TMEM126A cooperation unknown","How blocked cargo is sensed and routed to the iAAA protease undefined"]},{"year":2025,"claim":"Modeled the disease mechanism in muscle, connecting OXA1L loss to OXPHOS failure, ROS, NF-κB signaling, and apoptosis, and confirmed rescue requires the intact protein.","evidence":"hiPSC-derived myotubes, CRISPR knockout muscle cells, conditional knockout mice, OXPHOS/ROS assays, and NF-κB pathway analysis","pmids":["40551575"],"confidence":"Medium","gaps":["NF-κB placement is correlative rather than direct epistasis","Whether ROS-NF-κB axis is the primary cause of muscle pathology untested"]},{"year":null,"claim":"A high-resolution structure of the active mammalian OXA1L insertase engaged with the mitoribosome and a translocating substrate, and the molecular basis of substrate selection at the pore, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No atomic structure of the mammalian OXA1L pore in action","Rules governing which nuclear- and mtDNA-encoded substrates require OXA1L not fully defined","Mechanistic link from OXA1L loss to tissue-specific human disease incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[12,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,10,13]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[12,22]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,23]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,9,17]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,13,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,16]}],"complexes":["OXA1/OXA insertase complex","mitochondrial large ribosomal subunit (associated)"],"partners":["MRPL13","MRPL20","MRPL28","MRPL48","MRPL49","MRPL51","TMEM126A","TIMM23"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15070","full_name":"Mitochondrial inner membrane protein OXA1L","aliases":["OXA1Hs","Oxidase assembly 1-like protein","OXA1-like protein"],"length_aa":435,"mass_kda":48.5,"function":"Mitochondrial membrane insertase that mediates the cotranslational insertion of integral membrane proteins into the mitochondrial inner membrane (PubMed:17936786, PubMed:33602856, PubMed:7991568). Essential for the activity and assembly of cytochrome oxidase (PubMed:17936786, PubMed:7991568). Required for the correct biogenesis of ATP synthase and complex I in mitochondria (PubMed:17936786, PubMed:7991568)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q15070/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/OXA1L","classification":"Common Essential","n_dependent_lines":757,"n_total_lines":1208,"dependency_fraction":0.6266556291390728},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OXA1L","total_profiled":1310},"omim":[{"mim_id":"618583","title":"MITOCHONDRIAL TRANSCRIPTION RESCUE FACTOR 1; MTRES1","url":"https://www.omim.org/entry/618583"},{"mim_id":"617228","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 31; COXPD31","url":"https://www.omim.org/entry/617228"},{"mim_id":"613541","title":"MITOCHONDRIAL TRANSLATION RELEASE FACTOR IN RESCUE; MTRFR","url":"https://www.omim.org/entry/613541"},{"mim_id":"610428","title":"CYTOCHROME c OXIDASE ASSEMBLY FACTOR COX18; COX18","url":"https://www.omim.org/entry/610428"},{"mim_id":"602241","title":"MITOCHONDRIAL INTERMEDIATE PEPTIDASE; MIPEP","url":"https://www.omim.org/entry/602241"}],"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/OXA1L"},"hgnc":{"alias_symbol":["MGC133129","OXA1","OXA1L1"],"prev_symbol":[]},"alphafold":{"accession":"Q15070","domains":[{"cath_id":"-","chopping":"107-355","consensus_level":"high","plddt":87.661,"start":107,"end":355},{"cath_id":"1.20.5","chopping":"362-386","consensus_level":"medium","plddt":86.9368,"start":362,"end":386}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15070","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15070-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15070-F1-predicted_aligned_error_v6.png","plddt_mean":73.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OXA1L","jax_strain_url":"https://www.jax.org/strain/search?query=OXA1L"},"sequence":{"accession":"Q15070","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15070.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15070/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15070"}},"corpus_meta":[{"pmid":"11731127","id":"PMC_11731127","title":"Phylogenetic and structural analyses of the oxa1 family of protein translocases.","date":"2001","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/11731127","citation_count":276,"is_preprint":false},{"pmid":"14657018","id":"PMC_14657018","title":"Ribosome binding to the Oxa1 complex facilitates co-translational protein insertion in mitochondria.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/14657018","citation_count":208,"is_preprint":false},{"pmid":"2823258","id":"PMC_2823258","title":"Precise insertion of antibiotic resistance determinants into Tn21-like transposons: nucleotide sequence of the OXA-1 beta-lactamase gene.","date":"1987","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2823258","citation_count":203,"is_preprint":false},{"pmid":"8196054","id":"PMC_8196054","title":"OXA1, a Saccharomyces cerevisiae nuclear gene whose sequence is conserved from prokaryotes to eukaryotes controls cytochrome oxidase biogenesis.","date":"1994","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8196054","citation_count":184,"is_preprint":false},{"pmid":"14657017","id":"PMC_14657017","title":"Yeast Oxa1 interacts with mitochondrial ribosomes: the importance of the C-terminal region of Oxa1.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/14657017","citation_count":179,"is_preprint":false},{"pmid":"8612730","id":"PMC_8612730","title":"The Saccharomyces cerevisiae OXA1 gene is required for the correct assembly of cytochrome c oxidase and oligomycin-sensitive ATP synthase.","date":"1996","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8612730","citation_count":123,"is_preprint":false},{"pmid":"29281821","id":"PMC_29281821","title":"Identification of Oxa1 Homologs Operating in the Eukaryotic Endoplasmic Reticulum.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29281821","citation_count":114,"is_preprint":false},{"pmid":"8067742","id":"PMC_8067742","title":"Emergence of clinical isolates of Escherichia coli producing TEM-1 derivatives or an OXA-1 beta-lactamase conferring resistance to beta-lactamase inhibitors.","date":"1994","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/8067742","citation_count":114,"is_preprint":false},{"pmid":"19450532","id":"PMC_19450532","title":"YidC and Oxa1 form dimeric insertion pores on the translating ribosome.","date":"2009","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/19450532","citation_count":102,"is_preprint":false},{"pmid":"14507478","id":"PMC_14507478","title":"The Alb3/Oxa1/YidC protein family: membrane-localized chaperones facilitating membrane protein insertion?","date":"2003","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14507478","citation_count":101,"is_preprint":false},{"pmid":"7991568","id":"PMC_7991568","title":"Cloning of a human gene involved in cytochrome oxidase assembly by functional complementation of an oxa1- mutation in Saccharomyces cerevisiae.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7991568","citation_count":94,"is_preprint":false},{"pmid":"25947384","id":"PMC_25947384","title":"YidC/Alb3/Oxa1 Family of Insertases.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25947384","citation_count":93,"is_preprint":false},{"pmid":"12191770","id":"PMC_12191770","title":"Insertion of proteins into the inner membrane of mitochondria: the role of the Oxa1 complex.","date":"2002","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12191770","citation_count":88,"is_preprint":false},{"pmid":"20800571","id":"PMC_20800571","title":"Inserting membrane proteins: the YidC/Oxa1/Alb3 machinery in bacteria, mitochondria, and chloroplasts.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20800571","citation_count":84,"is_preprint":false},{"pmid":"17344477","id":"PMC_17344477","title":"Oxa1 directly interacts with Atp9 and mediates its assembly into the mitochondrial F1Fo-ATP synthase complex.","date":"2007","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17344477","citation_count":84,"is_preprint":false},{"pmid":"17936786","id":"PMC_17936786","title":"Knockdown of human Oxa1l impairs the biogenesis of F1Fo-ATP synthase and NADH:ubiquinone oxidoreductase.","date":"2007","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17936786","citation_count":79,"is_preprint":false},{"pmid":"11823466","id":"PMC_11823466","title":"The Oxa1 protein forms a homooligomeric complex and is an essential part of the mitochondrial export translocase in Neurospora crassa.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11823466","citation_count":72,"is_preprint":false},{"pmid":"18522806","id":"PMC_18522806","title":"Roles of Oxa1-related inner-membrane translocases in assembly of respiratory chain complexes.","date":"2008","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/18522806","citation_count":70,"is_preprint":false},{"pmid":"10816574","id":"PMC_10816574","title":"Absence of the mitochondrial AAA protease Yme1p restores F0-ATPase subunit accumulation in an oxa1 deletion mutant of Saccharomyces cerevisiae.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10816574","citation_count":68,"is_preprint":false},{"pmid":"30201738","id":"PMC_30201738","title":"OXA1L mutations cause mitochondrial encephalopathy and a combined oxidative phosphorylation defect.","date":"2018","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30201738","citation_count":63,"is_preprint":false},{"pmid":"12586834","id":"PMC_12586834","title":"Complementary impact of paralogous Oxa1-like proteins of Bacillus subtilis on post-translocational stages in protein secretion.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12586834","citation_count":62,"is_preprint":false},{"pmid":"14767059","id":"PMC_14767059","title":"The Oxa2 protein of Neurospora crassa plays a critical role in the biogenesis of cytochrome oxidase and defines a ubiquitous subbranch of the Oxa1/YidC/Alb3 protein family.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/14767059","citation_count":61,"is_preprint":false},{"pmid":"16092528","id":"PMC_16092528","title":"Oxa1/Alb3/YidC system for insertion of membrane proteins in mitochondria, chloroplasts and bacteria (review).","date":"2005","source":"Molecular membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/16092528","citation_count":53,"is_preprint":false},{"pmid":"24647004","id":"PMC_24647004","title":"Detection of OXA-1 β-lactamase gene of Klebsiella pneumoniae from blood stream infections (BSI) by conventional PCR and in-silico analysis to understand the mechanism of OXA mediated resistance.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24647004","citation_count":51,"is_preprint":false},{"pmid":"16669040","id":"PMC_16669040","title":"Iron uptake by plants from microbial siderophores : a study with 7-nitrobenz-2 oxa-1,3-diazole-desferrioxamine as fluorescent ferrioxamine B analog.","date":"1992","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16669040","citation_count":51,"is_preprint":false},{"pmid":"33664512","id":"PMC_33664512","title":"Structural and molecular mechanisms for membrane protein biogenesis by the Oxa1 superfamily.","date":"2021","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33664512","citation_count":49,"is_preprint":false},{"pmid":"21194367","id":"PMC_21194367","title":"Evolution of YidC/Oxa1/Alb3 insertases: three independent gene duplications followed by functional specialization in bacteria, mitochondria and chloroplasts.","date":"2011","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21194367","citation_count":47,"is_preprint":false},{"pmid":"16905652","id":"PMC_16905652","title":"The synechocystis sp PCC 6803 oxa1 homolog is essential for membrane integration of reaction center precursor protein pD1.","date":"2006","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/16905652","citation_count":46,"is_preprint":false},{"pmid":"19485421","id":"PMC_19485421","title":"Mutation of the active site carboxy-lysine (K70) of OXA-1 beta-lactamase results in a deacylation-deficient enzyme.","date":"2009","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19485421","citation_count":43,"is_preprint":false},{"pmid":"19783770","id":"PMC_19783770","title":"Mapping of the Saccharomyces cerevisiae Oxa1-mitochondrial ribosome interface and identification of MrpL40, a ribosomal protein in close proximity to Oxa1 and critical for oxidative phosphorylation complex assembly.","date":"2009","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/19783770","citation_count":42,"is_preprint":false},{"pmid":"20601428","id":"PMC_20601428","title":"Properties of the C-terminal tail of human mitochondrial inner membrane protein Oxa1L and its interactions with mammalian mitochondrial ribosomes.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20601428","citation_count":41,"is_preprint":false},{"pmid":"22829595","id":"PMC_22829595","title":"The mitochondrial oxidase assembly protein1 (Oxa1) insertase forms a membrane pore in lipid bilayers.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22829595","citation_count":39,"is_preprint":false},{"pmid":"15355998","id":"PMC_15355998","title":"A yeast mitochondrial membrane methyltransferase-like protein can compensate for oxa1 mutations.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15355998","citation_count":35,"is_preprint":false},{"pmid":"21742679","id":"PMC_21742679","title":"False extended-spectrum {beta}-lactamase phenotype in clinical isolates of Escherichia coli associated with increased expression of OXA-1 or TEM-1 penicillinases and loss of porins.","date":"2011","source":"The Journal of antimicrobial chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/21742679","citation_count":35,"is_preprint":false},{"pmid":"19307606","id":"PMC_19307606","title":"Translocation and assembly of mitochondrially coded Saccharomyces cerevisiae cytochrome c oxidase subunit Cox2 by Oxa1 and Yme1 in the absence of Cox18.","date":"2009","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19307606","citation_count":33,"is_preprint":false},{"pmid":"14593095","id":"PMC_14593095","title":"Protein export across the inner membrane of mitochondria: the nature of translocated domains determines the dependence on the Oxa1 translocase.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14593095","citation_count":33,"is_preprint":false},{"pmid":"10712694","id":"PMC_10712694","title":"The respiratory gene OXA1 has two fission yeast orthologues which together encode a function essential for cellular viability.","date":"2000","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10712694","citation_count":31,"is_preprint":false},{"pmid":"20739282","id":"PMC_20739282","title":"Identification of protein-protein and protein-ribosome interacting regions of the C-terminal tail of human mitochondrial inner membrane protein Oxa1L.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20739282","citation_count":30,"is_preprint":false},{"pmid":"22846909","id":"PMC_22846909","title":"The membrane insertase Oxa1 is required for efficient import of carrier proteins into mitochondria.","date":"2012","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22846909","citation_count":30,"is_preprint":false},{"pmid":"22904327","id":"PMC_22904327","title":"Oxa1-ribosome complexes coordinate the assembly of cytochrome C oxidase in mitochondria.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22904327","citation_count":30,"is_preprint":false},{"pmid":"23111630","id":"PMC_23111630","title":"The YidC/Oxa1/Alb3 protein family: common principles and distinct features.","date":"2012","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23111630","citation_count":29,"is_preprint":false},{"pmid":"22513091","id":"PMC_22513091","title":"The inner-mitochondrial distribution of Oxa1 depends on the growth conditions and on the availability of substrates.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22513091","citation_count":29,"is_preprint":false},{"pmid":"15545650","id":"PMC_15545650","title":"Interaction between the oxa1 and rmp1 genes modulates respiratory complex assembly and life span in Podospora anserina.","date":"2004","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15545650","citation_count":25,"is_preprint":false},{"pmid":"18559643","id":"PMC_18559643","title":"Inhibition of OXA-1 beta-lactamase by penems.","date":"2008","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/18559643","citation_count":25,"is_preprint":false},{"pmid":"35231030","id":"PMC_35231030","title":"The ER membrane complex (EMC) can functionally replace the Oxa1 insertase in mitochondria.","date":"2022","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/35231030","citation_count":24,"is_preprint":false},{"pmid":"35590320","id":"PMC_35590320","title":"Detection of carbapenemases blaOXA48-blaKPC-blaNDM-blaVIM and extended-spectrum-β-lactamase blaOXA1-blaSHV-blaTEM genes in Gram-negative bacterial isolates from ICU burns patients.","date":"2022","source":"Annals of clinical microbiology and antimicrobials","url":"https://pubmed.ncbi.nlm.nih.gov/35590320","citation_count":24,"is_preprint":false},{"pmid":"24443569","id":"PMC_24443569","title":"The different inhibition mechanisms of OXA-1 and OXA-24 β-lactamases are determined by the stability of active site carboxylated lysine.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24443569","citation_count":24,"is_preprint":false},{"pmid":"21123154","id":"PMC_21123154","title":"Detection of unrelated Escherichia coli strains harboring genes of CTX-M-15, OXA-1, and AAC(6')-Ib-cr enzymes in a Tunisian hospital and characterization of their integrons and virulence factors.","date":"2010","source":"Journal of chemotherapy (Florence, Italy)","url":"https://pubmed.ncbi.nlm.nih.gov/21123154","citation_count":22,"is_preprint":false},{"pmid":"38199007","id":"PMC_38199007","title":"Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38199007","citation_count":21,"is_preprint":false},{"pmid":"16253275","id":"PMC_16253275","title":"Conserved mechanism of Oxa1 insertion into the mitochondrial inner membrane.","date":"2005","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16253275","citation_count":20,"is_preprint":false},{"pmid":"3019237","id":"PMC_3019237","title":"Analysis by using DNA probes of the OXA-1 beta-lactamase gene and its transposon.","date":"1986","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/3019237","citation_count":20,"is_preprint":false},{"pmid":"26295796","id":"PMC_26295796","title":"Reduced Susceptibility to Cefepime in Clinical Isolates of Enterobacteriaceae Producing OXA-1 Beta-Lactamase.","date":"2015","source":"Microbial drug resistance (Larchmont, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/26295796","citation_count":18,"is_preprint":false},{"pmid":"19349278","id":"PMC_19349278","title":"Topogenesis of mammalian Oxa1, a component of the mitochondrial inner membrane protein export machinery.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19349278","citation_count":16,"is_preprint":false},{"pmid":"22429123","id":"PMC_22429123","title":"Site-saturation mutagenesis of position V117 in OXA-1 β-lactamase: effect of side chain polarity on enzyme carboxylation and substrate turnover.","date":"2012","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22429123","citation_count":16,"is_preprint":false},{"pmid":"29310909","id":"PMC_29310909","title":"Oxa1 Superfamily: New Members Found in the ER.","date":"2018","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29310909","citation_count":14,"is_preprint":false},{"pmid":"30103014","id":"PMC_30103014","title":"Draft genome sequence of an NDM-5, CTX-M-15 and OXA-1 co-producing Escherichia coli ST167 clinical strain isolated from a urine sample.","date":"2018","source":"Journal of global antimicrobial resistance","url":"https://pubmed.ncbi.nlm.nih.gov/30103014","citation_count":13,"is_preprint":false},{"pmid":"3010839","id":"PMC_3010839","title":"Genesis of a complex transposon encoding the OXA-1 (type II) beta-lactamase gene.","date":"1985","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/3010839","citation_count":13,"is_preprint":false},{"pmid":"16435202","id":"PMC_16435202","title":"Mutation detection in four candidate genes (OXA1L, MRS2L, YME1L and MIPEP) for combined deficiencies in the oxidative phosphorylation system.","date":"2005","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/16435202","citation_count":12,"is_preprint":false},{"pmid":"30032071","id":"PMC_30032071","title":"Polymorphisms in the DAD1 and OXA1L genes are associated with asthma and atopy in a South American population.","date":"2018","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30032071","citation_count":11,"is_preprint":false},{"pmid":"21767713","id":"PMC_21767713","title":"Characterization of a novel extended-spectrum β-lactamase phenotype from OXA-1 expression in Salmonella Typhimurium strains from Africa and Ireland.","date":"2011","source":"Diagnostic microbiology and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/21767713","citation_count":9,"is_preprint":false},{"pmid":"9247084","id":"PMC_9247084","title":"Sequence and structure of the human OXA1L gene and its upstream elements.","date":"1997","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9247084","citation_count":8,"is_preprint":false},{"pmid":"36416539","id":"PMC_36416539","title":"Evaluation of Piperacillin-Tazobactam ETEST for the Detection of OXA-1 Resistance Mechanism among Escherichia coli and Klebsiella pneumoniae.","date":"2022","source":"Journal of clinical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36416539","citation_count":8,"is_preprint":false},{"pmid":"32579605","id":"PMC_32579605","title":"ZapE/Afg1 interacts with Oxa1 and its depletion causes a multifaceted phenotype.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32579605","citation_count":7,"is_preprint":false},{"pmid":"19854151","id":"PMC_19854151","title":"Mammalian Oxa1 protein is useful for assessment of submitochondrial protein localization and mitochondrial membrane integrity.","date":"2009","source":"Analytical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19854151","citation_count":7,"is_preprint":false},{"pmid":"15908145","id":"PMC_15908145","title":"The transcriptional activator HAP4 is a high copy suppressor of an oxa1 yeast mutation.","date":"2005","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15908145","citation_count":7,"is_preprint":false},{"pmid":"34965471","id":"PMC_34965471","title":"Genomic characterisation of Escherichia coli isolates co-producing NDM-5 and OXA-1 from hospitalised patients with invasive infections.","date":"2021","source":"Journal of global antimicrobial resistance","url":"https://pubmed.ncbi.nlm.nih.gov/34965471","citation_count":7,"is_preprint":false},{"pmid":"33363717","id":"PMC_33363717","title":"β-lactamases (bla  ) and class C β-lactamases gene frequency in Pseudomonas aeruginosa isolated from various clinical specimens in Khartoum State, Sudan: a cross sectional study.","date":"2020","source":"F1000Research","url":"https://pubmed.ncbi.nlm.nih.gov/33363717","citation_count":7,"is_preprint":false},{"pmid":"11717515","id":"PMC_11717515","title":"Crystallization and preliminary X-ray study of OXA-1, a class D beta-lactamase.","date":"2001","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/11717515","citation_count":7,"is_preprint":false},{"pmid":"25102723","id":"PMC_25102723","title":"Clonal spread of Klebsiella pneumoniae producing OXA-1 betalactamase in a Spanish hospital.","date":"2013","source":"International microbiology : the official journal of the Spanish Society for Microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25102723","citation_count":6,"is_preprint":false},{"pmid":"40551575","id":"PMC_40551575","title":"OXA1L deficiency causes mitochondrial myopathy via reactive oxygen species regulated nuclear factor kappa B signalling pathway.","date":"2025","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40551575","citation_count":5,"is_preprint":false},{"pmid":"20025673","id":"PMC_20025673","title":"A mutational analysis reveals new functional interactions between domains of the Oxa1 protein in Saccharomyces cerevisiae.","date":"2009","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20025673","citation_count":5,"is_preprint":false},{"pmid":"24472117","id":"PMC_24472117","title":"The SFT-1 and OXA-1 respiratory chain complex assembly factors influence lifespan by distinct mechanisms in C. elegans.","date":"2013","source":"Longevity & healthspan","url":"https://pubmed.ncbi.nlm.nih.gov/24472117","citation_count":5,"is_preprint":false},{"pmid":"6397946","id":"PMC_6397946","title":"Different mechanisms of TEM-1 and Oxa-1 mediated resistance to piperacillin in E. coli.","date":"1984","source":"Zentralblatt fur Bakteriologie, Mikrobiologie, und Hygiene. Series A, Medical microbiology, infectious diseases, virology, parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/6397946","citation_count":5,"is_preprint":false},{"pmid":"34458404","id":"PMC_34458404","title":"Purification of Mitochondrial Ribosomes with the Translocase Oxa1L from HEK Cells.","date":"2021","source":"Bio-protocol","url":"https://pubmed.ncbi.nlm.nih.gov/34458404","citation_count":3,"is_preprint":false},{"pmid":"23198851","id":"PMC_23198851","title":"Partial suppression of Oxa1 mutants by mitochondria-targeted signal recognition particle provides insights into the evolution of the cotranslational insertion systems.","date":"2013","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/23198851","citation_count":3,"is_preprint":false},{"pmid":"39615807","id":"PMC_39615807","title":"New variants of the DAD1 and OXA1L genes are associated with asthma and atopy in an adult population.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/39615807","citation_count":2,"is_preprint":false},{"pmid":"39347609","id":"PMC_39347609","title":"Palladium-Catalyzed [7 + 5] and Higher-Order Annulations of Oxa-1,n-dipoles: Synthesis of 12- to 15-Membered Lactones.","date":"2024","source":"Organic letters","url":"https://pubmed.ncbi.nlm.nih.gov/39347609","citation_count":2,"is_preprint":false},{"pmid":"10410243","id":"PMC_10410243","title":"Expression of the divergent transcription unit containing the yeast PET122 and OXA1 genes.","date":"1999","source":"Biochemistry and molecular biology international","url":"https://pubmed.ncbi.nlm.nih.gov/10410243","citation_count":1,"is_preprint":false},{"pmid":"41602100","id":"PMC_41602100","title":"Correlation of OXA-1 and TEM-1 genes with antibiotic resistance to piperacillin/tazobactam in ESBL-producing Enterobacterales: insights from a multi-center analysis.","date":"2026","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/41602100","citation_count":1,"is_preprint":false},{"pmid":"40497048","id":"PMC_40497048","title":"Identification of an IncHI5-like plasmid co-harboring bla NDM-1 and bla OXA-1 in mcr-8.1-positive Klebsiella pneumoniae isolate.","date":"2025","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40497048","citation_count":1,"is_preprint":false},{"pmid":"37108900","id":"PMC_37108900","title":"A Correlation between 3'-UTR of OXA1 Gene and Yeast Mitochondrial Translation.","date":"2023","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37108900","citation_count":0,"is_preprint":false},{"pmid":"37834108","id":"PMC_37834108","title":"NMR-Based Characterization of the Interaction between Yeast Oxa1-CTD and Ribosomes.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37834108","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.05.658076","title":"Functional redundancy in Oxa1-family insertases supports robust membrane insertion of influenza A virus M2 viroporin","date":"2025-06-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.05.658076","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.01.662679","title":"Spatio-temporal mass spectrometry in living cells reveals regulators of cuproptosis","date":"2025-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.01.662679","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.27.600981","title":"A priority code in presequences: mitochondrial targeting signals assign specific import characteristics to precursor proteins","date":"2024-06-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.27.600981","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.13.628402","title":"YibN, a bona fide interactor of YidC with implications in membrane protein insertion and membrane lipid production","date":"2024-12-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.13.628402","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.26.656142","title":"Substrate-induced assembly and functional mechanism of the bacterial membrane protein insertase SecYEG-YidC","date":"2025-05-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.26.656142","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40845,"output_tokens":6137,"usd":0.107295,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15068,"output_tokens":4642,"usd":0.095695,"stage2_stop_reason":"end_turn"},"total_usd":0.20299,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"OXA1 (yeast) is required at a post-translational step in cytochrome oxidase biogenesis, likely at the level of assembly; null mutation causes complete respiratory deficiency and absence of cytochrome aa3. The human homolog (OXA1L) complements the yeast oxa1 mutant, restoring cytochrome oxidase assembly and oxygen consumption, indicating conserved function.\",\n      \"method\": \"Yeast genetics (oxa1 null mutant and disruption allele), cytochrome spectroscopy, functional complementation with human cDNA\",\n      \"journal\": \"Journal of molecular biology / Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent complementation and genetic disruption in two papers from different labs, multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"8196054\", \"7991568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Yeast Oxa1p is necessary for the correct assembly of both cytochrome c oxidase (complex IV) and the F1Fo-ATP synthase (complex V), as shown by absence of heme aa3 and dramatic decrease in oligomycin-sensitive ATPase activity in oxa1 deletion strains; analysis on non-denaturing gels confirmed failure to assemble both complexes.\",\n      \"method\": \"Yeast deletion mutant, cytochrome spectroscopy, enzymatic activity measurements, blue native PAGE\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods on clean deletion mutant, consistent with prior genetic findings\",\n      \"pmids\": [\"8612730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The matrix-exposed C-terminal region of yeast Oxa1 forms an alpha-helical domain that physically binds mitochondrial ribosomes (large subunit), and deletion of this domain strongly diminishes co-translational membrane insertion of the mitochondrially encoded Cox2 subunit.\",\n      \"method\": \"Biochemical ribosome-binding assay, deletion mutant analysis, in organello translation, mitochondria isolation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated in two independent labs (Szyrach et al. and Jia et al.) using complementary biochemical and genetic methods\",\n      \"pmids\": [\"14657018\", \"14657017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast Oxa1 physically associates with the large mitochondrial ribosomal subunit; the C-terminal region of Oxa1 supports this interaction. Oxa1 cross-links to Mrp20, a large ribosomal subunit protein homologous to bacterial L23 located adjacent to the peptide exit tunnel.\",\n      \"method\": \"Co-immunoprecipitation, chemical cross-linking, sucrose gradient sedimentation, truncation analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical evidence (co-IP + crosslinking) identifying specific ribosomal contact protein, replicated across two concurrent EMBO papers\",\n      \"pmids\": [\"14657017\", \"14657018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Oxa1 from Neurospora crassa forms a homo-oligomeric complex of ~170–180 kDa (likely a homotetramer of 43-kDa monomers), representing the core of the OXA translocase; cells with severely reduced Oxa1 are deficient in complex I and complex IV subunits.\",\n      \"method\": \"Neurospora crassa genetic depletion, native gel electrophoresis, molecular weight estimation of isolated complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, isolated native complex with mass estimation, functional phenotype confirmed by yeast complementation\",\n      \"pmids\": [\"11823466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human OXA1L localizes exclusively to mitochondria as an integral inner membrane protein of ~42 kDa, present in a 600–700 kDa complex. shRNA-mediated knockdown in HEK293 cells markedly decreases steady-state levels and activity of F1Fo-ATP synthase and moderately reduces NADH:ubiquinone oxidoreductase (complex I), but does not significantly affect cytochrome c oxidase or the bc1 complex.\",\n      \"method\": \"shRNA knockdown in HEK293 cells, blue native PAGE, enzymatic activity assays, mitochondrial fractionation, immunoblotting\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean shRNA knockdown with multiple activity readouts and native gel complex analysis in human cells, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17936786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Yeast Oxa1 directly and physically interacts with newly synthesized mitochondrially encoded Atp9 protein in a post-translational manner (unlike the co-translational interaction with COX subunits), and this interaction does not require the C-terminal matrix-localized region of Oxa1. In the absence of Oxa1, Atp9 assembles into an intermediate complex with F1 subunits but fails to associate with Atp6 of the Fo sector.\",\n      \"method\": \"Co-immunoprecipitation, in organello radiolabeling, blue native PAGE, deletion mutant analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physical interaction by co-IP with defined mutant analysis and assembly intermediate characterization; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17344477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cryo-EM structures of both E. coli YidC and S. cerevisiae Oxa1 bound to ribosome nascent chain complexes show that YidC and Oxa1 form dimers localized above the ribosomal tunnel exit, with the ribosome specifically stabilizing the dimeric state. Conserved transmembrane helices of Oxa1 localize to the dimer interface (by cysteine crosslinking), and both Oxa1 and YidC dimers contact the ribosome at ribosomal protein L23 and conserved rRNA helices 59 and 24.\",\n      \"method\": \"Cryo-electron microscopy, cysteine crosslinking\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure validated by crosslinking mutagenesis, published in high-impact journal\",\n      \"pmids\": [\"19450532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Chemical crosslinking maps the Saccharomyces cerevisiae Oxa1-ribosome interface and identifies MrpL40 (the yeast L24 homolog) as a ribosomal protein in close physical proximity to Oxa1 at the polypeptide exit site of the large ribosomal subunit.\",\n      \"method\": \"Chemical crosslinking, co-immunoprecipitation, mass spectrometry-based identification\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — crosslinking identifies specific ribosomal contact, single lab\",\n      \"pmids\": [\"19783770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mammalian OXA1L has a five-transmembrane topology in the mitochondrial inner membrane with N terminus and loop L2 exposed to the intermembrane space, and C-terminal region and loops L1/L3 exposed to the matrix. A conserved GLPWWG hexapeptide near the N terminus of TM1 is essential for correct topogenesis (export of N-terminal segment and L2 into the IMS). All five TMs cooperate for efficient membrane integration.\",\n      \"method\": \"Systematic deletion and mutation constructs in HeLa cells, protease protection assays, fluorescence microscopy, mitochondrial fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis in mammalian cells, multiple constructs, multiple orthogonal topology-mapping methods\",\n      \"pmids\": [\"19349278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The C-terminal tail of human OXA1L (Oxa1L-CTT, ~100 aa) binds mammalian mitochondrial ribosomes with Kd of 0.3–0.8 μM and a stoichiometry of 2; this binding is enthalpy-driven. Oxa1L-CTT cross-links to mammalian mitochondrial ribosomal proteins MRPL13, MRPL20, MRPL28, MRPL48, MRPL49, and MRPL51, but does NOT cross-link to proteins decorating the canonical exit tunnel (L22, L23, L24, L29), indicating a distinct ribosome-binding interface compared to yeast Oxa1.\",\n      \"method\": \"Isothermal titration calorimetry, chemical crosslinking, mass spectrometry identification of crosslinked partners\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ITC provides thermodynamic parameters, crosslinking identifies specific ribosomal contacts; multiple methods in single rigorous study\",\n      \"pmids\": [\"20601428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Oxa1L-CTT forms oligomers cooperatively (submicromolar Kd); a region near position 39 (within a long helix) mediates contacts during oligomer formation. Fluorescence correlation spectroscopy and anisotropy show that regions around positions 39, 67, and 94 of the CTT make extensive contacts with the ribosome, and the CTT undergoes conformational changes and induced oligomerization upon ribosome binding.\",\n      \"method\": \"Fluorescence anisotropy, fluorescence lifetime measurements, fluorescence correlation spectroscopy, cysteine-specific fluorescent labeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biophysical methods, single lab, provides structural detail on CTT-ribosome interface\",\n      \"pmids\": [\"20739282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Purified and reconstituted yeast Oxa1 forms a cation-selective membrane pore that specifically responds to mitochondrial export signals, with a restriction zone diameter of 0.6–2 nm sufficient for polypeptide translocation. Single-channel analyses suggest four cooperative hydrophilic pores per active unit; pore properties are regulated by membrane potential and substrate.\",\n      \"method\": \"Protein purification, lipid bilayer reconstitution, electrophysiology (single-channel analysis)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with electrophysiology, single lab but rigorous biophysical characterization\",\n      \"pmids\": [\"22829595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Insertion of flexible linkers (100 or 200 aa) between the Oxa1 insertase domain and ribosome-binding region causes length-dependent decrease in respiratory activity and decreased cytochrome c oxidase levels, specifically impairing assembly (rather than membrane insertion per se) of COX subunits. This implicates the close proximity of Oxa1 to ribosomes in coordinating assembly factor access during co-translational biogenesis.\",\n      \"method\": \"Yeast genetic engineering, mitochondria isolation, in organello translation, blue native PAGE, respiratory growth assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean domain-swap genetic approach with functional readouts, single lab\",\n      \"pmids\": [\"22904327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The inner-membrane distribution of Oxa1 between the inner boundary membrane (IBM) and cristae membrane (CM) is dynamic: under fermentable conditions Oxa1 is enriched in the IBM; under respiratory conditions it shifts to the CM. Enrichment in the CM requires both mitochondrial translation and the ribosome-binding domain of Oxa1. Overexpression of a nuclear-encoded Oxa1 substrate (Mdl1) shifts Oxa1 toward the IBM. Deletion of the ribosome receptor domain prevents CM enrichment.\",\n      \"method\": \"Stimulated emission depletion (STED) super-resolution microscopy, subcellular fractionation, yeast genetic mutants\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — super-resolution imaging with rigorous genetic controls linking localization to substrate availability and domain function, single lab\",\n      \"pmids\": [\"22513091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Oxa1 is required for efficient import of mitochondrial carrier proteins (e.g., Aac2/ATP-ADP carrier) into the inner membrane; temperature-sensitive oxa1 mutant mitochondria show severely reduced import rates of Aac2 and other carrier family members, while matrix protein import is unaffected. This extends the Oxa1 substrate spectrum beyond bacterial-homolog mitochondrial proteins to eukaryote-specific carriers.\",\n      \"method\": \"Temperature-sensitive oxa1 mutant, in vitro mitochondrial import assay, enzymatic activity measurement, immunoblotting\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel temperature-sensitive allele allows acute depletion; in vitro import assay provides direct evidence; single lab\",\n      \"pmids\": [\"22846909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In human patients with biallelic OXA1L variants (c.500_507dup and c.620G>T), there is deficiency of oxidative phosphorylation complexes I, IV, and V. Expression of wild-type human OXA1L in patient fibroblasts rescued the complex IV and V defects. Immunoprecipitation of OXA1L revealed enrichment of mtDNA-encoded subunits of complexes I, IV, and V as interacting partners. OXA1L depletion in Drosophila recapitulated complex I, IV, and V defects.\",\n      \"method\": \"Whole exome sequencing, complementation in patient fibroblasts, co-immunoprecipitation of OXA1L with respiratory complex subunits, BN-PAGE, Drosophila RNAi model\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (patient cells, rescue experiment, Co-IP, Drosophila model), single lab with comprehensive mechanistic data\",\n      \"pmids\": [\"30201738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM126A is identified as an OXA1L-interacting protein; it associates with mitochondrial ribosomes and translation products. Loss of TMEM126A destabilizes mitochondrial translation products, triggering iAAA protease-dependent degradation at the inner membrane. Upon TMEM126A loss, OXA1L insertase complexes with blocked cargo undergo proteolytic clearance by the iAAA protease, revealing TMEM126A as a quality control co-factor that cooperates with OXA1L in co-translational protein insertion.\",\n      \"method\": \"Co-immunoprecipitation/affinity purification, mitochondrial ribosome profiling, proteomics, iAAA protease inhibitor/mutant analysis, TMEM126A knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identifies new binding partner with multiple orthogonal methods (co-IP, ribosome association, protease epistasis), published in high-impact journal\",\n      \"pmids\": [\"38199007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NMR characterization of yeast Oxa1 C-terminal domain (CTD) reveals it forms a transient α-helical structure within residues P342–Q385. Two conserved ribosome contact sites are identified: a very N-terminal site (V321–I327) and a central stretch (I348–Q370) that undergoes transient-to-stable conformational transition upon ribosome binding.\",\n      \"method\": \"NMR spectroscopy (solution NMR), binding to E. coli 70S ribosomes\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR provides structural detail but uses heterologous E. coli ribosome; single lab, no mutagenesis validation of identified sites\",\n      \"pmids\": [\"37834108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OXA1L deficiency in patient-specific hiPSC-derived myotubes and OXA1L-knockout immortalized skeletal muscle cells causes combined mitochondrial respiratory chain defects and OXPHOS impairment. Rescue with wild-type OXA1L (but not truncated mutant) restores respiratory chain function. Skeletal muscle conditional Oxa1l-knockout mice exhibit OXPHOS deficiencies and muscle morphofunctional abnormalities. Mechanistically, OXPHOS impairment leads to elevated ROS, which activates NF-κB signaling, triggering apoptosis.\",\n      \"method\": \"hiPSC differentiation to myotubes, CRISPR/Cas9 knockout in IHSMC, conditional mouse knockout, OXPHOS activity assays, ROS measurement, NF-κB pathway analysis\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems and rescue experiment; NF-κB pathway placement is correlative (ROS measurement + pathway markers) rather than direct epistasis; single lab\",\n      \"pmids\": [\"40551575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Oxa1 biogenesis involves initial accumulation at Tim23 (the inner membrane protein translocase) immediately after mitochondrial import; presequence cleavage requires mtHsp70, but subsequent membrane insertion of mature Oxa1 is essentially mtHsp70-independent, indicating that membrane integration occurs downstream of Tim23 docking and is distinct from matrix import.\",\n      \"method\": \"In vitro mitochondrial import assay, crosslinking to Tim23, mtHsp70 mutant analysis, protease protection\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution with defined pathway intermediates; single lab\",\n      \"pmids\": [\"16253275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In yeast, Fo-ATPase subunits (Atp4p, Atp6p, Atp17p) are specifically degraded in the absence of Oxa1p by the iAAA protease Yme1p; deletion of YME1 in oxa1Δ cells stabilizes these subunits and restores oligomycin-sensitive ATPase activity, demonstrating that Yme1p-mediated proteolysis is responsible for F0 subunit degradation when Oxa1p is absent and that Oxa1p is not strictly essential for export of these ATPase subunits.\",\n      \"method\": \"Yeast double-mutant analysis, enzymatic assays, cytochrome spectroscopy, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis (double mutant) with biochemical readouts; single lab\",\n      \"pmids\": [\"10816574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The dependence of intermembrane space domain translocation on Oxa1 correlates with the net charge of the translocated domain (negatively charged domains require Oxa1), not with its position within the protein sequence, as demonstrated using fusion proteins in a yeast mitochondrial genome deletion mutant.\",\n      \"method\": \"Yeast genetic analysis, fusion protein constructs, in organello translation, alkaline extraction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical dissection of substrate determinants; single lab\",\n      \"pmids\": [\"14593095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human OXA1L gene spans 5 kb, is composed of 10 exons and 9 introns, and encodes a protein with a 24-amino acid N-terminal mitochondrial presequence, confirming its mitochondrial targeting.\",\n      \"method\": \"Long PCR amplification, genomic sequencing, exon-intron structure determination\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — sequencing and structural genomics of a single gene; confirms presequence but no functional experiment\",\n      \"pmids\": [\"9247084\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OXA1L is a conserved integral protein of the mitochondrial inner membrane that functions as an insertase/translocase mediating co-translational and post-translational insertion of mtDNA-encoded subunits of respiratory chain complexes I, IV, and V and select nuclear-encoded inner membrane proteins (including carrier proteins) from the matrix into the inner membrane; its matrix-exposed C-terminal tail directly binds the large subunit of mitochondrial ribosomes (contacts MRPL13, MRPL20, MRPL28, MRPL48, MRPL49, MRPL51 in humans), tethering the ribosome to the insertase for co-translational insertion, while the five-TM hydrophobic core forms a cation-selective pore capable of accommodating translocating polypeptides; OXA1L cooperates with TMEM126A for quality-controlled protein insertion, with blocked cargo cleared by the iAAA protease, and its depletion causes combined OXPHOS deficiency (complexes I, IV, V), elevated ROS, NF-κB activation, and mitochondrial myopathy or encephalopathy in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OXA1L is a conserved integral protein of the mitochondrial inner membrane that functions as an insertase/translocase mediating membrane insertion and assembly of respiratory chain complexes, a role established by the ability of human OXA1L to complement a respiratory-deficient yeast oxa1 null mutant [#0]. It is required for the correct assembly of cytochrome c oxidase and the F1Fo-ATP synthase [#1], and in human cells its depletion reduces complex V and complex I [#5] while biallelic patient variants produce combined deficiency of complexes I, IV, and V that is rescued by wild-type protein [#16]. The protein adopts a five-transmembrane topology with N terminus and loop L2 facing the intermembrane space and the C terminus and loops L1/L3 in the matrix, with a conserved GLPWWG hexapeptide near TM1 governing topogenesis [#9]; its reconstituted hydrophobic core forms a cation-selective, substrate-responsive membrane pore wide enough to translocate polypeptides [#12]. The matrix-exposed C-terminal tail directly and cooperatively binds the large subunit of the mitochondrial ribosome — in mammals contacting MRPL13, MRPL20, MRPL28, MRPL48, MRPL49, and MRPL51 [#10] and in yeast docking at the polypeptide exit site near Mrp20/MrpL40 [#3, #8] — thereby tethering the translating ribosome to the insertase for co-translational insertion of mtDNA-encoded subunits [#2]; close ribosome proximity is further required to coordinate downstream assembly [#13]. OXA1L additionally inserts nuclear-encoded inner-membrane carrier proteins such as the ADP/ATP carrier [#15] and cooperates with TMEM126A in quality-controlled insertion, with stalled cargo cleared by the iAAA protease [#17, #21]. Biallelic OXA1L mutations cause a human combined OXPHOS deficiency disorder presenting as mitochondrial myopathy/encephalopathy [#16], and OXA1L loss in muscle models drives OXPHOS impairment, elevated ROS, NF-\\u03baB activation, and apoptosis [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that OXA1 is required for cytochrome oxidase biogenesis and that this function is evolutionarily conserved to humans, defining OXA1L as the human ortholog.\",\n      \"evidence\": \"Yeast oxa1 null/disruption mutants with cytochrome spectroscopy and functional complementation by human OXA1L cDNA\",\n      \"pmids\": [\"8196054\", \"7991568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define whether the role was in insertion, translocation, or assembly\", \"No biochemical mechanism for how the human protein substitutes\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Broadened the substrate scope beyond complex IV by showing Oxa1 is also required for assembly of the F1Fo-ATP synthase.\",\n      \"evidence\": \"Yeast deletion mutant analyzed by cytochrome spectroscopy, ATPase activity, and blue native PAGE\",\n      \"pmids\": [\"8612730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish a direct insertase role from an indirect assembly defect\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the physical core of the translocase by showing Oxa1 forms a homo-oligomeric complex whose loss depletes complex I and IV subunits.\",\n      \"evidence\": \"Neurospora crassa depletion with native gel electrophoresis and mass estimation\",\n      \"pmids\": [\"11823466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oligomeric state inferred from native mass estimation only\", \"No structural validation of the homotetramer\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the mechanism coupling insertion to translation: the matrix C-terminal domain binds the large ribosomal subunit at the peptide exit tunnel to enable co-translational insertion.\",\n      \"evidence\": \"Ribosome-binding assays, crosslinking to Mrp20/L23 homolog, truncation analysis, and in organello translation in yeast\",\n      \"pmids\": [\"14657018\", \"14657017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structure of the ribosome-insertase interface\", \"Substrate handoff from tunnel to membrane pore not visualized\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected Oxa1 substrate dependence to a physical property by showing translocation requirement correlates with the net negative charge of the IMS-exposed domain.\",\n      \"evidence\": \"Yeast fusion-protein constructs in a mitochondrial genome deletion mutant with in organello translation and alkaline extraction\",\n      \"pmids\": [\"14593095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Charge-recognition mechanism at the pore not defined\", \"Single-substrate-family scope\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed Oxa1 membrane integration downstream of the TIM23 import pathway, separating its insertion step from matrix import.\",\n      \"evidence\": \"In vitro import assays, crosslinking to Tim23, and mtHsp70 mutant analysis\",\n      \"pmids\": [\"16253275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How mature Oxa1 transfers from Tim23 to the membrane not defined\", \"In vitro reconstitution from one lab\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated the human ortholog's relevance by showing OXA1L knockdown preferentially impairs human ATP synthase and complex I, and revealed post-translational substrate engagement with Atp9.\",\n      \"evidence\": \"shRNA knockdown in HEK293 with BN-PAGE and activity assays; co-IP of newly synthesized Atp9 in yeast with deletion analysis\",\n      \"pmids\": [\"17936786\", \"17344477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human substrate spectrum incompletely mapped\", \"Reason for differing complex sensitivities between human and yeast unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided structural and topological frameworks: Oxa1 forms ribosome-stabilized dimers above the exit tunnel, and mammalian OXA1L has a defined five-TM topology requiring a conserved GLPWWG motif.\",\n      \"evidence\": \"Cryo-EM of ribosome-nascent-chain complexes with cysteine crosslinking; systematic mutagenesis and protease-protection topology mapping in human cells; additional crosslinking to MrpL40\",\n      \"pmids\": [\"19450532\", \"19349278\", \"19783770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pore-lining residues and gating not resolved structurally\", \"No high-resolution structure of the mammalian protein\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Quantified the mammalian OXA1L C-terminal-tail/ribosome interaction and revealed a distinct ribosomal interface (MRPL13/20/28/48/49/51) different from yeast.\",\n      \"evidence\": \"Isothermal titration calorimetry, crosslinking with mass spectrometry, and biophysical anisotropy/FCS analysis of the CTT\",\n      \"pmids\": [\"20601428\", \"20739282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of distinct mammalian interface not tested by mutagenesis\", \"Structure of the bound CTT not solved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the pore function biophysically and tied ribosome proximity, substrate availability, and submembrane localization to insertase activity and carrier import.\",\n      \"evidence\": \"Reconstituted electrophysiology of purified Oxa1; linker-insertion genetics; STED imaging of IBM/CM distribution; temperature-sensitive import assays for carrier proteins\",\n      \"pmids\": [\"22829595\", \"22904327\", \"22513091\", \"22846909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct visualization of a polypeptide traversing the pore lacking\", \"Mechanism of carrier-protein recognition by Oxa1 undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established OXA1L as a human disease gene, linking biallelic variants to combined complex I/IV/V deficiency rescuable by wild-type protein.\",\n      \"evidence\": \"Whole exome sequencing, fibroblast complementation, co-IP of OXA1L with mtDNA-encoded subunits, BN-PAGE, and Drosophila RNAi\",\n      \"pmids\": [\"30201738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlation across patients limited\", \"Tissue-specific vulnerability not explained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined the ribosome-binding region of the yeast CTD at residue resolution, identifying conserved contact stretches that undergo conformational transition on binding.\",\n      \"evidence\": \"Solution NMR of the yeast Oxa1 CTD bound to E. coli 70S ribosomes\",\n      \"pmids\": [\"37834108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Used heterologous bacterial ribosome rather than mitoribosome\", \"Identified contact sites not validated by mutagenesis\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified TMEM126A as a quality-control co-factor, integrating OXA1L insertion with iAAA-protease-mediated clearance of stalled cargo.\",\n      \"evidence\": \"Affinity purification, mitochondrial ribosome profiling, proteomics, and iAAA protease epistasis with TMEM126A knockdown\",\n      \"pmids\": [\"38199007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of OXA1L-TMEM126A cooperation unknown\", \"How blocked cargo is sensed and routed to the iAAA protease undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Modeled the disease mechanism in muscle, connecting OXA1L loss to OXPHOS failure, ROS, NF-\\u03baB signaling, and apoptosis, and confirmed rescue requires the intact protein.\",\n      \"evidence\": \"hiPSC-derived myotubes, CRISPR knockout muscle cells, conditional knockout mice, OXPHOS/ROS assays, and NF-\\u03baB pathway analysis\",\n      \"pmids\": [\"40551575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NF-\\u03baB placement is correlative rather than direct epistasis\", \"Whether ROS-NF-\\u03baB axis is the primary cause of muscle pathology untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of the active mammalian OXA1L insertase engaged with the mitoribosome and a translocating substrate, and the molecular basis of substrate selection at the pore, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic structure of the mammalian OXA1L pore in action\", \"Rules governing which nuclear- and mtDNA-encoded substrates require OXA1L not fully defined\", \"Mechanistic link from OXA1L loss to tissue-specific human disease incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [12, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 10, 13]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [12, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 23]},\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [5, 9, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1428517\", \"supporting_discovery_ids\": [1, 5, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 9, 17]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 13, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 16]}\n    ],\n    \"complexes\": [\n      \"OXA1/OXA insertase complex\",\n      \"mitochondrial large ribosomal subunit (associated)\"\n    ],\n    \"partners\": [\n      \"MRPL13\",\n      \"MRPL20\",\n      \"MRPL28\",\n      \"MRPL48\",\n      \"MRPL49\",\n      \"MRPL51\",\n      \"TMEM126A\",\n      \"TIMM23\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}