{"gene":"OPA1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1993,"finding":"MGM1 (yeast ortholog of OPA1) encodes a dynamin-like GTPase required for normal mitochondrial morphology and maintenance of mitochondrial DNA; loss of MGM1 causes slow growth on non-fermentable carbon sources and mtDNA loss.","method":"Genetic deletion in yeast, growth assays, mitochondrial marker immunofluorescence","journal":"Current genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotypes, foundational study replicated by subsequent work","pmids":["7916673"],"is_preprint":false},{"year":2003,"finding":"The large isoform of Mgm1 (l-Mgm1) is an integral inner membrane protein facing the intermembrane space; the rhomboid-type serine protease Pcp1 cleaves l-Mgm1 to generate the short isoform (s-Mgm1), and both isoforms together (but not either alone) are required for wild-type mitochondrial morphology and mtDNA maintenance.","method":"Yeast genetics, deletion mutants, expression of individual isoforms, complementation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution-like complementation with isoform-specific constructs, replicated across labs","pmids":["12707284"],"is_preprint":false},{"year":2004,"finding":"OPA1/Mgm1 localizes to the mitochondrial intermembrane space tightly bound to the outer surface of the inner membrane; loss of OPA1 by siRNA causes mitochondrial swelling, localized constrictions, and disorganized cristae prior to fragmentation.","method":"siRNA knockdown, electron microscopy, subcellular fractionation, immunofluorescence in mammalian cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by fractionation, EM ultrastructure, loss-of-function with defined morphological phenotype","pmids":["14970223"],"is_preprint":false},{"year":2004,"finding":"Alternative topogenesis of Mgm1 generates two isoforms dependent on the hydrophobicity of the N-terminal segment, a functional protein import motor, and matrix ATP levels; altering hydrophobicity or import motor function shifts the l/s-Mgm1 ratio and causes mitochondrial fragmentation.","method":"Mutagenesis of hydrophobic segments, import motor mutants, ATP manipulation in yeast","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal genetic and biochemical perturbations, mechanistic follow-through","pmids":["15096522"],"is_preprint":false},{"year":2006,"finding":"Mgm1 is required for mitochondrial inner-membrane fusion and cristae maintenance; Mgm1 tethers and fuses inner membranes in a GTP hydrolysis- and inner-membrane electrical potential-dependent manner, distinct from outer-membrane fusion.","method":"In vitro mitochondrial fusion assay, GTPase mutants, membrane potential manipulation in yeast","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of inner-membrane fusion, mechanistic dissection with mutants, published in high-impact journal","pmids":["17055438"],"is_preprint":false},{"year":2007,"finding":"OPA1 forms oligomers in the inner mitochondrial membrane together with a soluble form; these oligomers are disrupted early during apoptosis. The rhomboid protease PARL participates in generating a soluble form of OPA1 and in cristae remodeling; PARL itself is regulated by phosphorylation-dependent proteolysis.","method":"Co-immunoprecipitation, biochemical fractionation, apoptosis assays, review of primary experimental data","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review synthesizing primary experimental findings; oligomer disruption and PARL cleavage established in cited primary work","pmids":["17464328"],"is_preprint":false},{"year":2009,"finding":"l- and s-Mgm1 exist as inactive GTPase monomers in the absence of membrane, but together in trans form a functional dimer in a cardiolipin-dependent manner that is the building block for higher-order assemblies required for inner membrane fusion.","method":"Biochemical reconstitution, GTPase assays, electron microscopy of assemblies, cardiolipin dependence assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins, cardiolipin requirement established biochemically, multiple orthogonal methods","pmids":["19752025"],"is_preprint":false},{"year":2009,"finding":"s-Mgm1 binds specifically to negatively charged phospholipids characteristic of the mitochondrial inner membrane; lipid binding stimulates GTPase activity ~50-fold, promotes liposome interaction and tethering, and s-Mgm1 assembles onto liposomes as oligomeric rings with 3-fold (trimeric) symmetry. Point mutants defective in oligomerization or lipid binding lose GTPase stimulation and fail in vivo.","method":"Purified protein biochemistry, lipid-binding assays, GTPase activity assays, electron microscopy, in vivo complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis, structural EM, in vivo validation","pmids":["19703904"],"is_preprint":false},{"year":2012,"finding":"Mgm1 tethers opposing membranes to a ~15 nm gap and undergoes a GTP-dependent conformational change that drives membrane fusion; cryo-EM and in vitro liposome fusion assays demonstrate this mechanism for both inner-membrane fusion and cristae maintenance.","method":"Cryo-electron microscopy, in vitro liposome fusion assays, GTP-dependent conformational analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with in vitro fusion assay and nucleotide-dependent conformational analysis","pmids":["22977249"],"is_preprint":false},{"year":2012,"finding":"Phosphatidylethanolamine (PE), synthesized by Psd1, regulates mitochondrial fusion by altering membrane biophysical properties (lipid mixing kinetics) and by promoting biogenesis of s-Mgm1; loss of Psd1 reduces s-Mgm1 levels and impairs fusion, and increasing s-Mgm1 in Δpsd1 cells reduces mitochondrial aggregation.","method":"Yeast genetics, liposome lipid-mixing assays, biochemical isoform analysis, rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro lipid-mixing reconstitution combined with genetic epistasis and biochemical rescue","pmids":["23045528"],"is_preprint":false},{"year":2013,"finding":"SIRT3 deacetylates OPA1 at lysine 926 and 931, elevating its GTPase activity; in SIRT3-deficient cells OPA1 is hyperacetylated at these sites, reducing GTPase activity. A deacetylation-mimetic OPA1 rescues mitochondrial functions in OPA1-null cells, protecting cardiomyocytes from doxorubicin-induced death.","method":"Mass spectrometry identification of acetylation sites, site-directed mutagenesis, GTPase activity assays, complementation in OPA1-null cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mass spectrometry + mutagenesis + enzymatic assay + functional rescue, multiple orthogonal methods in one study","pmids":["24344202"],"is_preprint":false},{"year":2013,"finding":"Higd-1a (HIMP1-a/HIG1), a mitochondrial inner membrane protein, physically binds to OPA1 (long isoforms) via a region in or proximal to the membrane; Higd-1a depletion causes OPA1 cleavage with loss of long isoforms, mitochondrial fission, cristae disorganization, and mtDNA depletion. Ectopic Higd-1a inhibits OPA1 cleavage and mitochondrial fission induced by membrane potential loss.","method":"Co-immunoprecipitation, siRNA knockdown, OPA1 isoform analysis by western blot, electron microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, loss-of-function with multiple defined readouts, rescue with noncleavable OPA1","pmids":["23878241"],"is_preprint":false},{"year":2015,"finding":"OPA1-dependent cristae stabilization increases mitochondrial respiratory efficiency and blunts cytochrome c release, ROS production, and mitochondrial dysfunction; genetic inhibition of the OPA1 cristae remodeling pathway in vivo protects mice from denervation-induced muscular atrophy, ischemic heart/brain damage, and hepatocellular apoptosis without affecting development.","method":"In vivo genetic mouse models (cristae remodeling pathway inhibition), ischemia models, denervation atrophy, cytochrome c release assays, ROS measurement, respiratory function assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic models with multiple tissue readouts, multiple orthogonal functional assays, replicated across tissue types","pmids":["26039448"],"is_preprint":false},{"year":2015,"finding":"Mgm1 association with membranes alters membrane topography, promotes local membrane bending, and creates tubular structures on supported lipid bilayers and liposomes, suggesting a mechanical force mechanism for initiating membrane fusion.","method":"AFM on supported lipid bilayers, electron microscopy of liposomes, in vitro membrane association assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct structural/biophysical assay with purified protein, single lab study","pmids":["25784211"],"is_preprint":false},{"year":2016,"finding":"OPA1 proteolytic processing by YME1L and OMA1 regulates the balance between long membrane-bound forms (required for fusion) and short soluble forms (limiting fusion); excessive stress-activated OMA1-mediated OPA1 processing causes mitochondrial fragmentation and promotes cell death.","method":"Protease activity assays, OPA1 isoform analysis, KO/KD studies, stress-induction experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection of protease-substrate relationships replicated across multiple labs","pmids":["27189080"],"is_preprint":false},{"year":2017,"finding":"SIRT4 physically interacts with OPA1 and increases levels of the long (membrane-bound) form of OPA1 (L-OPA1), promoting mitochondrial fusion and counteracting fission/mitophagy; this effect requires SIRT4 enzymatic activity.","method":"Co-immunoprecipitation, OPA1 isoform western blot analysis, SIRT4 overexpression and enzymatic mutant","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP, OPA1 isoform analysis, single lab","pmids":["29081403"],"is_preprint":false},{"year":2017,"finding":"L-OPA1 (not membrane fusion or OPA1 proteolytic processing) regulates mitopHlash (matrix alkalinization transients coupled to mitochondrial membrane potential drops), likely by stabilizing respiratory chain supercomplexes; a fusion-deficient OPA1-K301A mutant restores mitopHlash competence, and MFN1/2 or OMA1/YME1L absence does not affect mitopHlash.","method":"Genetically encoded pH probes, OPA1 ablation and rescue with fusion-deficient mutants, MFN1/2 KO cells, OMA1/YME1L KO cells","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic controls (fusion-deficient mutant, double-KO cells), two orthogonal probes, functional dissection","pmids":["28174208"],"is_preprint":false},{"year":2018,"finding":"L-OPA1 and cardiolipin (CL) cooperate in heterotypic inner membrane fusion: purified L-OPA1 on one membrane and CL on the opposing membrane are sufficient for mitochondrial inner membrane fusion in vitro; S-OPA1 promotes L-OPA1-dependent heterotypic fusion but is not alone sufficient.","method":"In vitro membrane fusion reconstitution with purified human L-OPA1 and S-OPA1, cardiolipin-containing liposomes, living cell confirmation","journal":"Biochimica et biophysica acta. Bioenergetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, mechanistic dissection of L- vs S-OPA1 and cardiolipin roles, confirmed in living cells","pmids":["29852142"],"is_preprint":false},{"year":2018,"finding":"Opa1 deficiency in muscle causes initial mitochondrial alterations (cristae disorganization, mtDNA instability) leading to TLR9-activated NF-κB signaling and inflammation in a cell-autonomous, mtDNA-dependent manner; depletion of mitochondrial DNA or blockage of TLR9 prevents NF-κB activation and inflammation.","method":"Muscle-specific Opa1 knockout mice, NF-κB reporter assays, mtDNA depletion, TLR9 knockdown/blockade, inflammatory gene expression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model with epistasis (TLR9 blockade rescues), cell-autonomous validation, mtDNA depletion rescue","pmids":["29632021"],"is_preprint":false},{"year":2019,"finding":"Crystal and cryo-tomography structures of Mgm1 reveal a GTPase domain, bundle signalling element, stalk, and paddle domain with a membrane-binding site; the stalk mediates assembly of bent tetramers into helical filaments on membranes; tetramer assembly on membranes is required for inner membrane remodeling.","method":"X-ray crystallography, cryo-electron tomography of Mgm1-decorated lipid tubes, fluorescence microscopy on reconstituted membrane tubes, biochemical experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + cryo-ET + biochemical validation, multiple orthogonal methods in one study","pmids":["31292547"],"is_preprint":false},{"year":2019,"finding":"OPA1 deficiency impairs respiratory chain supercomplex (RCS) assembly and mitochondrial bioenergetics; PTP-induced mitochondrial swelling stimulates L-OPA1 proteolytic cleavage, and OPA1 knockdown reduces PTP-induced swelling but enhances ROS production, demonstrating a PTP-OPA1 axis in RCS regulation.","method":"OPA1 knockdown in cardiac mitochondria and cell lines, Blue-Native PAGE for supercomplex analysis, ROS measurement, PTP inhibitor/inducer experiments","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple functional readouts but single lab, no reconstitution","pmids":["31870826"],"is_preprint":false},{"year":2020,"finding":"The GTPase domain of human OPA1 forms nucleotide-dependent dimers (GDP+BeF3- stabilized); a three-helix bundle domain tightly associates with the GTPase domain; the GTPase dimer interface is critical for mitochondrial morphology maintenance, and an N-terminal extension mediates nucleotide-independent dimerization facilitating membrane association.","method":"X-ray crystallography of OPA1 minimal GTPase domain, biochemical dimerization assays, cell-based morphology assays with interface mutants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure + biochemical assays + cell-based functional validation, single lab with multiple methods","pmids":["32379273"],"is_preprint":false},{"year":2020,"finding":"OPA1 is required for angiogenesis; in response to angiogenic stimuli, OPA1 limits NFκB signaling to allow angiogenic gene expression; endothelial Opa1 is required in an NFκB-dependent pathway for developmental and tumor angiogenesis.","method":"Endothelial-specific OPA1 knockout mice, pharmacological OPA1 inhibitor, NFκB reporter assays, in vivo tumor models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO + pharmacological inhibitor + NFκB pathway epistasis + in vivo tumor model","pmids":["32315597"],"is_preprint":false},{"year":2020,"finding":"Chchd2 stabilizes OPA1 by competing with P32 for YME1L binding; P32 co-immunoprecipitates with Chchd2 and YME1L, and the P32-YME1L interaction enhances YME1L activity promoting OPA1 degradation. Loss of Chchd2 reduces OPA1 levels and causes mitochondrial fragmentation.","method":"Co-immunoprecipitation, YME1L activity assays, OPA1 western blot, Drosophila genetics","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP of three-protein complex, functional enzyme activity assay, in vivo Drosophila model","pmids":["31907391"],"is_preprint":false},{"year":2021,"finding":"OPA1 in POMC neurons controls mitochondrial cristae architecture and Ca2+ handling; genetic inactivation of OPA1 in POMC neurons causes cristae topology disruption, reduced mitochondrial Ca2+ uptake, decreased α-MSH secretion, hyperphagia, and attenuated white adipose tissue lipolysis leading to obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program.","method":"POMC neuron-specific OPA1 knockout mice, electron microscopy of cristae, mitochondrial Ca2+ measurements, chemogenetics, pharmacological rescue","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined mechanistic pathway (Ca2+ → α-MSH → lipolysis), pharmacological rescue validates mechanism","pmids":["34343501"],"is_preprint":false},{"year":2021,"finding":"Opa1 promotes adipocyte browning through a urea cycle-cAMP-CREB-Kdm3a axis; Opa1-dependent higher cAMP levels activate CREB to transcribe urea cycle enzymes, leading to fumarate accumulation that drives beige differentiation. Adipocyte-specific Opa1 deletion curtails the urea cycle and beige differentiation, rescued by fumarate supplementation.","method":"Adipocyte-specific Opa1 KO and overexpression mice, transcriptomics, metabolomics, flux analyses, fumarate rescue experiments","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO + OE + metabolomics + flux analysis + metabolite rescue, multiple orthogonal methods","pmids":["34873337"],"is_preprint":false},{"year":2022,"finding":"Deletion of OPA1 in muscle stem cells (MuSCs) fragments mitochondria and transitions MuSCs from deep quiescence to G-alert quiescence by activating a glutathione (GSH)-redox signaling pathway that promotes cell-cycle progression and myogenic gene expression; chronic OPA1 loss causing mitochondrial dysfunction leads to G-alert with severe cell-cycle defects.","method":"MuSC-specific OPA1 deletion mouse model, quiescence state analysis, GSH pathway inhibitors, flow cytometry, single-cell analysis","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined stem cell phenotype, pathway epistasis via GSH inhibitors","pmids":["35998642"],"is_preprint":false},{"year":2022,"finding":"Myeloid-specific OPA1 deletion impairs M1-macrophage commitment; mechanistically, OPA1 loss causes TCA cycle metabolite accumulation and defective NF-κB signaling activation; in vivo, OPA1-knockout macrophages persist in damaged muscle, causing excess collagen deposition and impaired regeneration.","method":"Myeloid-specific Opa1 KO mice, metabolomics (TCA metabolites), NF-κB reporter assays, muscle injury model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO + metabolomics + NF-κB epistasis + in vivo regeneration model","pmids":["36307526"],"is_preprint":false},{"year":2022,"finding":"OPA1 modulates mitochondrial Ca2+ uptake through functional ER-mitochondria coupling, dependent on its GED domain; Opa1-deficient MEFs show closer ER-mitochondria contacts and require less ER Ca2+ mobilization to induce a mitochondrial Ca2+ rise. Acute expression of GTPase (but not GED) mutants partially restores cytosolic Ca2+ needed for mitochondrial Ca2+ uptake.","method":"OPA1 KO MEF rescue with domain-specific mutants, Ca2+ imaging, ER-mitochondria contact site measurements, ADOA patient fibroblasts","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific mutant rescue, multiple cell systems, Ca2+ imaging, single lab","pmids":["35047497"],"is_preprint":false},{"year":2023,"finding":"Human OPA1 embeds into cardiolipin-containing membranes through a lipid-binding paddle domain; a conserved loop within the paddle domain inserts deeply into the bilayer; OPA1 dimerization through the paddle domain promotes helical assembly of a flexible OPA1 lattice that drives mitochondrial fusion; OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out during membrane remodeling.","method":"Cryo-EM of OPA1 on lipid membrane tubes, cellular structural analysis, mutagenesis of assembly interfaces and membrane-binding loops, cell-based mitochondrial fragmentation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure + mutagenesis + cell-based functional validation, multiple orthogonal methods in one study","pmids":["37612504"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM helical structures of OPA1 on lipid membrane tubes reveal densely packed protein rungs with minimal inter-rung connectivity, nucleotide-dependent GTPase domain dimerization, and unique paddle domain secondary structures (membrane-inserting helices) that strengthen membrane association. Mutations disrupting assembly interfaces or membrane binding cause mitochondrial fragmentation in cells.","method":"Cryo-electron microscopy, helical reconstruction, mutagenesis of assembly interfaces and membrane-inserting helices, cell-based fragmentation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure + mutagenesis + cell-based validation, independent from the von der Malsburg study (same year, complementary structures)","pmids":["37612506"],"is_preprint":false},{"year":2023,"finding":"OPA1 GTPase and GED domain mutations have distinct effects: GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity; GTPase mutants can cause mitochondrial elongation (suggesting fission inhibition) whereas all mutants inhibit fusion; distinct aberrant cristae ultrastructures result from GTPase vs. GED mutations.","method":"Patient-derived cells (GTPase and GED domain mutants), OPA1-null MEF rescue, mitochondrial fusion assays, GTPase activity assays, electron microscopy of cristae","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — patient cells + null MEF rescue + enzymatic assays + EM, domain-specific mechanistic dissection","pmids":["36927155"],"is_preprint":false},{"year":2024,"finding":"In situ cryo-electron tomography of MEFs with defined OPA1 states shows increased l-OPA1 promotes cristae stacking and elongated mitochondria, while increased s-OPA1 correlates with irregular cristae packing and round mitochondria; l-OPA1 is required for wild-type apoptotic and calcium handling responses.","method":"In situ cryo-electron tomography (cryo-FIB milling), MEFs with controlled l-OPA1/s-OPA1 ratios, apoptosis assays, calcium handling assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in situ cryo-ET with defined genetic states, functional assays, single lab with multiple orthogonal methods","pmids":["38225406"],"is_preprint":false},{"year":2024,"finding":"OPA1 promotes ferroptosis by maintaining mitochondrial homeostasis and function, contributing to mitochondrial lipid ROS generation and suppressing an ATF4-mediated integrated stress response; ferroptosis sensitization requires OPA1 GTPase activity but is independent of OPA1-mediated mitochondrial fusion.","method":"OPA1 KO cells, OPA1 mutant reconstitution (GTPase-dead vs. fusion-deficient mutants), mitochondrial ROS measurement, ATF4 pathway analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — KO + domain-specific mutant reconstitution + pathway epistasis, functional dissection of fusion-independent GTPase role","pmids":["39142278"],"is_preprint":false},{"year":2024,"finding":"Copper transport by Slc25a3 is required for mitochondrial 'flickering' (short depolarization pulses); flickering activates OMA1, which proteolytically inactivates OPA1 to prevent deleterious hyperfusion. Copper-dependent enzymes SOD1 and cytochrome c oxidase regulate this flickering-OMA1-OPA1 axis.","method":"Live-imaging screen in mammalian cells, Slc25a3 KO, copper chelation, OMA1 and OPA1 isoform analysis, SOD1 and COX perturbations","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live-imaging screen + multiple genetic KOs + biochemical OPA1 cleavage assay, mechanistic pathway established","pmids":["38986607"],"is_preprint":false},{"year":2024,"finding":"OPA1 deficiency in skeletal muscle increases ATF4 (integrated stress response effector) expression, which drives tighter and more frequent ER-mitochondria contact sites (MERCs) with greater abundance of MERC calcium exchange proteins; reducing Atf4 prevents OPA1-loss-induced MERC tightening and partially restores mitochondrial and SR calcium.","method":"Muscle-specific OPA1 KD in mice and Drosophila, primary myotubes, electron microscopy of MERCs, ATF4 KD epistasis, Ca2+ measurements","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple model systems (mouse, Drosophila, primary cells), ATF4 epistasis, EM quantification of MERC structure","pmids":["38419397"],"is_preprint":false},{"year":2025,"finding":"Epithelial OPA1 is required for intestinal barrier function and immune homeostasis; OPA1 deficiency in gut epithelial cells causes microbial translocation, epithelial progenitor cell death, and spontaneous chronic intestinal inflammation; pharmacological DRP1 inhibition partially reverts OPA1-inhibitor-induced mitochondrial fragmentation in organoids.","method":"Intestinal epithelial-specific Opa1 KO mice, human IBD patient samples, organoids with OPA1 inhibitor, DRP1 inhibitor rescue","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO + human patient validation + organoid pharmacological rescue + epistasis with DRP1 inhibitor","pmids":["39813315"],"is_preprint":false}],"current_model":"OPA1 is a dynamin-related GTPase anchored in the mitochondrial inner membrane (IMM) that mediates IMM fusion and cristae remodeling through cardiolipin-dependent membrane embedding, paddle-domain dimerization, and helical lattice assembly; its proteolytic processing by YME1L and the stress-activated protease OMA1 (regulated by copper-dependent flickering) controls the balance between fusion-competent long forms and soluble short forms, while post-translational acetylation (written by stress, erased by SIRT3 at K926/K931) modulates GTPase activity, and through these structural and enzymatic mechanisms OPA1 governs mitochondrial respiratory supercomplex assembly, cytochrome c release during apoptosis, mtDNA maintenance, ER-mitochondria calcium coupling, and cell-type-specific processes including stem cell quiescence, macrophage activation, adipocyte browning, intestinal epithelial barrier integrity, and sensitivity to ferroptosis."},"narrative":{"mechanistic_narrative":"OPA1 is a dynamin-related GTPase of the mitochondrial inner membrane that mediates inner-membrane fusion and cristae remodeling, and through these activities governs mitochondrial bioenergetics, mtDNA maintenance, apoptosis, and a range of cell-type-specific physiological programs [PMID:7916673, PMID:14970223, PMID:17055438, PMID:26039448]. Conserved from the yeast ortholog Mgm1, the protein is anchored in or bound to the inner membrane facing the intermembrane space, and its loss causes cristae disorganization, mitochondrial swelling and fragmentation, and mtDNA loss [PMID:7916673, PMID:12707284, PMID:14970223]. OPA1 exists as long membrane-bound (L-OPA1) and short soluble (S-OPA1) isoforms whose ratio is set by alternative topogenesis and by proteolytic processing—L-OPA1 supports fusion while excess processing by the stress-activated protease OMA1 (balanced against YME1L) limits fusion and promotes fragmentation and death [PMID:12707284, PMID:15096522, PMID:27189080]. Mechanistically, OPA1 binds negatively charged inner-membrane lipids, embedding into cardiolipin-containing bilayers through a paddle domain whose conserved loop inserts into the bilayer; lipid binding stimulates GTPase activity and drives nucleotide-dependent dimerization and assembly of a helical lattice that tethers and bends opposing membranes to execute GTP hydrolysis-dependent fusion [PMID:19752025, PMID:19703904, PMID:22977249, PMID:31292547, PMID:37612504, PMID:37612506]. L-OPA1 together with cardiolipin on the opposing membrane is sufficient for heterotypic inner-membrane fusion in vitro [PMID:29852142]. OPA1-dependent cristae stabilization promotes respiratory supercomplex assembly and respiratory efficiency while restraining cytochrome c release and ROS, and genetic preservation of this pathway protects against atrophy, ischemia, and apoptosis in vivo [PMID:26039448, PMID:31870826, PMID:38225406]. GTPase activity is enhanced by SIRT3-mediated deacetylation at K926/K931 [PMID:24344202]. Through cristae architecture and ER-mitochondria calcium coupling, OPA1 controls tissue-specific outcomes including POMC-neuron control of feeding and lipolysis, adipocyte browning, muscle-stem-cell quiescence, macrophage M1 commitment, endothelial angiogenesis, intestinal epithelial barrier integrity, and ferroptosis sensitivity, with several of these roles depending on GTPase activity rather than fusion per se [PMID:32315597, PMID:34343501, PMID:34873337, PMID:35998642, PMID:36307526, PMID:35047497, PMID:39142278, PMID:39813315].","teleology":[{"year":1993,"claim":"Established that the OPA1 ortholog is a dynamin-like GTPase whose loss disrupts mitochondrial morphology and causes mtDNA loss, defining the gene's core cellular role.","evidence":"Genetic deletion of MGM1 in yeast with growth and mitochondrial morphology assays","pmids":["7916673"],"confidence":"High","gaps":["Did not resolve whether the morphology defect reflects fusion, fission, or membrane maintenance","No biochemical characterization of GTPase activity"]},{"year":2004,"claim":"Resolved that OPA1 is an intermembrane-space protein bound to the inner membrane whose loss disorganizes cristae before fragmentation, localizing its action to the inner membrane.","evidence":"siRNA knockdown, EM, and subcellular fractionation in mammalian cells","pmids":["14970223"],"confidence":"High","gaps":["Did not distinguish fusion from cristae maintenance mechanistically","No reconstitution"]},{"year":2004,"claim":"Defined how two OPA1 isoforms arise—rhomboid (Pcp1) cleavage and alternative topogenesis controlled by N-terminal hydrophobicity, import-motor function, and matrix ATP—and showed both isoforms are required for normal morphology.","evidence":"Yeast genetics, isoform-specific complementation, and mutagenesis of hydrophobic/import elements","pmids":["12707284","15096522"],"confidence":"High","gaps":["Mammalian protease assignments not yet established","Functional distinction between isoforms not yet mechanistically defined"]},{"year":2006,"claim":"Demonstrated OPA1 directly mediates inner-membrane fusion in a GTP- and membrane-potential-dependent manner distinct from outer-membrane fusion, separating its fusion function from cristae maintenance.","evidence":"In vitro mitochondrial fusion assay with GTPase mutants and potential manipulation in yeast","pmids":["17055438"],"confidence":"High","gaps":["Molecular structure of the fusion machine unknown","Lipid requirements not yet defined"]},{"year":2009,"claim":"Established the biochemical basis of fusion: lipid (cardiolipin/anionic phospholipid) binding stimulates GTPase activity ~50-fold and drives l/s dimerization and oligomeric ring assembly as the fusion building block.","evidence":"Purified-protein reconstitution, GTPase and lipid-binding assays, EM, and in vivo complementation","pmids":["19752025","19703904"],"confidence":"High","gaps":["High-resolution architecture of assemblies unresolved","Conformational coupling of GTP hydrolysis to membrane bending not defined"]},{"year":2012,"claim":"Showed OPA1 tethers opposing membranes to a ~15 nm gap and undergoes a GTP-dependent conformational change driving fusion, and identified PE as a lipid regulator of s-OPA1 biogenesis and fusion.","evidence":"Cryo-EM, in vitro liposome fusion, and yeast genetic/lipid-mixing analysis of Psd1/PE","pmids":["22977249","23045528"],"confidence":"High","gaps":["Atomic-resolution lattice geometry not yet determined","Mechanism linking conformational change to lipid mixing incomplete"]},{"year":2013,"claim":"Connected OPA1 activity to regulation: SIRT3 deacetylation at K926/K931 elevates GTPase activity and rescues OPA1-null mitochondrial function, and the inner-membrane protein Higd-1a binds L-OPA1 to block its cleavage.","evidence":"Mass spectrometry, mutagenesis, GTPase assays, Co-IP, and functional rescue in cardiomyocytes/cells","pmids":["24344202","23878241"],"confidence":"High","gaps":["Stress signals writing acetylation not identified","Structural basis of Higd-1a/OPA1 binding unresolved"]},{"year":2015,"claim":"Demonstrated in vivo that OPA1-dependent cristae stabilization improves respiratory efficiency and limits cytochrome c release/ROS, protecting tissues from atrophy, ischemia, and apoptosis.","evidence":"Cristae-remodeling-pathway genetic mouse models across multiple tissues with functional readouts","pmids":["26039448"],"confidence":"High","gaps":["Molecular link between OPA1 oligomers and supercomplexes not directly shown","Did not separate fusion from cristae effects in vivo"]},{"year":2016,"claim":"Formalized the L/S-OPA1 proteostatic switch: YME1L and OMA1 set the fusion-competent vs fusion-limiting balance, with stress-activated OMA1 processing driving fragmentation and death.","evidence":"Protease assays, isoform analysis, and KO/KD under stress","pmids":["27189080"],"confidence":"High","gaps":["Upstream activators of OMA1 not fully enumerated here","Quantitative thresholds of isoform ratio for fusion unclear"]},{"year":2017,"claim":"Began separating fusion-independent functions: L-OPA1 stabilizes respiratory supercomplexes to support mitopHlash independently of fusion or processing, and SIRT4 raises L-OPA1 to promote fusion.","evidence":"Fusion-deficient OPA1-K301A rescue, MFN1/2 and OMA1/YME1L KO cells with pH probes; Co-IP and isoform analysis for SIRT4","pmids":["28174208","29081403"],"confidence":"High","gaps":["SIRT4 finding rests on single Co-IP from one lab","Direct OPA1-supercomplex contacts not structurally shown"]},{"year":2018,"claim":"Showed L-OPA1 plus cardiolipin on the opposing membrane is sufficient for heterotypic inner-membrane fusion, and that muscle Opa1 loss triggers mtDNA/TLR9-dependent NF-κB inflammation, linking cristae integrity to innate immune signaling.","evidence":"Purified human L/S-OPA1 reconstitution with CL liposomes; muscle-specific KO with TLR9 and mtDNA-depletion epistasis","pmids":["29852142","29632021"],"confidence":"High","gaps":["How mtDNA reaches TLR9 not defined","Heterotypic fusion in vivo not directly visualized"]},{"year":2019,"claim":"Provided the structural framework: Mgm1 domains (GTPase, BSE, stalk, paddle) assemble bent tetramers into helical filaments on membranes required for inner-membrane remodeling, and OPA1 deficiency impairs supercomplex assembly via a PTP-OPA1 axis.","evidence":"Crystallography and cryo-ET of membrane-decorated Mgm1; OPA1 KD with Blue-Native PAGE and PTP perturbations","pmids":["31292547","31870826"],"confidence":"High","gaps":["Human OPA1 lattice not yet resolved at this stage","PTP-OPA1 supercomplex study single-lab without reconstitution"]},{"year":2020,"claim":"Dissected OPA1 self-assembly and proteostasis at higher resolution: nucleotide-dependent GTPase dimerization and an N-terminal dimerization extension drive membrane association/morphology, and Chchd2 stabilizes OPA1 by competing with P32 for YME1L.","evidence":"Crystallography of GTPase domain, biochemical dimerization and cell morphology assays; Co-IP and YME1L activity assays with Drosophila genetics","pmids":["32379273","31907391"],"confidence":"High","gaps":["Chchd2/P32/YME1L finding is Medium-confidence multiprotein Co-IP","Coupling of dimer interface to fusion stroke not fully defined"]},{"year":2020,"claim":"Extended OPA1 to physiology: endothelial OPA1 limits NF-κB to permit angiogenic gene expression and is required for developmental and tumor angiogenesis.","evidence":"Endothelial-specific KO, pharmacological inhibitor, NF-κB reporters, and in vivo tumor models","pmids":["32315597"],"confidence":"High","gaps":["Whether the angiogenic role depends on fusion vs cristae unresolved","Direct OPA1-NF-κB molecular link not defined"]},{"year":2021,"claim":"Tied OPA1-controlled cristae and ER-mitochondria calcium handling to organismal metabolism: POMC-neuron OPA1 governs Ca2+ uptake, α-MSH secretion and lipolysis, while adipocyte OPA1 drives browning via a urea-cycle-cAMP-CREB-Kdm3a-fumarate axis.","evidence":"Cell-type-specific KO mice, EM of cristae, Ca2+ imaging, metabolomics/flux, and pharmacological/metabolite rescue","pmids":["34343501","34873337"],"confidence":"High","gaps":["Mechanism coupling cristae shape to cAMP signaling not defined","Generality across tissues untested"]},{"year":2022,"claim":"Defined additional cell-type-specific roles and the GED-dependence of ER-mitochondria calcium coupling: OPA1 sets muscle-stem-cell quiescence via GSH-redox signaling, macrophage M1 commitment via TCA/NF-κB, and tunes MERC calcium through its GED domain.","evidence":"Conditional KO mouse models, GSH inhibitors, metabolomics, NF-κB reporters; domain-specific mutant rescue and Ca2+/contact-site imaging in MEFs and ADOA fibroblasts","pmids":["35998642","36307526","35047497"],"confidence":"High","gaps":["MERC calcium study is single-lab Medium-confidence","How fragmentation versus dysfunction segregate quiescence states incompletely defined"]},{"year":2023,"claim":"Resolved the human OPA1 membrane-remodeling mechanism at near-atomic detail—paddle-domain membrane insertion, nucleotide-dependent GTPase dimerization, and a flexible helical lattice—and separated GTPase from GED domain functions in fusion and cristae.","evidence":"Cryo-EM of OPA1 on lipid tubes with assembly/membrane-binding mutants and cell fragmentation assays; patient-cell and null-MEF rescue with domain mutants","pmids":["37612504","37612506","36927155"],"confidence":"High","gaps":["Dynamics of the conformational stroke during fusion not directly observed","In-cell lattice architecture only partly resolved"]},{"year":2024,"claim":"Linked OPA1 isoform states to in-situ cristae ultrastructure and uncovered fusion-independent GTPase functions: l-OPA1 drives cristae stacking and proper apoptosis/calcium responses, copper-dependent flickering activates OMA1 to inactivate OPA1, OPA1 promotes ferroptosis via GTPase-dependent lipid ROS, and OPA1 loss reshapes MERCs through ATF4.","evidence":"In situ cryo-ET of defined OPA1 states; live-imaging copper/OMA1 screen; KO with GTPase-dead vs fusion-deficient mutant reconstitution and ATF4 epistasis across mouse/Drosophila/cells","pmids":["38225406","38986607","39142278","38419397"],"confidence":"High","gaps":["How copper flickering mechanistically triggers OMA1 incompletely defined","Molecular basis of GTPase-dependent, fusion-independent ferroptosis role unresolved"]},{"year":2025,"claim":"Extended OPA1 requirement to epithelial barrier biology: gut-epithelial OPA1 maintains barrier function and immune homeostasis, with loss causing fragmentation, progenitor death, and chronic inflammation reversible by DRP1 inhibition.","evidence":"Intestinal epithelial-specific KO mice, IBD patient samples, and organoid OPA1/DRP1-inhibitor rescue","pmids":["39813315"],"confidence":"High","gaps":["Whether the barrier role depends on fusion vs cristae not resolved","Direct link between fragmentation and progenitor death not mechanistically defined"]},{"year":null,"claim":"How OPA1's conformational/GTP-hydrolysis cycle is mechanically coupled to lipid mixing in vivo, and how its many fusion-independent GTPase-dependent functions (ferroptosis, supercomplex/calcium signaling, tissue programs) are molecularly distinguished from its fusion role, remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No real-time structural visualization of the fusion stroke in membranes","Molecular effectors distinguishing fusion-independent GTPase functions not identified","Quantitative model linking isoform ratio to specific physiological outputs lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,4,6,7,10,21,31,33]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6,7,17,29,30]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,12]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,4,12,19,29]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,12,32,33]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,20,25]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[14,18,34,35]}],"complexes":[],"partners":["YME1L","OMA1","PARL","HIGD-1A","SIRT3","SIRT4","CHCHD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60313","full_name":"Dynamin-like GTPase OPA1, mitochondrial","aliases":["Optic atrophy protein 1"],"length_aa":960,"mass_kda":111.6,"function":"Dynamin-related GTPase that is essential for normal mitochondrial morphology by mediating fusion of the mitochondrial inner membranes, regulating cristae morphology and maintaining respiratory chain function (PubMed:16778770, PubMed:17709429, PubMed:20185555, PubMed:24616225, PubMed:28628083, PubMed:28746876, PubMed:31922487, PubMed:32228866, PubMed:32567732, PubMed:33130824, PubMed:33237841, PubMed:37612504, PubMed:37612506). Exists in two forms: the transmembrane, long form (Dynamin-like GTPase OPA1, long form; L-OPA1), which is tethered to the inner mitochondrial membrane, and the short soluble form (Dynamin-like GTPase OPA1, short form; S-OPA1), which results from proteolytic cleavage and localizes in the intermembrane space (PubMed:31922487, PubMed:32228866, PubMed:33237841, PubMed:37612504, PubMed:37612506). Both forms (L-OPA1 and S-OPA1) cooperate to catalyze the fusion of the mitochondrial inner membrane (PubMed:31922487, PubMed:37612504, PubMed:37612506). The equilibrium between L-OPA1 and S-OPA1 is essential: excess levels of S-OPA1, produced by cleavage by OMA1 following loss of mitochondrial membrane potential, lead to an impaired equilibrium between L-OPA1 and S-OPA1, inhibiting mitochondrial fusion (PubMed:20038677, PubMed:31922487). The balance between L-OPA1 and S-OPA1 also influences cristae shape and morphology (By similarity). Involved in remodeling cristae and the release of cytochrome c during apoptosis (By similarity). Proteolytic processing by PARL in response to intrinsic apoptotic signals may lead to disassembly of OPA1 oligomers and release of the caspase activator cytochrome C (CYCS) into the mitochondrial intermembrane space (By similarity). Acts as a regulator of T-helper Th17 cells, which are characterized by cells with fused mitochondria with tight cristae, by mediating mitochondrial membrane remodeling: OPA1 is required for interleukin-17 (IL-17) production (By similarity). Its role in mitochondrial morphology is required for mitochondrial genome maintenance (PubMed:18158317, PubMed:20974897) Constitutes the transmembrane long form (L-OPA1) that plays a central role in mitochondrial inner membrane fusion and cristae morphology (PubMed:31922487, PubMed:32228866, PubMed:37612504, PubMed:37612506). L-OPA1 and the soluble short form (S-OPA1) form higher-order helical assemblies that coordinate the fusion of mitochondrial inner membranes (PubMed:31922487, PubMed:37612504, PubMed:37612506). Inner membrane-anchored L-OPA1 molecules initiate membrane remodeling by recruiting soluble S-OPA1 to rapidly polymerize into a flexible cylindrical scaffold encaging the mitochondrial inner membrane (PubMed:37612504, PubMed:37612506). Once at the membrane surface, the formation of S-OPA1 helices induce bilayer curvature (PubMed:37612504, PubMed:37612506). OPA1 dimerization through the paddle region, which inserts into cardiolipin-containing membrane, promotes GTP hydrolysis and the helical assembly of a flexible OPA1 lattice on the membrane, which drives membrane curvature and mitochondrial fusion (PubMed:28628083, PubMed:37612504, PubMed:37612506). Plays a role in the maintenance and remodeling of mitochondrial cristae, some invaginations of the mitochondrial inner membrane that provide an increase in the surface area (PubMed:32567732, PubMed:33130824). Probably acts by forming helical filaments at the inside of inner membrane tubes with the shape and dimensions of crista junctions (By similarity). The equilibrium between L-OPA1 and S-OPA1 influences cristae shape and morphology: increased L-OPA1 levels promote cristae stacking and elongated mitochondria, while increased S-OPA1 levels correlated with irregular cristae packing and round mitochondria shape (By similarity) Constitutes the soluble short form (S-OPA1) generated by cleavage by OMA1, which plays a central role in mitochondrial inner membrane fusion and cristae morphology (PubMed:31922487, PubMed:32228866, PubMed:32245890, PubMed:37612504, PubMed:37612506). The transmembrane long form (L-OPA1) and the S-OPA1 form higher-order helical assemblies that coordinate the fusion of mitochondrial inner membranes (PubMed:31922487, PubMed:32228866, PubMed:37612504, PubMed:37612506). Inner membrane-anchored L-OPA1 molecules initiate membrane remodeling by recruiting soluble S-OPA1 to rapidly polymerize into a flexible cylindrical scaffold encaging the mitochondrial inner membrane (PubMed:32228866, PubMed:37612504, PubMed:37612506). Once at the membrane surface, the formation of S-OPA1 helices induce bilayer curvature (PubMed:37612504, PubMed:37612506). OPA1 dimerization through the paddle region, which inserts into cardiolipin-containing membrane, promotes GTP hydrolysis and the helical assembly of a flexible OPA1 lattice on the membrane, which drives membrane curvature and mitochondrial fusion (PubMed:28628083, PubMed:37612504, PubMed:37612506). Excess levels of S-OPA1 produced by cleavage by OMA1 following stress conditions that induce loss of mitochondrial membrane potential, lead to an impaired equilibrium between L-OPA1 and S-OPA1, thereby inhibiting mitochondrial fusion (PubMed:20038677). Involved in mitochondrial safeguard in response to transient mitochondrial membrane depolarization by mediating flickering: cleavage by OMA1 leads to excess production of S-OPA1, preventing mitochondrial hyperfusion (By similarity). Plays a role in the maintenance and remodeling of mitochondrial cristae, some invaginations of the mitochondrial inner membrane that provide an increase in the surface area (PubMed:32245890). Probably acts by forming helical filaments at the inside of inner membrane tubes with the shape and dimensions of crista junctions (By similarity). The equilibrium between L-OPA1 and S-OPA1 influences cristae shape and morphology: increased L-OPA1 levels promote cristae stacking and elongated mitochondria, while increased S-OPA1 levels correlated with irregular cristae packing and round mitochondria shape (By similarity) Coexpression of isoform 1 with shorter alternative products is required for optimal activity in promoting mitochondrial fusion Isoforms that contain the alternative exon 4b are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane Isoforms that contain the alternative exon 4b are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane","subcellular_location":"Mitochondrion intermembrane space","url":"https://www.uniprot.org/uniprotkb/O60313/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/OPA1","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":[{"gene":"TOMM20A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/OPA1","total_profiled":1310},"omim":[{"mim_id":"621481","title":"MITOCHONDRIAL DNA DEPLETION SYNDROME 14A (ENCEPHALOMYOPATHIC TYPE); MTDPS14A","url":"https://www.omim.org/entry/621481"},{"mim_id":"620765","title":"MITOCHONDRIAL FISSION REGULATOR 1-LIKE PROTEIN; MTFR1L","url":"https://www.omim.org/entry/620765"},{"mim_id":"620739","title":"RCC1-LIKE PROTEIN; RCC1L","url":"https://www.omim.org/entry/620739"},{"mim_id":"620629","title":"OPTIC ATROPHY 16; OPA16","url":"https://www.omim.org/entry/620629"},{"mim_id":"620583","title":"OPTIC ATROPHY 15; OPA15","url":"https://www.omim.org/entry/620583"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OPA1"},"hgnc":{"alias_symbol":["NTG","KIAA0567","FLJ12460","NPG","MGM1"],"prev_symbol":[]},"alphafold":{"accession":"O60313","domains":[{"cath_id":"3.40.50.300","chopping":"265-566","consensus_level":"medium","plddt":84.6269,"start":265,"end":566},{"cath_id":"-","chopping":"606-918","consensus_level":"medium","plddt":87.9931,"start":606,"end":918}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60313","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60313-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60313-F1-predicted_aligned_error_v6.png","plddt_mean":74.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OPA1","jax_strain_url":"https://www.jax.org/strain/search?query=OPA1"},"sequence":{"accession":"O60313","fasta_url":"https://rest.uniprot.org/uniprotkb/O60313.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60313/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60313"}},"corpus_meta":[{"pmid":"26039448","id":"PMC_26039448","title":"The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage.","date":"2015","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26039448","citation_count":389,"is_preprint":false},{"pmid":"14970223","id":"PMC_14970223","title":"Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14970223","citation_count":385,"is_preprint":false},{"pmid":"17055438","id":"PMC_17055438","title":"Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17055438","citation_count":382,"is_preprint":false},{"pmid":"24344202","id":"PMC_24344202","title":"SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24344202","citation_count":363,"is_preprint":false},{"pmid":"19493956","id":"PMC_19493956","title":"Mitochondrial OPA1, apoptosis, and heart failure.","date":"2009","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/19493956","citation_count":353,"is_preprint":false},{"pmid":"27189080","id":"PMC_27189080","title":"OPA1 processing in cell death and disease - 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\"method\": \"Genetic deletion in yeast, growth assays, mitochondrial marker immunofluorescence\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotypes, foundational study replicated by subsequent work\",\n      \"pmids\": [\"7916673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The large isoform of Mgm1 (l-Mgm1) is an integral inner membrane protein facing the intermembrane space; the rhomboid-type serine protease Pcp1 cleaves l-Mgm1 to generate the short isoform (s-Mgm1), and both isoforms together (but not either alone) are required for wild-type mitochondrial morphology and mtDNA maintenance.\",\n      \"method\": \"Yeast genetics, deletion mutants, expression of individual isoforms, complementation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution-like complementation with isoform-specific constructs, replicated across labs\",\n      \"pmids\": [\"12707284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"OPA1/Mgm1 localizes to the mitochondrial intermembrane space tightly bound to the outer surface of the inner membrane; loss of OPA1 by siRNA causes mitochondrial swelling, localized constrictions, and disorganized cristae prior to fragmentation.\",\n      \"method\": \"siRNA knockdown, electron microscopy, subcellular fractionation, immunofluorescence in mammalian cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by fractionation, EM ultrastructure, loss-of-function with defined morphological phenotype\",\n      \"pmids\": [\"14970223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Alternative topogenesis of Mgm1 generates two isoforms dependent on the hydrophobicity of the N-terminal segment, a functional protein import motor, and matrix ATP levels; altering hydrophobicity or import motor function shifts the l/s-Mgm1 ratio and causes mitochondrial fragmentation.\",\n      \"method\": \"Mutagenesis of hydrophobic segments, import motor mutants, ATP manipulation in yeast\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal genetic and biochemical perturbations, mechanistic follow-through\",\n      \"pmids\": [\"15096522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mgm1 is required for mitochondrial inner-membrane fusion and cristae maintenance; Mgm1 tethers and fuses inner membranes in a GTP hydrolysis- and inner-membrane electrical potential-dependent manner, distinct from outer-membrane fusion.\",\n      \"method\": \"In vitro mitochondrial fusion assay, GTPase mutants, membrane potential manipulation in yeast\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of inner-membrane fusion, mechanistic dissection with mutants, published in high-impact journal\",\n      \"pmids\": [\"17055438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"OPA1 forms oligomers in the inner mitochondrial membrane together with a soluble form; these oligomers are disrupted early during apoptosis. The rhomboid protease PARL participates in generating a soluble form of OPA1 and in cristae remodeling; PARL itself is regulated by phosphorylation-dependent proteolysis.\",\n      \"method\": \"Co-immunoprecipitation, biochemical fractionation, apoptosis assays, review of primary experimental data\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review synthesizing primary experimental findings; oligomer disruption and PARL cleavage established in cited primary work\",\n      \"pmids\": [\"17464328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"l- and s-Mgm1 exist as inactive GTPase monomers in the absence of membrane, but together in trans form a functional dimer in a cardiolipin-dependent manner that is the building block for higher-order assemblies required for inner membrane fusion.\",\n      \"method\": \"Biochemical reconstitution, GTPase assays, electron microscopy of assemblies, cardiolipin dependence assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins, cardiolipin requirement established biochemically, multiple orthogonal methods\",\n      \"pmids\": [\"19752025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"s-Mgm1 binds specifically to negatively charged phospholipids characteristic of the mitochondrial inner membrane; lipid binding stimulates GTPase activity ~50-fold, promotes liposome interaction and tethering, and s-Mgm1 assembles onto liposomes as oligomeric rings with 3-fold (trimeric) symmetry. Point mutants defective in oligomerization or lipid binding lose GTPase stimulation and fail in vivo.\",\n      \"method\": \"Purified protein biochemistry, lipid-binding assays, GTPase activity assays, electron microscopy, in vivo complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis, structural EM, in vivo validation\",\n      \"pmids\": [\"19703904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mgm1 tethers opposing membranes to a ~15 nm gap and undergoes a GTP-dependent conformational change that drives membrane fusion; cryo-EM and in vitro liposome fusion assays demonstrate this mechanism for both inner-membrane fusion and cristae maintenance.\",\n      \"method\": \"Cryo-electron microscopy, in vitro liposome fusion assays, GTP-dependent conformational analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with in vitro fusion assay and nucleotide-dependent conformational analysis\",\n      \"pmids\": [\"22977249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Phosphatidylethanolamine (PE), synthesized by Psd1, regulates mitochondrial fusion by altering membrane biophysical properties (lipid mixing kinetics) and by promoting biogenesis of s-Mgm1; loss of Psd1 reduces s-Mgm1 levels and impairs fusion, and increasing s-Mgm1 in Δpsd1 cells reduces mitochondrial aggregation.\",\n      \"method\": \"Yeast genetics, liposome lipid-mixing assays, biochemical isoform analysis, rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro lipid-mixing reconstitution combined with genetic epistasis and biochemical rescue\",\n      \"pmids\": [\"23045528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SIRT3 deacetylates OPA1 at lysine 926 and 931, elevating its GTPase activity; in SIRT3-deficient cells OPA1 is hyperacetylated at these sites, reducing GTPase activity. A deacetylation-mimetic OPA1 rescues mitochondrial functions in OPA1-null cells, protecting cardiomyocytes from doxorubicin-induced death.\",\n      \"method\": \"Mass spectrometry identification of acetylation sites, site-directed mutagenesis, GTPase activity assays, complementation in OPA1-null cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mass spectrometry + mutagenesis + enzymatic assay + functional rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24344202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Higd-1a (HIMP1-a/HIG1), a mitochondrial inner membrane protein, physically binds to OPA1 (long isoforms) via a region in or proximal to the membrane; Higd-1a depletion causes OPA1 cleavage with loss of long isoforms, mitochondrial fission, cristae disorganization, and mtDNA depletion. Ectopic Higd-1a inhibits OPA1 cleavage and mitochondrial fission induced by membrane potential loss.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, OPA1 isoform analysis by western blot, electron microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, loss-of-function with multiple defined readouts, rescue with noncleavable OPA1\",\n      \"pmids\": [\"23878241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"OPA1-dependent cristae stabilization increases mitochondrial respiratory efficiency and blunts cytochrome c release, ROS production, and mitochondrial dysfunction; genetic inhibition of the OPA1 cristae remodeling pathway in vivo protects mice from denervation-induced muscular atrophy, ischemic heart/brain damage, and hepatocellular apoptosis without affecting development.\",\n      \"method\": \"In vivo genetic mouse models (cristae remodeling pathway inhibition), ischemia models, denervation atrophy, cytochrome c release assays, ROS measurement, respiratory function assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic models with multiple tissue readouts, multiple orthogonal functional assays, replicated across tissue types\",\n      \"pmids\": [\"26039448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mgm1 association with membranes alters membrane topography, promotes local membrane bending, and creates tubular structures on supported lipid bilayers and liposomes, suggesting a mechanical force mechanism for initiating membrane fusion.\",\n      \"method\": \"AFM on supported lipid bilayers, electron microscopy of liposomes, in vitro membrane association assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct structural/biophysical assay with purified protein, single lab study\",\n      \"pmids\": [\"25784211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"OPA1 proteolytic processing by YME1L and OMA1 regulates the balance between long membrane-bound forms (required for fusion) and short soluble forms (limiting fusion); excessive stress-activated OMA1-mediated OPA1 processing causes mitochondrial fragmentation and promotes cell death.\",\n      \"method\": \"Protease activity assays, OPA1 isoform analysis, KO/KD studies, stress-induction experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection of protease-substrate relationships replicated across multiple labs\",\n      \"pmids\": [\"27189080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT4 physically interacts with OPA1 and increases levels of the long (membrane-bound) form of OPA1 (L-OPA1), promoting mitochondrial fusion and counteracting fission/mitophagy; this effect requires SIRT4 enzymatic activity.\",\n      \"method\": \"Co-immunoprecipitation, OPA1 isoform western blot analysis, SIRT4 overexpression and enzymatic mutant\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, OPA1 isoform analysis, single lab\",\n      \"pmids\": [\"29081403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"L-OPA1 (not membrane fusion or OPA1 proteolytic processing) regulates mitopHlash (matrix alkalinization transients coupled to mitochondrial membrane potential drops), likely by stabilizing respiratory chain supercomplexes; a fusion-deficient OPA1-K301A mutant restores mitopHlash competence, and MFN1/2 or OMA1/YME1L absence does not affect mitopHlash.\",\n      \"method\": \"Genetically encoded pH probes, OPA1 ablation and rescue with fusion-deficient mutants, MFN1/2 KO cells, OMA1/YME1L KO cells\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic controls (fusion-deficient mutant, double-KO cells), two orthogonal probes, functional dissection\",\n      \"pmids\": [\"28174208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"L-OPA1 and cardiolipin (CL) cooperate in heterotypic inner membrane fusion: purified L-OPA1 on one membrane and CL on the opposing membrane are sufficient for mitochondrial inner membrane fusion in vitro; S-OPA1 promotes L-OPA1-dependent heterotypic fusion but is not alone sufficient.\",\n      \"method\": \"In vitro membrane fusion reconstitution with purified human L-OPA1 and S-OPA1, cardiolipin-containing liposomes, living cell confirmation\",\n      \"journal\": \"Biochimica et biophysica acta. Bioenergetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, mechanistic dissection of L- vs S-OPA1 and cardiolipin roles, confirmed in living cells\",\n      \"pmids\": [\"29852142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Opa1 deficiency in muscle causes initial mitochondrial alterations (cristae disorganization, mtDNA instability) leading to TLR9-activated NF-κB signaling and inflammation in a cell-autonomous, mtDNA-dependent manner; depletion of mitochondrial DNA or blockage of TLR9 prevents NF-κB activation and inflammation.\",\n      \"method\": \"Muscle-specific Opa1 knockout mice, NF-κB reporter assays, mtDNA depletion, TLR9 knockdown/blockade, inflammatory gene expression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model with epistasis (TLR9 blockade rescues), cell-autonomous validation, mtDNA depletion rescue\",\n      \"pmids\": [\"29632021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal and cryo-tomography structures of Mgm1 reveal a GTPase domain, bundle signalling element, stalk, and paddle domain with a membrane-binding site; the stalk mediates assembly of bent tetramers into helical filaments on membranes; tetramer assembly on membranes is required for inner membrane remodeling.\",\n      \"method\": \"X-ray crystallography, cryo-electron tomography of Mgm1-decorated lipid tubes, fluorescence microscopy on reconstituted membrane tubes, biochemical experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + cryo-ET + biochemical validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31292547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OPA1 deficiency impairs respiratory chain supercomplex (RCS) assembly and mitochondrial bioenergetics; PTP-induced mitochondrial swelling stimulates L-OPA1 proteolytic cleavage, and OPA1 knockdown reduces PTP-induced swelling but enhances ROS production, demonstrating a PTP-OPA1 axis in RCS regulation.\",\n      \"method\": \"OPA1 knockdown in cardiac mitochondria and cell lines, Blue-Native PAGE for supercomplex analysis, ROS measurement, PTP inhibitor/inducer experiments\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple functional readouts but single lab, no reconstitution\",\n      \"pmids\": [\"31870826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The GTPase domain of human OPA1 forms nucleotide-dependent dimers (GDP+BeF3- stabilized); a three-helix bundle domain tightly associates with the GTPase domain; the GTPase dimer interface is critical for mitochondrial morphology maintenance, and an N-terminal extension mediates nucleotide-independent dimerization facilitating membrane association.\",\n      \"method\": \"X-ray crystallography of OPA1 minimal GTPase domain, biochemical dimerization assays, cell-based morphology assays with interface mutants\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure + biochemical assays + cell-based functional validation, single lab with multiple methods\",\n      \"pmids\": [\"32379273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OPA1 is required for angiogenesis; in response to angiogenic stimuli, OPA1 limits NFκB signaling to allow angiogenic gene expression; endothelial Opa1 is required in an NFκB-dependent pathway for developmental and tumor angiogenesis.\",\n      \"method\": \"Endothelial-specific OPA1 knockout mice, pharmacological OPA1 inhibitor, NFκB reporter assays, in vivo tumor models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO + pharmacological inhibitor + NFκB pathway epistasis + in vivo tumor model\",\n      \"pmids\": [\"32315597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Chchd2 stabilizes OPA1 by competing with P32 for YME1L binding; P32 co-immunoprecipitates with Chchd2 and YME1L, and the P32-YME1L interaction enhances YME1L activity promoting OPA1 degradation. Loss of Chchd2 reduces OPA1 levels and causes mitochondrial fragmentation.\",\n      \"method\": \"Co-immunoprecipitation, YME1L activity assays, OPA1 western blot, Drosophila genetics\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP of three-protein complex, functional enzyme activity assay, in vivo Drosophila model\",\n      \"pmids\": [\"31907391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OPA1 in POMC neurons controls mitochondrial cristae architecture and Ca2+ handling; genetic inactivation of OPA1 in POMC neurons causes cristae topology disruption, reduced mitochondrial Ca2+ uptake, decreased α-MSH secretion, hyperphagia, and attenuated white adipose tissue lipolysis leading to obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program.\",\n      \"method\": \"POMC neuron-specific OPA1 knockout mice, electron microscopy of cristae, mitochondrial Ca2+ measurements, chemogenetics, pharmacological rescue\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined mechanistic pathway (Ca2+ → α-MSH → lipolysis), pharmacological rescue validates mechanism\",\n      \"pmids\": [\"34343501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Opa1 promotes adipocyte browning through a urea cycle-cAMP-CREB-Kdm3a axis; Opa1-dependent higher cAMP levels activate CREB to transcribe urea cycle enzymes, leading to fumarate accumulation that drives beige differentiation. Adipocyte-specific Opa1 deletion curtails the urea cycle and beige differentiation, rescued by fumarate supplementation.\",\n      \"method\": \"Adipocyte-specific Opa1 KO and overexpression mice, transcriptomics, metabolomics, flux analyses, fumarate rescue experiments\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO + OE + metabolomics + flux analysis + metabolite rescue, multiple orthogonal methods\",\n      \"pmids\": [\"34873337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deletion of OPA1 in muscle stem cells (MuSCs) fragments mitochondria and transitions MuSCs from deep quiescence to G-alert quiescence by activating a glutathione (GSH)-redox signaling pathway that promotes cell-cycle progression and myogenic gene expression; chronic OPA1 loss causing mitochondrial dysfunction leads to G-alert with severe cell-cycle defects.\",\n      \"method\": \"MuSC-specific OPA1 deletion mouse model, quiescence state analysis, GSH pathway inhibitors, flow cytometry, single-cell analysis\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined stem cell phenotype, pathway epistasis via GSH inhibitors\",\n      \"pmids\": [\"35998642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Myeloid-specific OPA1 deletion impairs M1-macrophage commitment; mechanistically, OPA1 loss causes TCA cycle metabolite accumulation and defective NF-κB signaling activation; in vivo, OPA1-knockout macrophages persist in damaged muscle, causing excess collagen deposition and impaired regeneration.\",\n      \"method\": \"Myeloid-specific Opa1 KO mice, metabolomics (TCA metabolites), NF-κB reporter assays, muscle injury model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO + metabolomics + NF-κB epistasis + in vivo regeneration model\",\n      \"pmids\": [\"36307526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OPA1 modulates mitochondrial Ca2+ uptake through functional ER-mitochondria coupling, dependent on its GED domain; Opa1-deficient MEFs show closer ER-mitochondria contacts and require less ER Ca2+ mobilization to induce a mitochondrial Ca2+ rise. Acute expression of GTPase (but not GED) mutants partially restores cytosolic Ca2+ needed for mitochondrial Ca2+ uptake.\",\n      \"method\": \"OPA1 KO MEF rescue with domain-specific mutants, Ca2+ imaging, ER-mitochondria contact site measurements, ADOA patient fibroblasts\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific mutant rescue, multiple cell systems, Ca2+ imaging, single lab\",\n      \"pmids\": [\"35047497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human OPA1 embeds into cardiolipin-containing membranes through a lipid-binding paddle domain; a conserved loop within the paddle domain inserts deeply into the bilayer; OPA1 dimerization through the paddle domain promotes helical assembly of a flexible OPA1 lattice that drives mitochondrial fusion; OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out during membrane remodeling.\",\n      \"method\": \"Cryo-EM of OPA1 on lipid membrane tubes, cellular structural analysis, mutagenesis of assembly interfaces and membrane-binding loops, cell-based mitochondrial fragmentation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure + mutagenesis + cell-based functional validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"37612504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM helical structures of OPA1 on lipid membrane tubes reveal densely packed protein rungs with minimal inter-rung connectivity, nucleotide-dependent GTPase domain dimerization, and unique paddle domain secondary structures (membrane-inserting helices) that strengthen membrane association. Mutations disrupting assembly interfaces or membrane binding cause mitochondrial fragmentation in cells.\",\n      \"method\": \"Cryo-electron microscopy, helical reconstruction, mutagenesis of assembly interfaces and membrane-inserting helices, cell-based fragmentation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure + mutagenesis + cell-based validation, independent from the von der Malsburg study (same year, complementary structures)\",\n      \"pmids\": [\"37612506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OPA1 GTPase and GED domain mutations have distinct effects: GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity; GTPase mutants can cause mitochondrial elongation (suggesting fission inhibition) whereas all mutants inhibit fusion; distinct aberrant cristae ultrastructures result from GTPase vs. GED mutations.\",\n      \"method\": \"Patient-derived cells (GTPase and GED domain mutants), OPA1-null MEF rescue, mitochondrial fusion assays, GTPase activity assays, electron microscopy of cristae\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — patient cells + null MEF rescue + enzymatic assays + EM, domain-specific mechanistic dissection\",\n      \"pmids\": [\"36927155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In situ cryo-electron tomography of MEFs with defined OPA1 states shows increased l-OPA1 promotes cristae stacking and elongated mitochondria, while increased s-OPA1 correlates with irregular cristae packing and round mitochondria; l-OPA1 is required for wild-type apoptotic and calcium handling responses.\",\n      \"method\": \"In situ cryo-electron tomography (cryo-FIB milling), MEFs with controlled l-OPA1/s-OPA1 ratios, apoptosis assays, calcium handling assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in situ cryo-ET with defined genetic states, functional assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38225406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OPA1 promotes ferroptosis by maintaining mitochondrial homeostasis and function, contributing to mitochondrial lipid ROS generation and suppressing an ATF4-mediated integrated stress response; ferroptosis sensitization requires OPA1 GTPase activity but is independent of OPA1-mediated mitochondrial fusion.\",\n      \"method\": \"OPA1 KO cells, OPA1 mutant reconstitution (GTPase-dead vs. fusion-deficient mutants), mitochondrial ROS measurement, ATF4 pathway analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — KO + domain-specific mutant reconstitution + pathway epistasis, functional dissection of fusion-independent GTPase role\",\n      \"pmids\": [\"39142278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Copper transport by Slc25a3 is required for mitochondrial 'flickering' (short depolarization pulses); flickering activates OMA1, which proteolytically inactivates OPA1 to prevent deleterious hyperfusion. Copper-dependent enzymes SOD1 and cytochrome c oxidase regulate this flickering-OMA1-OPA1 axis.\",\n      \"method\": \"Live-imaging screen in mammalian cells, Slc25a3 KO, copper chelation, OMA1 and OPA1 isoform analysis, SOD1 and COX perturbations\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-imaging screen + multiple genetic KOs + biochemical OPA1 cleavage assay, mechanistic pathway established\",\n      \"pmids\": [\"38986607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OPA1 deficiency in skeletal muscle increases ATF4 (integrated stress response effector) expression, which drives tighter and more frequent ER-mitochondria contact sites (MERCs) with greater abundance of MERC calcium exchange proteins; reducing Atf4 prevents OPA1-loss-induced MERC tightening and partially restores mitochondrial and SR calcium.\",\n      \"method\": \"Muscle-specific OPA1 KD in mice and Drosophila, primary myotubes, electron microscopy of MERCs, ATF4 KD epistasis, Ca2+ measurements\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems (mouse, Drosophila, primary cells), ATF4 epistasis, EM quantification of MERC structure\",\n      \"pmids\": [\"38419397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Epithelial OPA1 is required for intestinal barrier function and immune homeostasis; OPA1 deficiency in gut epithelial cells causes microbial translocation, epithelial progenitor cell death, and spontaneous chronic intestinal inflammation; pharmacological DRP1 inhibition partially reverts OPA1-inhibitor-induced mitochondrial fragmentation in organoids.\",\n      \"method\": \"Intestinal epithelial-specific Opa1 KO mice, human IBD patient samples, organoids with OPA1 inhibitor, DRP1 inhibitor rescue\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO + human patient validation + organoid pharmacological rescue + epistasis with DRP1 inhibitor\",\n      \"pmids\": [\"39813315\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OPA1 is a dynamin-related GTPase anchored in the mitochondrial inner membrane (IMM) that mediates IMM fusion and cristae remodeling through cardiolipin-dependent membrane embedding, paddle-domain dimerization, and helical lattice assembly; its proteolytic processing by YME1L and the stress-activated protease OMA1 (regulated by copper-dependent flickering) controls the balance between fusion-competent long forms and soluble short forms, while post-translational acetylation (written by stress, erased by SIRT3 at K926/K931) modulates GTPase activity, and through these structural and enzymatic mechanisms OPA1 governs mitochondrial respiratory supercomplex assembly, cytochrome c release during apoptosis, mtDNA maintenance, ER-mitochondria calcium coupling, and cell-type-specific processes including stem cell quiescence, macrophage activation, adipocyte browning, intestinal epithelial barrier integrity, and sensitivity to ferroptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OPA1 is a dynamin-related GTPase of the mitochondrial inner membrane that mediates inner-membrane fusion and cristae remodeling, and through these activities governs mitochondrial bioenergetics, mtDNA maintenance, apoptosis, and a range of cell-type-specific physiological programs [#0, #2, #4, #12]. Conserved from the yeast ortholog Mgm1, the protein is anchored in or bound to the inner membrane facing the intermembrane space, and its loss causes cristae disorganization, mitochondrial swelling and fragmentation, and mtDNA loss [#0, #1, #2]. OPA1 exists as long membrane-bound (L-OPA1) and short soluble (S-OPA1) isoforms whose ratio is set by alternative topogenesis and by proteolytic processing—L-OPA1 supports fusion while excess processing by the stress-activated protease OMA1 (balanced against YME1L) limits fusion and promotes fragmentation and death [#1, #3, #14]. Mechanistically, OPA1 binds negatively charged inner-membrane lipids, embedding into cardiolipin-containing bilayers through a paddle domain whose conserved loop inserts into the bilayer; lipid binding stimulates GTPase activity and drives nucleotide-dependent dimerization and assembly of a helical lattice that tethers and bends opposing membranes to execute GTP hydrolysis-dependent fusion [#6, #7, #8, #19, #29, #30]. L-OPA1 together with cardiolipin on the opposing membrane is sufficient for heterotypic inner-membrane fusion in vitro [#17]. OPA1-dependent cristae stabilization promotes respiratory supercomplex assembly and respiratory efficiency while restraining cytochrome c release and ROS, and genetic preservation of this pathway protects against atrophy, ischemia, and apoptosis in vivo [#12, #20, #32]. GTPase activity is enhanced by SIRT3-mediated deacetylation at K926/K931 [#10]. Through cristae architecture and ER-mitochondria calcium coupling, OPA1 controls tissue-specific outcomes including POMC-neuron control of feeding and lipolysis, adipocyte browning, muscle-stem-cell quiescence, macrophage M1 commitment, endothelial angiogenesis, intestinal epithelial barrier integrity, and ferroptosis sensitivity, with several of these roles depending on GTPase activity rather than fusion per se [#22, #24, #25, #26, #27, #28, #33, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that the OPA1 ortholog is a dynamin-like GTPase whose loss disrupts mitochondrial morphology and causes mtDNA loss, defining the gene's core cellular role.\",\n      \"evidence\": \"Genetic deletion of MGM1 in yeast with growth and mitochondrial morphology assays\",\n      \"pmids\": [\"7916673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether the morphology defect reflects fusion, fission, or membrane maintenance\", \"No biochemical characterization of GTPase activity\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved that OPA1 is an intermembrane-space protein bound to the inner membrane whose loss disorganizes cristae before fragmentation, localizing its action to the inner membrane.\",\n      \"evidence\": \"siRNA knockdown, EM, and subcellular fractionation in mammalian cells\",\n      \"pmids\": [\"14970223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not distinguish fusion from cristae maintenance mechanistically\", \"No reconstitution\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined how two OPA1 isoforms arise—rhomboid (Pcp1) cleavage and alternative topogenesis controlled by N-terminal hydrophobicity, import-motor function, and matrix ATP—and showed both isoforms are required for normal morphology.\",\n      \"evidence\": \"Yeast genetics, isoform-specific complementation, and mutagenesis of hydrophobic/import elements\",\n      \"pmids\": [\"12707284\", \"15096522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian protease assignments not yet established\", \"Functional distinction between isoforms not yet mechanistically defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated OPA1 directly mediates inner-membrane fusion in a GTP- and membrane-potential-dependent manner distinct from outer-membrane fusion, separating its fusion function from cristae maintenance.\",\n      \"evidence\": \"In vitro mitochondrial fusion assay with GTPase mutants and potential manipulation in yeast\",\n      \"pmids\": [\"17055438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular structure of the fusion machine unknown\", \"Lipid requirements not yet defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the biochemical basis of fusion: lipid (cardiolipin/anionic phospholipid) binding stimulates GTPase activity ~50-fold and drives l/s dimerization and oligomeric ring assembly as the fusion building block.\",\n      \"evidence\": \"Purified-protein reconstitution, GTPase and lipid-binding assays, EM, and in vivo complementation\",\n      \"pmids\": [\"19752025\", \"19703904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution architecture of assemblies unresolved\", \"Conformational coupling of GTP hydrolysis to membrane bending not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed OPA1 tethers opposing membranes to a ~15 nm gap and undergoes a GTP-dependent conformational change driving fusion, and identified PE as a lipid regulator of s-OPA1 biogenesis and fusion.\",\n      \"evidence\": \"Cryo-EM, in vitro liposome fusion, and yeast genetic/lipid-mixing analysis of Psd1/PE\",\n      \"pmids\": [\"22977249\", \"23045528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution lattice geometry not yet determined\", \"Mechanism linking conformational change to lipid mixing incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected OPA1 activity to regulation: SIRT3 deacetylation at K926/K931 elevates GTPase activity and rescues OPA1-null mitochondrial function, and the inner-membrane protein Higd-1a binds L-OPA1 to block its cleavage.\",\n      \"evidence\": \"Mass spectrometry, mutagenesis, GTPase assays, Co-IP, and functional rescue in cardiomyocytes/cells\",\n      \"pmids\": [\"24344202\", \"23878241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stress signals writing acetylation not identified\", \"Structural basis of Higd-1a/OPA1 binding unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated in vivo that OPA1-dependent cristae stabilization improves respiratory efficiency and limits cytochrome c release/ROS, protecting tissues from atrophy, ischemia, and apoptosis.\",\n      \"evidence\": \"Cristae-remodeling-pathway genetic mouse models across multiple tissues with functional readouts\",\n      \"pmids\": [\"26039448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between OPA1 oligomers and supercomplexes not directly shown\", \"Did not separate fusion from cristae effects in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Formalized the L/S-OPA1 proteostatic switch: YME1L and OMA1 set the fusion-competent vs fusion-limiting balance, with stress-activated OMA1 processing driving fragmentation and death.\",\n      \"evidence\": \"Protease assays, isoform analysis, and KO/KD under stress\",\n      \"pmids\": [\"27189080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activators of OMA1 not fully enumerated here\", \"Quantitative thresholds of isoform ratio for fusion unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Began separating fusion-independent functions: L-OPA1 stabilizes respiratory supercomplexes to support mitopHlash independently of fusion or processing, and SIRT4 raises L-OPA1 to promote fusion.\",\n      \"evidence\": \"Fusion-deficient OPA1-K301A rescue, MFN1/2 and OMA1/YME1L KO cells with pH probes; Co-IP and isoform analysis for SIRT4\",\n      \"pmids\": [\"28174208\", \"29081403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SIRT4 finding rests on single Co-IP from one lab\", \"Direct OPA1-supercomplex contacts not structurally shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed L-OPA1 plus cardiolipin on the opposing membrane is sufficient for heterotypic inner-membrane fusion, and that muscle Opa1 loss triggers mtDNA/TLR9-dependent NF-κB inflammation, linking cristae integrity to innate immune signaling.\",\n      \"evidence\": \"Purified human L/S-OPA1 reconstitution with CL liposomes; muscle-specific KO with TLR9 and mtDNA-depletion epistasis\",\n      \"pmids\": [\"29852142\", \"29632021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How mtDNA reaches TLR9 not defined\", \"Heterotypic fusion in vivo not directly visualized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural framework: Mgm1 domains (GTPase, BSE, stalk, paddle) assemble bent tetramers into helical filaments on membranes required for inner-membrane remodeling, and OPA1 deficiency impairs supercomplex assembly via a PTP-OPA1 axis.\",\n      \"evidence\": \"Crystallography and cryo-ET of membrane-decorated Mgm1; OPA1 KD with Blue-Native PAGE and PTP perturbations\",\n      \"pmids\": [\"31292547\", \"31870826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human OPA1 lattice not yet resolved at this stage\", \"PTP-OPA1 supercomplex study single-lab without reconstitution\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Dissected OPA1 self-assembly and proteostasis at higher resolution: nucleotide-dependent GTPase dimerization and an N-terminal dimerization extension drive membrane association/morphology, and Chchd2 stabilizes OPA1 by competing with P32 for YME1L.\",\n      \"evidence\": \"Crystallography of GTPase domain, biochemical dimerization and cell morphology assays; Co-IP and YME1L activity assays with Drosophila genetics\",\n      \"pmids\": [\"32379273\", \"31907391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chchd2/P32/YME1L finding is Medium-confidence multiprotein Co-IP\", \"Coupling of dimer interface to fusion stroke not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended OPA1 to physiology: endothelial OPA1 limits NF-κB to permit angiogenic gene expression and is required for developmental and tumor angiogenesis.\",\n      \"evidence\": \"Endothelial-specific KO, pharmacological inhibitor, NF-κB reporters, and in vivo tumor models\",\n      \"pmids\": [\"32315597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the angiogenic role depends on fusion vs cristae unresolved\", \"Direct OPA1-NF-κB molecular link not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tied OPA1-controlled cristae and ER-mitochondria calcium handling to organismal metabolism: POMC-neuron OPA1 governs Ca2+ uptake, α-MSH secretion and lipolysis, while adipocyte OPA1 drives browning via a urea-cycle-cAMP-CREB-Kdm3a-fumarate axis.\",\n      \"evidence\": \"Cell-type-specific KO mice, EM of cristae, Ca2+ imaging, metabolomics/flux, and pharmacological/metabolite rescue\",\n      \"pmids\": [\"34343501\", \"34873337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling cristae shape to cAMP signaling not defined\", \"Generality across tissues untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined additional cell-type-specific roles and the GED-dependence of ER-mitochondria calcium coupling: OPA1 sets muscle-stem-cell quiescence via GSH-redox signaling, macrophage M1 commitment via TCA/NF-κB, and tunes MERC calcium through its GED domain.\",\n      \"evidence\": \"Conditional KO mouse models, GSH inhibitors, metabolomics, NF-κB reporters; domain-specific mutant rescue and Ca2+/contact-site imaging in MEFs and ADOA fibroblasts\",\n      \"pmids\": [\"35998642\", \"36307526\", \"35047497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MERC calcium study is single-lab Medium-confidence\", \"How fragmentation versus dysfunction segregate quiescence states incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the human OPA1 membrane-remodeling mechanism at near-atomic detail—paddle-domain membrane insertion, nucleotide-dependent GTPase dimerization, and a flexible helical lattice—and separated GTPase from GED domain functions in fusion and cristae.\",\n      \"evidence\": \"Cryo-EM of OPA1 on lipid tubes with assembly/membrane-binding mutants and cell fragmentation assays; patient-cell and null-MEF rescue with domain mutants\",\n      \"pmids\": [\"37612504\", \"37612506\", \"36927155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of the conformational stroke during fusion not directly observed\", \"In-cell lattice architecture only partly resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked OPA1 isoform states to in-situ cristae ultrastructure and uncovered fusion-independent GTPase functions: l-OPA1 drives cristae stacking and proper apoptosis/calcium responses, copper-dependent flickering activates OMA1 to inactivate OPA1, OPA1 promotes ferroptosis via GTPase-dependent lipid ROS, and OPA1 loss reshapes MERCs through ATF4.\",\n      \"evidence\": \"In situ cryo-ET of defined OPA1 states; live-imaging copper/OMA1 screen; KO with GTPase-dead vs fusion-deficient mutant reconstitution and ATF4 epistasis across mouse/Drosophila/cells\",\n      \"pmids\": [\"38225406\", \"38986607\", \"39142278\", \"38419397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How copper flickering mechanistically triggers OMA1 incompletely defined\", \"Molecular basis of GTPase-dependent, fusion-independent ferroptosis role unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended OPA1 requirement to epithelial barrier biology: gut-epithelial OPA1 maintains barrier function and immune homeostasis, with loss causing fragmentation, progenitor death, and chronic inflammation reversible by DRP1 inhibition.\",\n      \"evidence\": \"Intestinal epithelial-specific KO mice, IBD patient samples, and organoid OPA1/DRP1-inhibitor rescue\",\n      \"pmids\": [\"39813315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the barrier role depends on fusion vs cristae not resolved\", \"Direct link between fragmentation and progenitor death not mechanistically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OPA1's conformational/GTP-hydrolysis cycle is mechanically coupled to lipid mixing in vivo, and how its many fusion-independent GTPase-dependent functions (ferroptosis, supercomplex/calcium signaling, tissue programs) are molecularly distinguished from its fusion role, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No real-time structural visualization of the fusion stroke in membranes\", \"Molecular effectors distinguishing fusion-independent GTPase functions not identified\", \"Quantitative model linking isoform ratio to specific physiological outputs lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 4, 6, 7, 10, 21, 31, 33]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6, 7, 17, 29, 30]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 4, 12, 19, 29]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 12, 32, 33]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 20, 25]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [14, 18, 34, 35]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"YME1L\", \"OMA1\", \"PARL\", \"Higd-1a\", \"SIRT3\", \"SIRT4\", \"CHCHD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}