Affinage

OPA1

Dynamin-like GTPase OPA1, mitochondrial · UniProt O60313

Length
960 aa
Mass
111.6 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1993 High

    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

    PMID:7916673

    Open questions at the time
    • Did not resolve whether the morphology defect reflects fusion, fission, or membrane maintenance
    • No biochemical characterization of GTPase activity
  2. 2004 High

    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

    PMID:14970223

    Open questions at the time
    • Did not distinguish fusion from cristae maintenance mechanistically
    • No reconstitution
  3. 2004 High

    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

    PMID:12707284 PMID:15096522

    Open questions at the time
    • Mammalian protease assignments not yet established
    • Functional distinction between isoforms not yet mechanistically defined
  4. 2006 High

    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

    PMID:17055438

    Open questions at the time
    • Molecular structure of the fusion machine unknown
    • Lipid requirements not yet defined
  5. 2009 High

    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

    PMID:19703904 PMID:19752025

    Open questions at the time
    • High-resolution architecture of assemblies unresolved
    • Conformational coupling of GTP hydrolysis to membrane bending not defined
  6. 2012 High

    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

    PMID:22977249 PMID:23045528

    Open questions at the time
    • Atomic-resolution lattice geometry not yet determined
    • Mechanism linking conformational change to lipid mixing incomplete
  7. 2013 High

    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

    PMID:23878241 PMID:24344202

    Open questions at the time
    • Stress signals writing acetylation not identified
    • Structural basis of Higd-1a/OPA1 binding unresolved
  8. 2015 High

    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

    PMID:26039448

    Open questions at the time
    • Molecular link between OPA1 oligomers and supercomplexes not directly shown
    • Did not separate fusion from cristae effects in vivo
  9. 2016 High

    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

    PMID:27189080

    Open questions at the time
    • Upstream activators of OMA1 not fully enumerated here
    • Quantitative thresholds of isoform ratio for fusion unclear
  10. 2017 High

    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

    PMID:28174208 PMID:29081403

    Open questions at the time
    • SIRT4 finding rests on single Co-IP from one lab
    • Direct OPA1-supercomplex contacts not structurally shown
  11. 2018 High

    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

    PMID:29632021 PMID:29852142

    Open questions at the time
    • How mtDNA reaches TLR9 not defined
    • Heterotypic fusion in vivo not directly visualized
  12. 2019 High

    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

    PMID:31292547 PMID:31870826

    Open questions at the time
    • Human OPA1 lattice not yet resolved at this stage
    • PTP-OPA1 supercomplex study single-lab without reconstitution
  13. 2020 High

    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

    PMID:31907391 PMID:32379273

    Open questions at the time
    • Chchd2/P32/YME1L finding is Medium-confidence multiprotein Co-IP
    • Coupling of dimer interface to fusion stroke not fully defined
  14. 2020 High

    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

    PMID:32315597

    Open questions at the time
    • Whether the angiogenic role depends on fusion vs cristae unresolved
    • Direct OPA1-NF-κB molecular link not defined
  15. 2021 High

    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

    PMID:34343501 PMID:34873337

    Open questions at the time
    • Mechanism coupling cristae shape to cAMP signaling not defined
    • Generality across tissues untested
  16. 2022 High

    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

    PMID:35047497 PMID:35998642 PMID:36307526

    Open questions at the time
    • MERC calcium study is single-lab Medium-confidence
    • How fragmentation versus dysfunction segregate quiescence states incompletely defined
  17. 2023 High

    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

    PMID:36927155 PMID:37612504 PMID:37612506

    Open questions at the time
    • Dynamics of the conformational stroke during fusion not directly observed
    • In-cell lattice architecture only partly resolved
  18. 2024 High

    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

    PMID:38225406 PMID:38419397 PMID:38986607 PMID:39142278

    Open questions at the time
    • How copper flickering mechanistically triggers OMA1 incompletely defined
    • Molecular basis of GTPase-dependent, fusion-independent ferroptosis role unresolved
  19. 2025 High

    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

    PMID:39813315

    Open questions at the time
    • Whether the barrier role depends on fusion vs cristae not resolved
    • Direct link between fragmentation and progenitor death not mechanistically defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 8 GO:0008289 lipid binding 5 GO:0140657 ATP-dependent activity 1
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1430728 Metabolism 3
Partners
CHCHD2HIGD-1AOMA1PARLSIRT3SIRT4YME1L

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 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. Genetic deletion in yeast, growth assays, mitochondrial marker immunofluorescence Current genetics High 7916673
2003 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. Yeast genetics, deletion mutants, expression of individual isoforms, complementation assays The Journal of biological chemistry High 12707284
2004 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. siRNA knockdown, electron microscopy, subcellular fractionation, immunofluorescence in mammalian cells The Journal of biological chemistry High 14970223
2004 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. Mutagenesis of hydrophobic segments, import motor mutants, ATP manipulation in yeast The Journal of cell biology High 15096522
2006 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. In vitro mitochondrial fusion assay, GTPase mutants, membrane potential manipulation in yeast Cell High 17055438
2007 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. Co-immunoprecipitation, biochemical fractionation, apoptosis assays, review of primary experimental data Cell death and differentiation Medium 17464328
2009 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. Biochemical reconstitution, GTPase assays, electron microscopy of assemblies, cardiolipin dependence assay The Journal of cell biology High 19752025
2009 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. Purified protein biochemistry, lipid-binding assays, GTPase activity assays, electron microscopy, in vivo complementation The Journal of biological chemistry High 19703904
2012 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. Cryo-electron microscopy, in vitro liposome fusion assays, GTP-dependent conformational analysis The Journal of biological chemistry High 22977249
2012 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. Yeast genetics, liposome lipid-mixing assays, biochemical isoform analysis, rescue experiments The Journal of biological chemistry High 23045528
2013 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. Mass spectrometry identification of acetylation sites, site-directed mutagenesis, GTPase activity assays, complementation in OPA1-null cells Molecular and cellular biology High 24344202
2013 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. Co-immunoprecipitation, siRNA knockdown, OPA1 isoform analysis by western blot, electron microscopy Proceedings of the National Academy of Sciences of the United States of America High 23878241
2015 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. In vivo genetic mouse models (cristae remodeling pathway inhibition), ischemia models, denervation atrophy, cytochrome c release assays, ROS measurement, respiratory function assays Cell metabolism High 26039448
2015 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. AFM on supported lipid bilayers, electron microscopy of liposomes, in vitro membrane association assays Journal of molecular biology Medium 25784211
2016 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. Protease activity assays, OPA1 isoform analysis, KO/KD studies, stress-induction experiments Journal of cell science High 27189080
2017 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. Co-immunoprecipitation, OPA1 isoform western blot analysis, SIRT4 overexpression and enzymatic mutant Aging Medium 29081403
2017 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. Genetically encoded pH probes, OPA1 ablation and rescue with fusion-deficient mutants, MFN1/2 KO cells, OMA1/YME1L KO cells EMBO reports High 28174208
2018 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. In vitro membrane fusion reconstitution with purified human L-OPA1 and S-OPA1, cardiolipin-containing liposomes, living cell confirmation Biochimica et biophysica acta. Bioenergetics High 29852142
2018 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. Muscle-specific Opa1 knockout mice, NF-κB reporter assays, mtDNA depletion, TLR9 knockdown/blockade, inflammatory gene expression The EMBO journal High 29632021
2019 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. X-ray crystallography, cryo-electron tomography of Mgm1-decorated lipid tubes, fluorescence microscopy on reconstituted membrane tubes, biochemical experiments Nature High 31292547
2019 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. OPA1 knockdown in cardiac mitochondria and cell lines, Blue-Native PAGE for supercomplex analysis, ROS measurement, PTP inhibitor/inducer experiments Mitochondrion Medium 31870826
2020 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. X-ray crystallography of OPA1 minimal GTPase domain, biochemical dimerization assays, cell-based morphology assays with interface mutants The Journal of cell biology High 32379273
2020 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. Endothelial-specific OPA1 knockout mice, pharmacological OPA1 inhibitor, NFκB reporter assays, in vivo tumor models Cell metabolism High 32315597
2020 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. Co-immunoprecipitation, YME1L activity assays, OPA1 western blot, Drosophila genetics Cell death and differentiation Medium 31907391
2021 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. POMC neuron-specific OPA1 knockout mice, electron microscopy of cristae, mitochondrial Ca2+ measurements, chemogenetics, pharmacological rescue Cell metabolism High 34343501
2021 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. Adipocyte-specific Opa1 KO and overexpression mice, transcriptomics, metabolomics, flux analyses, fumarate rescue experiments Nature metabolism High 34873337
2022 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. MuSC-specific OPA1 deletion mouse model, quiescence state analysis, GSH pathway inhibitors, flow cytometry, single-cell analysis Cell stem cell High 35998642
2022 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. Myeloid-specific Opa1 KO mice, metabolomics (TCA metabolites), NF-κB reporter assays, muscle injury model Cell death and differentiation High 36307526
2022 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. OPA1 KO MEF rescue with domain-specific mutants, Ca2+ imaging, ER-mitochondria contact site measurements, ADOA patient fibroblasts Frontiers in cell and developmental biology Medium 35047497
2023 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. Cryo-EM of OPA1 on lipid membrane tubes, cellular structural analysis, mutagenesis of assembly interfaces and membrane-binding loops, cell-based mitochondrial fragmentation assays Nature High 37612504
2023 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. Cryo-electron microscopy, helical reconstruction, mutagenesis of assembly interfaces and membrane-inserting helices, cell-based fragmentation assays Nature High 37612506
2023 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. Patient-derived cells (GTPase and GED domain mutants), OPA1-null MEF rescue, mitochondrial fusion assays, GTPase activity assays, electron microscopy of cristae Proceedings of the National Academy of Sciences of the United States of America High 36927155
2024 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. In situ cryo-electron tomography (cryo-FIB milling), MEFs with controlled l-OPA1/s-OPA1 ratios, apoptosis assays, calcium handling assays The EMBO journal High 38225406
2024 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. OPA1 KO cells, OPA1 mutant reconstitution (GTPase-dead vs. fusion-deficient mutants), mitochondrial ROS measurement, ATF4 pathway analysis Molecular cell High 39142278
2024 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. Live-imaging screen in mammalian cells, Slc25a3 KO, copper chelation, OMA1 and OPA1 isoform analysis, SOD1 and COX perturbations Developmental cell High 38986607
2024 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. Muscle-specific OPA1 KD in mice and Drosophila, primary myotubes, electron microscopy of MERCs, ATF4 KD epistasis, Ca2+ measurements Journal of cellular physiology High 38419397
2025 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. Intestinal epithelial-specific Opa1 KO mice, human IBD patient samples, organoids with OPA1 inhibitor, DRP1 inhibitor rescue Science translational medicine High 39813315

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell metabolism 389 26039448
2004 Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. The Journal of biological chemistry 385 14970223
2006 Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell 382 17055438
2013 SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Molecular and cellular biology 363 24344202
2009 Mitochondrial OPA1, apoptosis, and heart failure. Cardiovascular research 353 19493956
2016 OPA1 processing in cell death and disease - the long and short of it. Journal of cell science 349 27189080
2003 Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA. The Journal of biological chemistry 300 12707284
2001 Mutation spectrum and splicing variants in the OPA1 gene. Human genetics 296 11810270
2009 Coassembly of Mgm1 isoforms requires cardiolipin and mediates mitochondrial inner membrane fusion. The Journal of cell biology 224 19752025
2004 Alternative topogenesis of Mgm1 and mitochondrial morphology depend on ATP and a functional import motor. The Journal of cell biology 185 15096522
2012 OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability. Journal of the American Heart Association 178 23316298
2018 Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. The EMBO journal 170 29632021
2020 Developmental and Tumor Angiogenesis Requires the Mitochondria-Shaping Protein Opa1. Cell metabolism 162 32315597
2015 Syndromic parkinsonism and dementia associated with OPA1 missense mutations. Annals of neurology 153 25820230
2002 OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease. Molecular genetics and metabolism 150 11855928
2018 Eight human OPA1 isoforms, long and short: What are they for? Biochimica et biophysica acta. Bioenergetics 140 29382469
2009 OPA1-associated disorders: phenotypes and pathophysiology. The international journal of biochemistry & cell biology 121 19389487
2017 SIRT4 interacts with OPA1 and regulates mitochondrial quality control and mitophagy. Aging 119 29081403
2007 A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis. Cell death and differentiation 119 17464328
1993 Normal mitochondrial structure and genome maintenance in yeast requires the dynamin-like product of the MGM1 gene. Current genetics 119 7916673
2021 Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response. Frontiers in cell and developmental biology 112 33842456
2020 OPA1 and MICOS Regulate mitochondrial crista dynamics and formation. Cell death & disease 112 33130824
2010 MARF and Opa1 control mitochondrial and cardiac function in Drosophila. Circulation research 108 21148429
2013 Dominant optic atrophy, OPA1, and mitochondrial quality control: understanding mitochondrial network dynamics. Molecular neurodegeneration 107 24067127
2023 Structural mechanism of mitochondrial membrane remodelling by human OPA1. Nature 104 37612504
2012 The dynamin GTPase OPA1: more than mitochondria? Biochimica et biophysica acta 98 22902477
2019 Structure and assembly of the mitochondrial membrane remodelling GTPase Mgm1. Nature 96 31292547
2020 Mitochondrial Fusion Via OPA1 and MFN1 Supports Liver Tumor Cell Metabolism and Growth. Cells 90 31947947
2024 OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response. Molecular cell 88 39142278
2022 OPA1 regulation of mitochondrial dynamics in skeletal and cardiac muscle. Trends in endocrinology and metabolism: TEM 88 35945104
2012 Phosphatidylserine decarboxylase 1 (Psd1) promotes mitochondrial fusion by regulating the biophysical properties of the mitochondrial membrane and alternative topogenesis of mitochondrial genome maintenance protein 1 (Mgm1). The Journal of biological chemistry 87 23045528
2021 The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites. Nature metabolism 80 34873337
2016 Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations. Neurology 80 27974645
2017 TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB-Dependent Activation of OPA1 Expression. Circulation research 78 28637784
2022 The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells. Cell stem cell 74 35998642
2009 OPA1 functions in mitochondria and dysfunctions in optic nerve. The international journal of biochemistry & cell biology 74 19389483
2012 Opa1 is essential for retinal ganglion cell synaptic architecture and connectivity. Brain : a journal of neurology 73 22300878
2021 Role of inner mitochondrial protein OPA1 in mitochondrial dysfunction by tobacco smoking and in the pathogenesis of COPD. Redox biology 71 34214709
2019 OPA1 regulates respiratory supercomplexes assembly: The role of mitochondrial swelling. Mitochondrion 70 31870826
2021 Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis. Cell metabolism 61 34343501
2019 OPA1 overexpression ameliorates mitochondrial cristae remodeling, mitochondrial dysfunction, and neuronal apoptosis in prion diseases. Cell death & disease 61 31551424
2005 Expression of the Opa1 mitochondrial protein in retinal ganglion cells: its downregulation causes aggregation of the mitochondrial network. Investigative ophthalmology & visual science 61 16249510
2023 OPA1 helical structures give perspective to mitochondrial dysfunction. Nature 58 37612506
2020 Dimethyl fumarate alleviates the nitroglycerin (NTG)-induced migraine in mice. Journal of neuroinflammation 58 32066464
2018 Mitochondrial Membrane Dynamics-Functional Positioning of OPA1. Antioxidants (Basel, Switzerland) 57 30544804
2009 Phospholipid association is essential for dynamin-related protein Mgm1 to function in mitochondrial membrane fusion. The Journal of biological chemistry 57 19703904
2006 The OPA1 gene polymorphism is associated with normal tension and high tension glaucoma. American journal of ophthalmology 57 17188046
2013 Higd-1a interacts with Opa1 and is required for the morphological and functional integrity of mitochondria. Proceedings of the National Academy of Sciences of the United States of America 56 23878241
2018 OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model. Scientific reports 51 29410463
2018 OPA1: How much do we know to approach therapy? Pharmacological research 51 29454676
2008 Glutamate receptor activation triggers OPA1 release and induces apoptotic cell death in ischemic rat retina. Molecular vision 50 19122832
2018 Relationship between OPA1 and cardiolipin in mitochondrial inner-membrane fusion. Biochimica et biophysica acta. Bioenergetics 49 29852142
2015 OPA1-related disorders: Diversity of clinical expression, modes of inheritance and pathophysiology. Neurobiology of disease 49 26311407
2010 OPA1 (dys)functions. Seminars in cell & developmental biology 49 20045077
2021 High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts. EMBO molecular medicine 48 34014035
2006 OPA1 and PARL keep a lid on apoptosis. Cell 48 16839872
2022 Inhibition of the mitochondrial protein Opa1 curtails breast cancer growth. Journal of experimental & clinical cancer research : CR 47 35279198
2005 OPA1 expression in the normal rat retina and optic nerve. The Journal of comparative neurology 46 15912498
2024 In situ architecture of Opa1-dependent mitochondrial cristae remodeling. The EMBO journal 44 38225406
2017 A novel ADOA-associated OPA1 mutation alters the mitochondrial function, membrane potential, ROS production and apoptosis. Scientific reports 44 28720802
2020 Chchd2 regulates mitochondrial morphology by modulating the levels of Opa1. Cell death and differentiation 42 31907391
2020 Structural insights into G domain dimerization and pathogenic mutation of OPA1. The Journal of cell biology 42 32379273
2018 Deciphering OPA1 mutations pathogenicity by combined analysis of human, mouse and yeast cell models. Biochimica et biophysica acta. Molecular basis of disease 42 30293569
2022 OPA1 Regulates Lipid Metabolism and Cold-Induced Browning of White Adipose Tissue in Mice. Diabetes 41 36170659
2022 OPA1 drives macrophage metabolism and functional commitment via p65 signaling. Cell death and differentiation 41 36307526
2023 TIM-4 orchestrates mitochondrial homeostasis to promote lung cancer progression via ANXA2/PI3K/AKT/OPA1 axis. Cell death & disease 40 36806050
2015 Restoration of Opa1-long isoform inhibits retinal injury-induced neurodegeneration. Journal of molecular medicine (Berlin, Germany) 40 26530815
2023 The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury. Nature communications 38 37872238
2003 A novel mutation in the OPA1 gene in a Japanese patient with optic atrophy. American journal of ophthalmology 38 12566046
2021 Protective role of the mitochondrial fusion protein OPA1 in hypertension. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 34133045
2018 Meta-analysis of genotype-phenotype analysis of OPA1 mutations in autosomal dominant optic atrophy. Mitochondrion 37 30165240
2020 CHCHD10-regulated OPA1-mitofilin complex mediates TDP-43-induced mitochondrial phenotypes associated with frontotemporal dementia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 32369233
2023 Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinomaresistant cell line. Cell death & disease 35 37019897
2023 Empagliflozin targets Mfn1 and Opa1 to attenuate microglia-mediated neuroinflammation in retinal ischemia and reperfusion injury. Journal of neuroinflammation 34 38082266
2022 SIRT3 promotes metabolic maturation of human iPSC-derived cardiomyocytes via OPA1-controlled mitochondrial dynamics. Free radical biology & medicine 33 36596388
2012 Association of OPA1 polymorphisms with NTG and HTG: a meta-analysis. PloS one 30 22879959
2022 OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling. Frontiers in cell and developmental biology 29 35047497
2024 ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle. Journal of cellular physiology 28 38419397
2023 OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion. Proceedings of the National Academy of Sciences of the United States of America 27 36927155
2020 Opa1 Deficiency Leads to Diminished Mitochondrial Bioenergetics With Compensatory Increased Mitochondrial Motility. Investigative ophthalmology & visual science 27 32561926
2019 Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells. Nucleic acids research 27 30986824
2017 L-OPA1 regulates mitoflash biogenesis independently from membrane fusion. EMBO reports 26 28174208
2015 Mitochondrial Genome Maintenance 1 (Mgm1) Protein Alters Membrane Topology and Promotes Local Membrane Bending. Journal of molecular biology 26 25784211
2024 TRPA1-PI3K/Akt-OPA1-ferroptosis axis in ozone-induced bronchial epithelial cell and lung injury. The Science of the total environment 25 38320701
2024 Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard. Developmental cell 25 38986607
2006 OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy. Genetics in medicine : official journal of the American College of Medical Genetics 25 16617242
2006 OPA1 expression in the human retina and optic nerve. Experimental eye research 25 16857190
2022 Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis. Antioxidants (Basel, Switzerland) 24 35739974
2020 Opa1 Reduces Hypoxia-Induced Cardiomyocyte Death by Improving Mitochondrial Quality Control. Frontiers in cell and developmental biology 24 32984338
2018 NTG-101: A Novel Molecular Therapy that Halts the Progression of Degenerative Disc Disease. Scientific reports 23 30429487
2023 Human retinal organoids with an OPA1 mutation are defective in retinal ganglion cell differentiation and function. Stem cell reports 22 38101398
2017 OPA1 in Lipid Metabolism: Function of OPA1 in Lipolysis and Thermogenesis of Adipocytes. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 22 28427098
2019 Expression of OPA1 and Mic60 genes and their association with mitochondrial cristae morphology in Tibetan sheep. Cell and tissue research 21 30612186
2015 Validation of a MGM1/OPA1 chimeric gene for functional analysis in yeast of mutations associated with dominant optic atrophy. Mitochondrion 21 26455272
2022 Modelling autosomal dominant optic atrophy associated with OPA1 variants in iPSC-derived retinal ganglion cells. Human molecular genetics 20 35652445
2018 Effect of Resveratrol on Sirtuins, OPA1, and Fis1 Expression in Adult Zebrafish Retina. Investigative ophthalmology & visual science 20 30208422
2015 OPA1 in Cardiovascular Health and Disease. Current drug targets 20 25557256
2015 Influence of Opa1 Mutation on Survival and Function of Retinal Ganglion Cells. Investigative ophthalmology & visual science 20 26218912
2025 Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease. Science translational medicine 19 39813315
2012 Membrane tethering and nucleotide-dependent conformational changes drive mitochondrial genome maintenance (Mgm1) protein-mediated membrane fusion. The Journal of biological chemistry 19 22977249

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