{"gene":"OMA1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2003,"finding":"OMA1 (Oma1) is a novel membrane-embedded metallopeptidase in the mitochondrial inner membrane that degrades misfolded membrane proteins in an ATP-independent manner, with its proteolytic center exposed to the matrix side. It cleaves the misfolded Oxa1 derivative at loop regions on both membrane surfaces and acts redundantly with the m-AAA protease in quality control of inner membrane proteins.","method":"Genetic identification in yeast, in vitro proteolytic assays, cleavage-site mapping, topology/fractionation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — founding paper with in vitro assays, cleavage-site mapping, and genetic epistasis establishing the protease as ATP-independent inner-membrane metallopeptidase","pmids":["12963738"],"is_preprint":false},{"year":2009,"finding":"OMA1 mediates stress-induced (inducible) cleavage of OPA1 in mammalian cells. Specifically, OMA1 cleaves OPA1 isoforms that are not constitutively cleaved by YME1L when mitochondria lose membrane potential or ATP, converting long OPA1 forms to short forms and inhibiting fusion. OMA1 siRNA knockdown inhibits inducible cleavage, retains fusion competence, and slows apoptosis onset. OMA1 itself is constitutively cleaved from 60 kDa to 40 kDa by another protease, and loss of membrane potential causes 60 kDa OMA1 to accumulate, suggesting attenuation by proteolytic degradation.","method":"siRNA knockdown, Western blot, mitochondrial membrane potential dissipation (CCCP/oligomycin), fluorescence microscopy for fusion competence, apoptosis assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, membrane potential manipulation, fusion assay, apoptosis readout), replicated across independent labs in concurrent paper (PMID:20038678)","pmids":["20038677"],"is_preprint":false},{"year":2009,"finding":"Two classes of metallopeptidases regulate OPA1 cleavage at the mitochondrial inner membrane: m-AAA protease isoenzymes (paraplegin, AFG3L1/2) ensure constitutive balanced accumulation of long and short OPA1 isoforms; OMA1 mediates stress-induced OPA1 cleavage (e.g., upon mitochondrial DNA depletion or impaired mitochondrial activities), causing accumulation of short OPA1 variants. Loss of AFG3L2 induces OPA1 processing by OMA1.","method":"Mouse knockout/knockdown of m-AAA subunits, dominant-negative AFG3L2 expression, mtDNA depletion, siRNA against OMA1, Western blot for OPA1 isoforms","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic perturbations (KO mice, KD, dominant-negative) with orthogonal readouts, independently replicated","pmids":["20038678"],"is_preprint":false},{"year":2012,"finding":"In vivo, OMA1 is essential for proteolytic inactivation of OPA1 under stress. Oma1-deficient mice fail to properly cleave OPA1 under stress conditions, resulting in disrupted mitochondrial fusion-fission equilibrium, obesity, hepatic steatosis, decreased energy expenditure, and defective thermogenesis—demonstrating that the OMA1-OPA1 system is required for metabolic homeostasis and adaptive responses to metabolic stress.","method":"Oma1 knockout mouse generation, metabolic phenotyping (body weight, adipose mass, energy expenditure, thermogenesis), OPA1 Western blot in multiple tissues, high-fat diet and cold-shock challenges","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — whole-animal KO with multiple orthogonal metabolic and molecular readouts","pmids":["22433842"],"is_preprint":false},{"year":2014,"finding":"YME1L and OMA1 cleave OPA1 at two distinct sites constitutively; stress-induced OMA1 activity converts all OPA1 to short isoforms, inhibiting fusion and triggering fragmentation. Long OPA1 forms are sufficient for fusion; short OPA1 forms are associated with fission and partially colocalize with ER-mitochondria contact sites and the fission machinery. Deletion of Oma1 restored mitochondrial tubulation, cristae morphogenesis, and apoptotic resistance in YME1L-null cells.","method":"Double/single KO cell lines (YME1L, OMA1, or both), mitochondrial morphology imaging, cristae EM, OPA1 isoform Western blot, apoptosis assays, colocalization microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic backgrounds, orthogonal structural and functional readouts","pmids":["24616225"],"is_preprint":false},{"year":2014,"finding":"OMA1 is constitutively active but displays strongly enhanced proteolytic activity in response to various stress insults (heat shock, membrane depolarization, etc.). OMA1 contains an N-terminal stress-sensor domain (present only in higher eukaryotes) that modulates its activation. OMA1 activation is associated with autocatalytic degradation initiating from both termini, resulting in complete OMA1 turnover, which ensures reversibility of the stress response and allows OPA1-mediated fusion to resume after stress alleviation.","method":"Mutagenesis of OMA1 stress-sensor domain, Western blot for OMA1 and OPA1 isoforms under diverse stress conditions, pulse-chase for OMA1 turnover","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis combined with multiple stress conditions and turnover analysis in a single rigorous study","pmids":["24550258"],"is_preprint":false},{"year":2014,"finding":"Oligomerized Bax and Bak activate OMA1, which cleaves OPA1 (required for mitochondrial cristae remodeling), and OMA1 knockdown/knockout attenuates cytochrome c release during apoptosis. Thus Bax/Bak trigger apoptosis both by permeabilizing the outer membrane and by activating OMA1.","method":"Inducible Bim/tBid expression cell lines, Bax/Bak knockout, OMA1 siRNA and CRISPR KO, Western blot for OPA1 processing, cytochrome c release assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible apoptosis system, multiple genetic perturbations (KO + KD), orthogonal functional readouts","pmids":["25275009"],"is_preprint":false},{"year":2014,"finding":"OMA1 mediates OPA1 proteolysis and mitochondrial fragmentation in ischemic acute kidney injury. OMA1 knockdown in renal tubular cells suppressed OPA1 proteolysis, mitochondrial fragmentation, cytochrome c release, and apoptosis after ATP depletion. OMA1-deficient mice were protected from ischemic AKI.","method":"OMA1 siRNA in renal proximal tubular cells, OMA1 KO mice, renal ischemia-reperfusion model, OPA1 Western blot, cytochrome c release, mitochondrial morphology imaging","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — both in vitro KD and in vivo KO with orthogonal functional readouts","pmids":["24671334"],"is_preprint":false},{"year":2014,"finding":"p53 regulates OMA1 activation and consequent L-OPA1 cleavage in gynecologic cancer cells treated with cisplatin. Silencing p53 attenuates cisplatin-induced increase in OMA1 (40 kDa form), L-OPA1 processing, mitochondrial fragmentation, and apoptosis; conversely, p53 reconstitution in p53-null cells induces OMA1 activation and L-OPA1 processing independently of cisplatin.","method":"siRNA against OMA1 and p53, p53 cDNA reconstitution, Western blot for OMA1/OPA1, immunofluorescence for mitochondrial morphology, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary genetic approaches in a single lab, orthogonal readouts","pmids":["25112877"],"is_preprint":false},{"year":2016,"finding":"In yeast, OMA1 is important for adaptive responses to homeostatic insults (changes in membrane potential, oxidative stress, chronic hyperpolarization). Stress-triggered OMA1 proteolytic activation is associated with conformational changes in the OMA1 homo-oligomeric complex involving C-terminal residues; substitutions in the conserved C-terminal region impair its ability to form a labile proteolytically active complex under stress.","method":"Yeast genetics, OMA1 C-terminal mutagenesis, in-gel activity assays, stress treatments, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional activity assays in a single lab","pmids":["24648523"],"is_preprint":false},{"year":2019,"finding":"OMA1 cleaves PINK1 when PINK1 fails to arrest at the outer mitochondrial membrane (either due to mutation of its negatively charged motif C-terminal to the transmembrane domain or deletion of Tom7). Tom7 and OMA1 act antagonistically ('tug of war') to regulate PINK1 import arrest and activation on damaged mitochondria; OMA1 suppression rescues import and accumulation defects of certain Parkinson's disease PINK1 mutations.","method":"PINK1 mutagenesis, Tom7 KO, OMA1 KO/knockdown, PINK1 accumulation and autophosphorylation assays, mitochondrial depolarization","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic perturbations and orthogonal functional readouts (import, cleavage, kinase activation)","pmids":["30733118"],"is_preprint":false},{"year":2019,"finding":"Prohibitin (PHB) promotes OMA1 turnover by stabilizing cardiolipin (CL). OMA1 directly binds cardiolipin; deletion of the CL-binding domain of OMA1 decreases its turnover rate. PHB-mediated CL stabilization thus modulates OMA1 levels and stress responses including cytochrome c release.","method":"PHB KO neurons, OMA1 CL-binding domain deletion, CL-binding assay, OMA1 turnover measurement, cytochrome c release assay, caspase 9 activation","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay and domain deletion with turnover measurement; single lab, two orthogonal approaches","pmids":["31819158"],"is_preprint":false},{"year":2019,"finding":"OMA1 proteolytic activity is redox-dependent. OMA1 exists in a semi-oxidized state; two conserved IMS-exposed cysteine residues (Cys272 and Cys332) form a disulfide bond that plays a structural role influencing conformational stability and activity of the OMA1 oligomeric complex. Reduction/oxidation dynamically tunes OMA1 activity and stability.","method":"Biochemical redox state analysis (alkylation/shift assays), cysteine mutagenesis (Cys272, Cys332), in vitro substrate engagement under redox conditions, yeast and mammalian systems","journal":"Antioxidants & redox signaling","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of specific residues with in vitro activity/stability assays, evolutionarily conserved mechanism tested in two model systems","pmids":["31044600"],"is_preprint":false},{"year":2020,"finding":"Mitochondrial stress activates OMA1-dependent cleavage of DELE1, releasing a DELE1 fragment to the cytosol where it interacts with and activates the eIF2α kinase HRI, thereby triggering the integrated stress response (phospho-eIF2α → ATF4). DELE1 was identified as an inner mitochondrial membrane-associated OMA1 substrate. This OMA1-DELE1-HRI pathway relays mitochondrial stress to the cytosol.","method":"Genome-wide CRISPR interference screen, OMA1 KO, DELE1 KO, HRI KO, Western blot for DELE1 cleavage, eIF2α phosphorylation, ATF4 induction, co-IP of DELE1-HRI, subcellular fractionation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide screen plus multiple KO validations with orthogonal readouts across independent groups; published in Nature","pmids":["32132707"],"is_preprint":false},{"year":2020,"finding":"Loss of CHCHD2 and CHCHD10 activates OMA1, which cleaves L-OPA1 causing disrupted mitochondrial cristae. This was shown in C2/C10 double knockout mice and mutant C10 knock-in mice; OMA1 activation is a mechanism underlying cristae abnormalities caused by these mutations.","method":"CHCHD2/10 double KO and C10 KI mice, OMA1 activation assay (L-OPA1 cleavage as readout), EM for cristae ultrastructure","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models with orthogonal structural and molecular readouts, single lab","pmids":["32338760"],"is_preprint":false},{"year":2020,"finding":"p32/C1QBP regulates OMA1-dependent proteolytic processing of OPA1: genetic ablation of p32/C1QBP activates OMA1, leading to OPA1 cleavage, mitochondrial fragmentation, and swelling, with downstream metabolic consequences including reduced mitochondrial respiration and a shift to glycolysis.","method":"p32/C1QBP knockout, OPA1 Western blot, mitochondrial morphology imaging, oxygen consumption assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with orthogonal functional readouts; single lab","pmids":["32606429"],"is_preprint":false},{"year":2021,"finding":"OMA1 dynamically associates with the MICOS complex via the subunit MIC60, independently of OPA1. This association is important for stability of MICOS, maintenance of intermembrane connectivity, optimal bioenergetic output, and apoptosis. Loss of OMA1 disrupts these activities, which can be alleviated by a MICOS-emulating intermembrane bridge.","method":"Co-IP, proximity ligation, OMA1 KO, MICOS subunit knockdown, MICOS stability assays, oxygen consumption, apoptosis assays, intermembrane bridge rescue","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus KO rescue experiments with functional readouts; single lab","pmids":["33644718"],"is_preprint":false},{"year":2021,"finding":"A mitochondrial dynamic balance threshold exists, dependent on transmembrane potential (ΔΨm), coordinately mediated by DRP1-driven fission and OMA1-dependent OPA1 cleavage. Cells lacking OMA1 were insensitive to Δψm loss and maintained an obligately fused morphology; OMA1 is thus required for ΔΨm-dependent mitochondrial fragmentation.","method":"OMA1 KO cells, DRP1 KO cells, TMRE flow cytometry, mitochondrial morphology confocal imaging, CCCP/oligomycin/ρ0 cell treatments","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cell lines with quantitative Δψm measurement and morphology; single lab","pmids":["27858084"],"is_preprint":false},{"year":2022,"finding":"In CHCHD10 mitochondrial myopathy (G58R knock-in mice), OMA1 mediates a dual stress response: locally within mitochondria it causes fragmentation by cleaving OPA1, and globally it signals outside mitochondria by cleaving DELE1 to activate the integrated stress response. Survival of CHCHD10-KI mice depended on this OMA1-mediated protective response.","method":"CHCHD10 G58R knock-in mice, OMA1 KO cross, DELE1 cleavage Western blot, OPA1 processing, ATF4 pathway readouts, mitochondrial morphology EM, isoform switch analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KI/KO genetic epistasis with multiple orthogonal mechanistic readouts","pmids":["35700042"],"is_preprint":false},{"year":2023,"finding":"OMA1 protects against DNA damage in a metabolism-dependent manner. OMA1-deficient cells show reduced glycolysis and accumulate OXPHOS proteins upon DNA damage; OXPHOS inhibition restores glycolysis and confers resistance against DNA damage. The protective effect is independent of OMA1-mediated OPA1 and DELE1 processing.","method":"CRISPR screen (metabolism-focused), OMA1 KO, chemotherapeutic DNA damage, glycolysis and OXPHOS measurements, OXPHOS inhibitor rescue","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen validated with KO and metabolic rescue; single lab, orthogonal approaches","pmids":["37002921"],"is_preprint":false},{"year":2023,"finding":"TIM23 forms a complex with PINK1 and promotes PINK1 accumulation in response to depolarization by protecting it from OMA1-mediated degradation. OMA1 inactivation enhances PINK1 accumulation, and OMA1 inactivation rescues PINK1 accumulation defects caused by TIM23 downregulation and by some PD-associated PINK1 mutations that fail to interact with TIM23.","method":"Co-IP/mass spectrometry, TIM23 KD, OMA1 KO, PINK1 accumulation and autophosphorylation assays, pathogenic PINK1 mutant complementation","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus MS identification, combined with KD/KO functional epistasis and mutant rescue","pmids":["37160114"],"is_preprint":false},{"year":2024,"finding":"OMA1 cleaves arrested protein import intermediates upon mitochondrial depolarization in human cells. When precursor proteins stall in TOM/TIM translocase channels, OMA1-dependent proteolytic cleavage releases the blocked fragment, which is then cleared by VCP/p97 and the proteasome.","method":"Translocase clogging model in human cells, OMA1 KO/knockdown, OPA1 processing as activation control, proteasome and VCP inhibitors, Western blot for cleavage fragments","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered clogging model with KO validation and pharmacological epistasis; single lab","pmids":["38530280"],"is_preprint":false},{"year":2024,"finding":"OMA1 interacts with HSPA9 in GBM cells to promote mitophagy and activate the cGAS-STING pathway, leading to increased mitochondrial DNA release and upregulation of PD-L1, thereby mediating immune evasion.","method":"Co-IP, mass spectrometry, Western blot, OMA1 KD/OE, mitophagy assays, cGAS-STING pathway readouts, immunofluorescence","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS plus functional KD/OE; single lab","pmids":["38604814"],"is_preprint":false},{"year":2024,"finding":"OMA1 and Parkin act synergistically to safeguard mitochondrial structure and genome through mitochondrial fusion mediated by MFN1 (outer membrane) and OPA1 (inner membrane). Individual loss of Parkin or OMA1 does not affect mitochondrial integrity, but combined loss causes small body size, low locomotor activity, premature death, mitochondrial abnormalities, and innate immune responses.","method":"18 single/double/triple KO and mutant mouse models, systematic mitochondrial morphology analysis, untargeted metabolomics, RNA sequencing","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive in vivo genetic epistasis with 18 mouse models and multiple orthogonal readouts","pmids":["39972141"],"is_preprint":false},{"year":2024,"finding":"Oxidative stress is both sufficient to increase OMA1 activity and necessary for depolarization-induced OPA1 proteolysis in neuronal cells. OMA1 KO cells display exacerbated acute fragmentation upon FCCP but better restorative fusion capacity due to preserved L-OPA1. During oxygen-glucose deprivation, OPA1 processing and OMA1 activation are initiated in an ROS-dependent manner.","method":"OMA1 KO HT22 cells, ROS induction/scavenging, mitochondrial morphology assays, OGD/R model, membrane potential measurements","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cell line with pharmacological dissection of ROS contribution; single lab","pmids":["39312414"],"is_preprint":false},{"year":2024,"finding":"OMA1 deficiency in osteosarcoma cells increases PINK1 and Parkin levels, induces excessive mitophagy, and reduces cytosolic p53-Parkin association while increasing mitochondrial p53, leading to increased apoptosis. OMA1 loss also reduces mitochondrial ROS, increases cytosolic GSK3β, promotes β-catenin degradation, and reduces cell proliferation and invasion.","method":"OMA1 KO in OS cells, xenograft mouse models, Western blot, co-IP for p53-Parkin, mitophagy assays, GSK3β/β-catenin pathway analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with in vivo validation and multiple molecular pathway readouts; single lab","pmids":["39487118"],"is_preprint":false},{"year":2025,"finding":"OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under mitochondrial dysfunction; non-imported preproteins accumulate at the ER, inducing an unfolded protein response.","method":"In vitro cleavage assay, mass spectrometry-based proteomics, OMA1 KO, DNAJC15 KO, protein import assays, OXPHOS biogenesis measurements, ER stress readouts","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro cleavage plus in vivo KO genetics with proteomic validation and multiple orthogonal functional readouts","pmids":["41760807"],"is_preprint":false},{"year":2026,"finding":"OMA1 cleaves the membrane-anchored IMS protein AIFM1 under stress conditions (with slower kinetics than OPA1 cleavage), causing dislocation of AIFM1 from the inner mitochondrial membrane, reduced interaction with OXPHOS subunits, decreased respiratory activity, and impaired cell growth. Under steady state, AIFM1 safeguards mitochondrial proteome by mediating import of respiratory complex I subunits via TIM23.","method":"In vitro and in vivo multiproteomic and biochemical approaches, OMA1 KO, AIFM1 cleavage site mapping, co-IP for OXPHOS interactions, oxygen consumption assays, protein import assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro cleavage plus in vivo KO with proteomic and functional validation across multiple orthogonal readouts in a single rigorous study","pmids":["41876740"],"is_preprint":false},{"year":2019,"finding":"A fluorescence-based direct activity assay for OMA1 was developed using an 8-amino-acid peptide derived from the S1 OMA1 cleavage site in OPA1, flanked by a fluorophore and quencher. This assay measures OMA1 enzymatic activity quantitatively in whole cell lysates.","method":"Fluorescent peptide substrate assay, whole cell lysate, validation against OMA1-depleted controls","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with validated peptide substrate; single lab","pmids":["30926535"],"is_preprint":false},{"year":2022,"finding":"A conserved cysteine residue (C403 in mouse OMA1, corresponding to the IMS-exposed redox-sensing switch) is required for proper OMA1-mediated stress responses including mitochondrial fission and apoptosis. Prime-edited C403A mutant sarcoma cells show impaired mitochondrial stress responses, resistance to apoptosis, enhanced mitochondrial DNA release, and altered tumor immunogenicity.","method":"Prime editing (C403A mutation), mitochondrial morphology, ATP production, apoptosis assays, mtDNA release measurement, syngeneic tumor models with immune readouts","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — precise site-directed mutation via prime editing with in vitro and in vivo functional validation; single lab","pmids":["37024121"],"is_preprint":false},{"year":2018,"finding":"Leptin promotes OMA1 ubiquitination and proteasomal degradation via GSK3 phosphorylation (inhibition), thereby preventing OMA1-mediated cleavage of L-OPA1 and maintaining mitochondrial fusion and integrity in MSCs. Proteasome inhibitor MG132 and GSK3 inhibitor SB216763 prevent leptin-induced OMA1 degradation.","method":"siRNA, inhibitor treatments (MG132, SB216763), OMA1 ubiquitination assay, Western blot for OMA1/OPA1, mitochondrial morphology imaging","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic approaches with ubiquitination assay; single lab","pmids":["29748581"],"is_preprint":false}],"current_model":"OMA1 is a stress-activated ATP-independent zinc metalloprotease embedded in the mitochondrial inner membrane that, upon stress stimuli (loss of membrane potential, oxidative stress, proteotoxic insults), undergoes autocatalytic activation and cleaves multiple substrates including OPA1 (abolishing inner membrane fusion and triggering fragmentation), DELE1 (releasing it to the cytosol to activate the HRI–eIF2α–ATF4 integrated stress response), PINK1 (routing it to degradation on intact mitochondria), DNAJC15 (limiting OXPHOS biogenesis), and AIFM1 (reducing respiratory activity); its activity is regulated by IMS-exposed disulfide bonds (Cys272/Cys332), an N-terminal stress-sensor domain, cardiolipin binding (modulated by prohibitin), and ubiquitin-proteasome-mediated degradation (regulated by GSK3), and it acts in concert with Parkin to safeguard mitochondrial fusion and genome integrity under physiological conditions."},"narrative":{"mechanistic_narrative":"OMA1 is a stress-activated, ATP-independent zinc metallopeptidase of the mitochondrial inner membrane that serves as a central proteolytic relay coupling mitochondrial stress to organelle morphology, bioenergetics, and cytosolic signaling [PMID:12963738, PMID:24550258]. First identified in yeast as a membrane-embedded metallopeptidase that degrades misfolded inner-membrane proteins redundantly with the m-AAA protease [PMID:12963738], OMA1 was established in mammalian cells as the protease responsible for stress-induced cleavage of OPA1: upon loss of membrane potential, oxidative stress, or impaired mitochondrial activity, OMA1 converts long OPA1 to short isoforms, abolishing inner-membrane fusion and driving fragmentation [PMID:20038677, PMID:20038678, PMID:24616225]. OMA1 is constitutively active but its proteolytic activity is strongly enhanced by diverse stress insults through an N-terminal stress-sensor domain and an autocatalytic turnover that renders the response reversible [PMID:24550258]; its activity is further tuned by IMS-exposed redox-sensing cysteines that form a structural disulfide [PMID:31044600, PMID:37024121], by cardiolipin binding stabilized by prohibitin [PMID:31819158], and by GSK3-dependent ubiquitin-proteasome degradation [PMID:29748581]. Beyond OPA1, OMA1 cleaves DELE1 to release a cytosolic fragment that activates the HRI–eIF2α–ATF4 integrated stress response, transmitting mitochondrial stress to the cytosol [PMID:32132707, PMID:35700042]; it degrades PINK1 when import arrest fails, acting antagonistically to TOM7 and TIM23 to gate PINK1 accumulation on damaged mitochondria [PMID:30733118, PMID:37160114]; it cleaves the chaperone DNAJC15 to limit OXPHOS biogenesis [PMID:41760807] and the IMS protein AIFM1 to reduce respiratory activity [PMID:41876740]; and it clears protein import intermediates stalled in the translocases for downstream VCP/proteasome degradation [PMID:38530280]. Through OPA1 processing OMA1 governs mitochondrial dynamics in response to membrane potential and is required for apoptotic cristae remodeling and cytochrome c release downstream of Bax/Bak [PMID:25275009, PMID:27858084], with whole-animal consequences for metabolic homeostasis [PMID:22433842] and a synergistic role with Parkin in safeguarding mitochondrial structure and genome integrity [PMID:39972141].","teleology":[{"year":2003,"claim":"Established the founding biochemical identity of OMA1 as a membrane-embedded, ATP-independent metallopeptidase performing inner-membrane protein quality control, answering what kind of enzyme it is.","evidence":"Genetic identification in yeast with in vitro proteolytic assays, cleavage-site mapping, and topology/fractionation","pmids":["12963738"],"confidence":"High","gaps":["No mammalian substrates identified","Physiological triggers of activity not yet defined","Stress-sensing mechanism unknown"]},{"year":2009,"claim":"Defined OMA1's signature mammalian function by showing it mediates stress-induced cleavage of OPA1 distinct from constitutive YME1L processing, linking the protease to mitochondrial fusion control.","evidence":"siRNA knockdown, membrane-potential dissipation, fusion and apoptosis assays, plus parallel m-AAA genetic perturbations in cells and mice","pmids":["20038677","20038678"],"confidence":"High","gaps":["Activation mechanism of OMA1 under stress not resolved","Cleavage site on OPA1 not mapped at this stage","Reversibility of the response unaddressed"]},{"year":2012,"claim":"Showed the OMA1–OPA1 axis is physiologically required in vivo for metabolic homeostasis, moving the system from cell biology to organismal relevance.","evidence":"Oma1 knockout mice with metabolic phenotyping, high-fat and cold-shock challenges, and tissue OPA1 Western blots","pmids":["22433842"],"confidence":"High","gaps":["Tissue-specific contributions not dissected","Molecular link between OPA1 processing and energy expenditure incomplete"]},{"year":2014,"claim":"Resolved OMA1 activation logic and its role in apoptosis and disease stress, establishing an N-terminal stress-sensor domain, autocatalytic reversible turnover, and activation downstream of Bax/Bak and p53.","evidence":"Domain mutagenesis, pulse-chase turnover, YME1L/OMA1 double-KO morphology/cristae EM, inducible apoptosis systems, ischemic AKI models, and cisplatin/p53 manipulation","pmids":["24550258","24616225","25275009","24671334","25112877"],"confidence":"High","gaps":["Precise biochemical trigger sensed by the N-terminal domain unknown","How p53 and Bax/Bak signals reach OMA1 not mechanistically linked"]},{"year":2019,"claim":"Uncovered the molecular regulators of OMA1 stability and activity—redox-sensing cysteines, cardiolipin/prohibitin, and conformational oligomer changes—explaining how the protease is tuned.","evidence":"Cysteine mutagenesis (Cys272/Cys332) with redox-state assays, OMA1 cardiolipin-binding domain deletion in prohibitin-KO neurons, C-terminal mutagenesis with in-gel activity assays, and a fluorescent peptide activity assay","pmids":["31044600","31819158","24648523","30926535"],"confidence":"High","gaps":["Upstream redox source coupling to the disulfide not defined","Structural model of the active oligomer lacking"]},{"year":2019,"claim":"Revealed OMA1 as a regulator of PINK1 fate, cleaving PINK1 that fails to arrest at the outer membrane and gating Parkinson's-relevant mitophagy signaling.","evidence":"PINK1 mutagenesis, Tom7 knockout, OMA1 KO/knockdown with PINK1 accumulation and autophosphorylation assays","pmids":["30733118"],"confidence":"High","gaps":["Direct PINK1 cleavage site not mapped here","Selectivity of OMA1 for stalled versus arrested PINK1 incompletely defined"]},{"year":2020,"claim":"Established OMA1 as a cytosolic stress transmitter by identifying DELE1 as a substrate whose cleaved fragment activates HRI and the integrated stress response.","evidence":"Genome-wide CRISPRi screen with OMA1/DELE1/HRI knockouts, DELE1 cleavage and eIF2α/ATF4 readouts, DELE1–HRI co-IP, and fractionation","pmids":["32132707"],"confidence":"High","gaps":["DELE1 cleavage site and OMA1 recognition determinants not defined","Kinetics relative to OPA1 processing unaddressed"]},{"year":2020,"claim":"Connected OMA1 activation to mitochondrial cristae disease genes and metabolic state, showing CHCHD2/10 loss and p32/C1QBP ablation activate OMA1-dependent OPA1 cleavage.","evidence":"CHCHD2/10 double-KO and C10 knock-in mice with cristae EM, and p32/C1QBP KO with morphology and oxygen consumption assays","pmids":["32338760","32606429"],"confidence":"Medium","gaps":["Mechanism by which these proteins restrain OMA1 unknown","Direct versus indirect regulation not distinguished"]},{"year":2021,"claim":"Identified an OPA1-independent structural role for OMA1 at the MICOS complex and clarified its requirement for membrane-potential-dependent fragmentation.","evidence":"Co-IP and proximity ligation with MIC60, OMA1 KO with MICOS stability/bioenergetic readouts and intermembrane bridge rescue, plus TMRE/morphology in OMA1 and DRP1 KO cells","pmids":["33644718","27858084"],"confidence":"Medium","gaps":["Whether MICOS association regulates OMA1 protease activity unclear","Single-lab MICOS interaction without broad replication"]},{"year":2022,"claim":"Demonstrated in vivo that OMA1 mediates a dual local (fragmentation) and global (integrated stress response) protective program in CHCHD10 myopathy, and that a redox-sensing cysteine is functionally required.","evidence":"CHCHD10 G58R knock-in crossed to OMA1 KO with OPA1/DELE1/ATF4 readouts, and prime-edited C403A sarcoma cells with stress-response and tumor immunogenicity assays","pmids":["35700042","37024121"],"confidence":"High","gaps":["Balance between protective and deleterious OMA1 output not fully parsed","How C403 oxidation status is set in vivo unknown"]},{"year":2023,"claim":"Expanded OMA1 regulation of PINK1 import (via TIM23 antagonism) and uncovered an OPA1/DELE1-independent metabolic role in protecting against DNA damage.","evidence":"Co-IP/MS with TIM23 knockdown and PINK1 mutant rescue, and a metabolism-focused CRISPR screen with OMA1 KO and OXPHOS-inhibitor rescue of DNA damage sensitivity","pmids":["37160114","37002921"],"confidence":"High","gaps":["Substrate underlying the metabolic/DNA-damage protection not identified","How OMA1 controls glycolysis-OXPHOS balance mechanistically unresolved"]},{"year":2024,"claim":"Broadened the OMA1 substrate and partner repertoire (stalled import intermediates, HSPA9) and established its synergy with Parkin in safeguarding mitochondrial structure and genome integrity.","evidence":"Translocase clogging model with VCP/proteasome inhibitors, OMA1–HSPA9 co-IP/MS with cGAS-STING readouts in glioblastoma, OMA1 KO osteosarcoma with PINK1/Parkin/p53/GSK3β analysis, and a 18-genotype Parkin/OMA1 mouse epistasis study","pmids":["38530280","38604814","39487118","39972141","39312414"],"confidence":"High","gaps":["Direct versus stress-relayed nature of several substrate cleavages not fully separated","Tumor-context interactions (HSPA9, p53-Parkin) from single labs"]},{"year":2026,"claim":"Extended the substrate spectrum to bioenergetic regulators by showing OMA1 cleaves DNAJC15 (limiting OXPHOS biogenesis) and AIFM1 (reducing respiratory activity), defining OMA1 as a tuner of respiratory chain biogenesis.","evidence":"In vitro cleavage assays with proteomics, OMA1/DNAJC15/AIFM1 knockouts, AIFM1 cleavage-site mapping, protein import and oxygen consumption assays","pmids":["41760807","41876740"],"confidence":"High","gaps":["Hierarchy and kinetics among OMA1 substrates under a given stress not unified","Physiological conditions selectively engaging each substrate undefined"]},{"year":null,"claim":"It remains unresolved how a single protease achieves substrate selectivity and ordered cleavage among OPA1, DELE1, PINK1, DNAJC15, and AIFM1, and what high-resolution structural state defines its stress-activated active oligomer.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of active OMA1 oligomer","Substrate prioritization rules unknown","Integration of redox, cardiolipin, and ubiquitin inputs into a unified activation model lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,5,10,13,21,26,27]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,28]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5,12,24,29]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,4,16]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,4,16,17]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,13,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,7,25]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,21,26,27]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,20,22,25]}],"complexes":["MICOS"],"partners":["OPA1","DELE1","PINK1","MIC60","HSPA9","AFG3L2","AIFM1","DNAJC15"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96E52","full_name":"Metalloendopeptidase OMA1, mitochondrial","aliases":["Metalloprotease-related protein 1","MPRP-1","Overlapping with the m-AAA protease 1 homolog"],"length_aa":524,"mass_kda":60.1,"function":"Metalloprotease that is part of the quality control system in the inner membrane of mitochondria (PubMed:20038677, PubMed:25605331, PubMed:32132706, PubMed:32132707). Activated in response to various mitochondrial stress, leading to the proteolytic cleavage of target proteins, such as OPA1, UQCC3 and DELE1 (PubMed:20038677, PubMed:25275009, PubMed:32132706, PubMed:32132707). Involved in the fusion of the mitochondrial inner membranes by mediating cleavage of OPA1 at S1 position, generating the soluble OPA1 (S-OPA1), which cooperates with the membrane form (L-OPA1) to coordinate the fusion of mitochondrial inner membranes (PubMed:31922487). Following stress conditions that induce loss of mitochondrial membrane potential, mediates cleavage of OPA1, leading to excess production of soluble OPA1 (S-OPA1) and negative regulation of mitochondrial fusion (PubMed:20038677, PubMed:25275009). Involved in mitochondrial safeguard in response to transient mitochondrial membrane depolarization (flickering) by catalyzing cleavage of OPA1, leading to excess production of S-OPA1, preventing mitochondrial hyperfusion (By similarity). Also acts as a regulator of apoptosis: upon BAK and BAX aggregation, mediates cleavage of OPA1, leading to the remodeling of mitochondrial cristae and allowing the release of cytochrome c from mitochondrial cristae (PubMed:25275009). In depolarized mitochondria, may also act as a backup protease for PINK1 by mediating PINK1 cleavage and promoting its subsequent degradation by the proteasome (PubMed:30733118). May also cleave UQCC3 in response to mitochondrial depolarization (PubMed:25605331). Also acts as an activator of the integrated stress response (ISR): in response to mitochondrial stress, mediates cleavage of DELE1 to generate the processed form of DELE1 (S-DELE1), which translocates to the cytosol and activates EIF2AK1/HRI to trigger the ISR (PubMed:32132706, PubMed:32132707). Its role in mitochondrial quality control is essential for regulating lipid metabolism as well as to maintain body temperature and energy expenditure under cold-stress conditions (By similarity). Binds cardiolipin, possibly regulating its protein turnover (By similarity). Required for the stability of the respiratory supercomplexes (By similarity)","subcellular_location":"Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/Q96E52/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OMA1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OMA1","total_profiled":1310},"omim":[{"mim_id":"618977","title":"OPTIC ATROPHY 12; OPA12","url":"https://www.omim.org/entry/618977"},{"mim_id":"617081","title":"OMA1 ZINC METALLOPEPTIDASE; OMA1","url":"https://www.omim.org/entry/617081"},{"mim_id":"616209","title":"MYOPATHY, ISOLATED MITOCHONDRIAL, AUTOSOMAL DOMINANT; IMMD","url":"https://www.omim.org/entry/616209"},{"mim_id":"615903","title":"COILED-COIL-HELIX-COILED-COIL-HELIX DOMAIN-CONTAINING PROTEIN 10; CHCHD10","url":"https://www.omim.org/entry/615903"},{"mim_id":"615741","title":"DAP3-BINDING CELL DEATH ENHANCER 1; DELE1","url":"https://www.omim.org/entry/615741"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OMA1"},"hgnc":{"alias_symbol":["MPRP-1","YKR087C","ZMPOMA1","FLJ33782"],"prev_symbol":[]},"alphafold":{"accession":"Q96E52","domains":[{"cath_id":"-","chopping":"225-467","consensus_level":"medium","plddt":91.8609,"start":225,"end":467}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96E52","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96E52-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96E52-F1-predicted_aligned_error_v6.png","plddt_mean":71.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OMA1","jax_strain_url":"https://www.jax.org/strain/search?query=OMA1"},"sequence":{"accession":"Q96E52","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96E52.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96E52/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96E52"}},"corpus_meta":[{"pmid":"24616225","id":"PMC_24616225","title":"The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24616225","citation_count":652,"is_preprint":false},{"pmid":"32132707","id":"PMC_32132707","title":"Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32132707","citation_count":531,"is_preprint":false},{"pmid":"20038678","id":"PMC_20038678","title":"Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20038678","citation_count":482,"is_preprint":false},{"pmid":"20038677","id":"PMC_20038677","title":"Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20038677","citation_count":418,"is_preprint":false},{"pmid":"24550258","id":"PMC_24550258","title":"Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics.","date":"2014","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/24550258","citation_count":282,"is_preprint":false},{"pmid":"22433842","id":"PMC_22433842","title":"Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22433842","citation_count":226,"is_preprint":false},{"pmid":"25275009","id":"PMC_25275009","title":"Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25275009","citation_count":182,"is_preprint":false},{"pmid":"11702779","id":"PMC_11702779","title":"Two zinc finger proteins, OMA-1 and OMA-2, are redundantly required for oocyte maturation in C. elegans.","date":"2001","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/11702779","citation_count":153,"is_preprint":false},{"pmid":"30733118","id":"PMC_30733118","title":"Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30733118","citation_count":145,"is_preprint":false},{"pmid":"12963738","id":"PMC_12963738","title":"Oma1, a novel membrane-bound metallopeptidase in mitochondria with activities overlapping with the m-AAA protease.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12963738","citation_count":129,"is_preprint":false},{"pmid":"33842456","id":"PMC_33842456","title":"Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure/Function and Cellular Stress Response.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33842456","citation_count":112,"is_preprint":false},{"pmid":"24671334","id":"PMC_24671334","title":"OMA1 mediates OPA1 proteolysis and mitochondrial fragmentation in experimental models of ischemic kidney injury.","date":"2014","source":"American journal of physiology. 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It cleaves the misfolded Oxa1 derivative at loop regions on both membrane surfaces and acts redundantly with the m-AAA protease in quality control of inner membrane proteins.\",\n      \"method\": \"Genetic identification in yeast, in vitro proteolytic assays, cleavage-site mapping, topology/fractionation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — founding paper with in vitro assays, cleavage-site mapping, and genetic epistasis establishing the protease as ATP-independent inner-membrane metallopeptidase\",\n      \"pmids\": [\"12963738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"OMA1 mediates stress-induced (inducible) cleavage of OPA1 in mammalian cells. Specifically, OMA1 cleaves OPA1 isoforms that are not constitutively cleaved by YME1L when mitochondria lose membrane potential or ATP, converting long OPA1 forms to short forms and inhibiting fusion. OMA1 siRNA knockdown inhibits inducible cleavage, retains fusion competence, and slows apoptosis onset. OMA1 itself is constitutively cleaved from 60 kDa to 40 kDa by another protease, and loss of membrane potential causes 60 kDa OMA1 to accumulate, suggesting attenuation by proteolytic degradation.\",\n      \"method\": \"siRNA knockdown, Western blot, mitochondrial membrane potential dissipation (CCCP/oligomycin), fluorescence microscopy for fusion competence, apoptosis assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, membrane potential manipulation, fusion assay, apoptosis readout), replicated across independent labs in concurrent paper (PMID:20038678)\",\n      \"pmids\": [\"20038677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Two classes of metallopeptidases regulate OPA1 cleavage at the mitochondrial inner membrane: m-AAA protease isoenzymes (paraplegin, AFG3L1/2) ensure constitutive balanced accumulation of long and short OPA1 isoforms; OMA1 mediates stress-induced OPA1 cleavage (e.g., upon mitochondrial DNA depletion or impaired mitochondrial activities), causing accumulation of short OPA1 variants. Loss of AFG3L2 induces OPA1 processing by OMA1.\",\n      \"method\": \"Mouse knockout/knockdown of m-AAA subunits, dominant-negative AFG3L2 expression, mtDNA depletion, siRNA against OMA1, Western blot for OPA1 isoforms\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic perturbations (KO mice, KD, dominant-negative) with orthogonal readouts, independently replicated\",\n      \"pmids\": [\"20038678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In vivo, OMA1 is essential for proteolytic inactivation of OPA1 under stress. Oma1-deficient mice fail to properly cleave OPA1 under stress conditions, resulting in disrupted mitochondrial fusion-fission equilibrium, obesity, hepatic steatosis, decreased energy expenditure, and defective thermogenesis—demonstrating that the OMA1-OPA1 system is required for metabolic homeostasis and adaptive responses to metabolic stress.\",\n      \"method\": \"Oma1 knockout mouse generation, metabolic phenotyping (body weight, adipose mass, energy expenditure, thermogenesis), OPA1 Western blot in multiple tissues, high-fat diet and cold-shock challenges\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — whole-animal KO with multiple orthogonal metabolic and molecular readouts\",\n      \"pmids\": [\"22433842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"YME1L and OMA1 cleave OPA1 at two distinct sites constitutively; stress-induced OMA1 activity converts all OPA1 to short isoforms, inhibiting fusion and triggering fragmentation. Long OPA1 forms are sufficient for fusion; short OPA1 forms are associated with fission and partially colocalize with ER-mitochondria contact sites and the fission machinery. Deletion of Oma1 restored mitochondrial tubulation, cristae morphogenesis, and apoptotic resistance in YME1L-null cells.\",\n      \"method\": \"Double/single KO cell lines (YME1L, OMA1, or both), mitochondrial morphology imaging, cristae EM, OPA1 isoform Western blot, apoptosis assays, colocalization microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic backgrounds, orthogonal structural and functional readouts\",\n      \"pmids\": [\"24616225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OMA1 is constitutively active but displays strongly enhanced proteolytic activity in response to various stress insults (heat shock, membrane depolarization, etc.). OMA1 contains an N-terminal stress-sensor domain (present only in higher eukaryotes) that modulates its activation. OMA1 activation is associated with autocatalytic degradation initiating from both termini, resulting in complete OMA1 turnover, which ensures reversibility of the stress response and allows OPA1-mediated fusion to resume after stress alleviation.\",\n      \"method\": \"Mutagenesis of OMA1 stress-sensor domain, Western blot for OMA1 and OPA1 isoforms under diverse stress conditions, pulse-chase for OMA1 turnover\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis combined with multiple stress conditions and turnover analysis in a single rigorous study\",\n      \"pmids\": [\"24550258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Oligomerized Bax and Bak activate OMA1, which cleaves OPA1 (required for mitochondrial cristae remodeling), and OMA1 knockdown/knockout attenuates cytochrome c release during apoptosis. Thus Bax/Bak trigger apoptosis both by permeabilizing the outer membrane and by activating OMA1.\",\n      \"method\": \"Inducible Bim/tBid expression cell lines, Bax/Bak knockout, OMA1 siRNA and CRISPR KO, Western blot for OPA1 processing, cytochrome c release assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible apoptosis system, multiple genetic perturbations (KO + KD), orthogonal functional readouts\",\n      \"pmids\": [\"25275009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OMA1 mediates OPA1 proteolysis and mitochondrial fragmentation in ischemic acute kidney injury. OMA1 knockdown in renal tubular cells suppressed OPA1 proteolysis, mitochondrial fragmentation, cytochrome c release, and apoptosis after ATP depletion. OMA1-deficient mice were protected from ischemic AKI.\",\n      \"method\": \"OMA1 siRNA in renal proximal tubular cells, OMA1 KO mice, renal ischemia-reperfusion model, OPA1 Western blot, cytochrome c release, mitochondrial morphology imaging\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both in vitro KD and in vivo KO with orthogonal functional readouts\",\n      \"pmids\": [\"24671334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p53 regulates OMA1 activation and consequent L-OPA1 cleavage in gynecologic cancer cells treated with cisplatin. Silencing p53 attenuates cisplatin-induced increase in OMA1 (40 kDa form), L-OPA1 processing, mitochondrial fragmentation, and apoptosis; conversely, p53 reconstitution in p53-null cells induces OMA1 activation and L-OPA1 processing independently of cisplatin.\",\n      \"method\": \"siRNA against OMA1 and p53, p53 cDNA reconstitution, Western blot for OMA1/OPA1, immunofluorescence for mitochondrial morphology, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary genetic approaches in a single lab, orthogonal readouts\",\n      \"pmids\": [\"25112877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In yeast, OMA1 is important for adaptive responses to homeostatic insults (changes in membrane potential, oxidative stress, chronic hyperpolarization). Stress-triggered OMA1 proteolytic activation is associated with conformational changes in the OMA1 homo-oligomeric complex involving C-terminal residues; substitutions in the conserved C-terminal region impair its ability to form a labile proteolytically active complex under stress.\",\n      \"method\": \"Yeast genetics, OMA1 C-terminal mutagenesis, in-gel activity assays, stress treatments, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional activity assays in a single lab\",\n      \"pmids\": [\"24648523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OMA1 cleaves PINK1 when PINK1 fails to arrest at the outer mitochondrial membrane (either due to mutation of its negatively charged motif C-terminal to the transmembrane domain or deletion of Tom7). Tom7 and OMA1 act antagonistically ('tug of war') to regulate PINK1 import arrest and activation on damaged mitochondria; OMA1 suppression rescues import and accumulation defects of certain Parkinson's disease PINK1 mutations.\",\n      \"method\": \"PINK1 mutagenesis, Tom7 KO, OMA1 KO/knockdown, PINK1 accumulation and autophosphorylation assays, mitochondrial depolarization\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic perturbations and orthogonal functional readouts (import, cleavage, kinase activation)\",\n      \"pmids\": [\"30733118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Prohibitin (PHB) promotes OMA1 turnover by stabilizing cardiolipin (CL). OMA1 directly binds cardiolipin; deletion of the CL-binding domain of OMA1 decreases its turnover rate. PHB-mediated CL stabilization thus modulates OMA1 levels and stress responses including cytochrome c release.\",\n      \"method\": \"PHB KO neurons, OMA1 CL-binding domain deletion, CL-binding assay, OMA1 turnover measurement, cytochrome c release assay, caspase 9 activation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay and domain deletion with turnover measurement; single lab, two orthogonal approaches\",\n      \"pmids\": [\"31819158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OMA1 proteolytic activity is redox-dependent. OMA1 exists in a semi-oxidized state; two conserved IMS-exposed cysteine residues (Cys272 and Cys332) form a disulfide bond that plays a structural role influencing conformational stability and activity of the OMA1 oligomeric complex. Reduction/oxidation dynamically tunes OMA1 activity and stability.\",\n      \"method\": \"Biochemical redox state analysis (alkylation/shift assays), cysteine mutagenesis (Cys272, Cys332), in vitro substrate engagement under redox conditions, yeast and mammalian systems\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of specific residues with in vitro activity/stability assays, evolutionarily conserved mechanism tested in two model systems\",\n      \"pmids\": [\"31044600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mitochondrial stress activates OMA1-dependent cleavage of DELE1, releasing a DELE1 fragment to the cytosol where it interacts with and activates the eIF2α kinase HRI, thereby triggering the integrated stress response (phospho-eIF2α → ATF4). DELE1 was identified as an inner mitochondrial membrane-associated OMA1 substrate. This OMA1-DELE1-HRI pathway relays mitochondrial stress to the cytosol.\",\n      \"method\": \"Genome-wide CRISPR interference screen, OMA1 KO, DELE1 KO, HRI KO, Western blot for DELE1 cleavage, eIF2α phosphorylation, ATF4 induction, co-IP of DELE1-HRI, subcellular fractionation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide screen plus multiple KO validations with orthogonal readouts across independent groups; published in Nature\",\n      \"pmids\": [\"32132707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of CHCHD2 and CHCHD10 activates OMA1, which cleaves L-OPA1 causing disrupted mitochondrial cristae. This was shown in C2/C10 double knockout mice and mutant C10 knock-in mice; OMA1 activation is a mechanism underlying cristae abnormalities caused by these mutations.\",\n      \"method\": \"CHCHD2/10 double KO and C10 KI mice, OMA1 activation assay (L-OPA1 cleavage as readout), EM for cristae ultrastructure\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models with orthogonal structural and molecular readouts, single lab\",\n      \"pmids\": [\"32338760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p32/C1QBP regulates OMA1-dependent proteolytic processing of OPA1: genetic ablation of p32/C1QBP activates OMA1, leading to OPA1 cleavage, mitochondrial fragmentation, and swelling, with downstream metabolic consequences including reduced mitochondrial respiration and a shift to glycolysis.\",\n      \"method\": \"p32/C1QBP knockout, OPA1 Western blot, mitochondrial morphology imaging, oxygen consumption assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with orthogonal functional readouts; single lab\",\n      \"pmids\": [\"32606429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OMA1 dynamically associates with the MICOS complex via the subunit MIC60, independently of OPA1. This association is important for stability of MICOS, maintenance of intermembrane connectivity, optimal bioenergetic output, and apoptosis. Loss of OMA1 disrupts these activities, which can be alleviated by a MICOS-emulating intermembrane bridge.\",\n      \"method\": \"Co-IP, proximity ligation, OMA1 KO, MICOS subunit knockdown, MICOS stability assays, oxygen consumption, apoptosis assays, intermembrane bridge rescue\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus KO rescue experiments with functional readouts; single lab\",\n      \"pmids\": [\"33644718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A mitochondrial dynamic balance threshold exists, dependent on transmembrane potential (ΔΨm), coordinately mediated by DRP1-driven fission and OMA1-dependent OPA1 cleavage. Cells lacking OMA1 were insensitive to Δψm loss and maintained an obligately fused morphology; OMA1 is thus required for ΔΨm-dependent mitochondrial fragmentation.\",\n      \"method\": \"OMA1 KO cells, DRP1 KO cells, TMRE flow cytometry, mitochondrial morphology confocal imaging, CCCP/oligomycin/ρ0 cell treatments\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cell lines with quantitative Δψm measurement and morphology; single lab\",\n      \"pmids\": [\"27858084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In CHCHD10 mitochondrial myopathy (G58R knock-in mice), OMA1 mediates a dual stress response: locally within mitochondria it causes fragmentation by cleaving OPA1, and globally it signals outside mitochondria by cleaving DELE1 to activate the integrated stress response. Survival of CHCHD10-KI mice depended on this OMA1-mediated protective response.\",\n      \"method\": \"CHCHD10 G58R knock-in mice, OMA1 KO cross, DELE1 cleavage Western blot, OPA1 processing, ATF4 pathway readouts, mitochondrial morphology EM, isoform switch analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KI/KO genetic epistasis with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"35700042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OMA1 protects against DNA damage in a metabolism-dependent manner. OMA1-deficient cells show reduced glycolysis and accumulate OXPHOS proteins upon DNA damage; OXPHOS inhibition restores glycolysis and confers resistance against DNA damage. The protective effect is independent of OMA1-mediated OPA1 and DELE1 processing.\",\n      \"method\": \"CRISPR screen (metabolism-focused), OMA1 KO, chemotherapeutic DNA damage, glycolysis and OXPHOS measurements, OXPHOS inhibitor rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen validated with KO and metabolic rescue; single lab, orthogonal approaches\",\n      \"pmids\": [\"37002921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIM23 forms a complex with PINK1 and promotes PINK1 accumulation in response to depolarization by protecting it from OMA1-mediated degradation. OMA1 inactivation enhances PINK1 accumulation, and OMA1 inactivation rescues PINK1 accumulation defects caused by TIM23 downregulation and by some PD-associated PINK1 mutations that fail to interact with TIM23.\",\n      \"method\": \"Co-IP/mass spectrometry, TIM23 KD, OMA1 KO, PINK1 accumulation and autophosphorylation assays, pathogenic PINK1 mutant complementation\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus MS identification, combined with KD/KO functional epistasis and mutant rescue\",\n      \"pmids\": [\"37160114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OMA1 cleaves arrested protein import intermediates upon mitochondrial depolarization in human cells. When precursor proteins stall in TOM/TIM translocase channels, OMA1-dependent proteolytic cleavage releases the blocked fragment, which is then cleared by VCP/p97 and the proteasome.\",\n      \"method\": \"Translocase clogging model in human cells, OMA1 KO/knockdown, OPA1 processing as activation control, proteasome and VCP inhibitors, Western blot for cleavage fragments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered clogging model with KO validation and pharmacological epistasis; single lab\",\n      \"pmids\": [\"38530280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OMA1 interacts with HSPA9 in GBM cells to promote mitophagy and activate the cGAS-STING pathway, leading to increased mitochondrial DNA release and upregulation of PD-L1, thereby mediating immune evasion.\",\n      \"method\": \"Co-IP, mass spectrometry, Western blot, OMA1 KD/OE, mitophagy assays, cGAS-STING pathway readouts, immunofluorescence\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS plus functional KD/OE; single lab\",\n      \"pmids\": [\"38604814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OMA1 and Parkin act synergistically to safeguard mitochondrial structure and genome through mitochondrial fusion mediated by MFN1 (outer membrane) and OPA1 (inner membrane). Individual loss of Parkin or OMA1 does not affect mitochondrial integrity, but combined loss causes small body size, low locomotor activity, premature death, mitochondrial abnormalities, and innate immune responses.\",\n      \"method\": \"18 single/double/triple KO and mutant mouse models, systematic mitochondrial morphology analysis, untargeted metabolomics, RNA sequencing\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive in vivo genetic epistasis with 18 mouse models and multiple orthogonal readouts\",\n      \"pmids\": [\"39972141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Oxidative stress is both sufficient to increase OMA1 activity and necessary for depolarization-induced OPA1 proteolysis in neuronal cells. OMA1 KO cells display exacerbated acute fragmentation upon FCCP but better restorative fusion capacity due to preserved L-OPA1. During oxygen-glucose deprivation, OPA1 processing and OMA1 activation are initiated in an ROS-dependent manner.\",\n      \"method\": \"OMA1 KO HT22 cells, ROS induction/scavenging, mitochondrial morphology assays, OGD/R model, membrane potential measurements\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cell line with pharmacological dissection of ROS contribution; single lab\",\n      \"pmids\": [\"39312414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OMA1 deficiency in osteosarcoma cells increases PINK1 and Parkin levels, induces excessive mitophagy, and reduces cytosolic p53-Parkin association while increasing mitochondrial p53, leading to increased apoptosis. OMA1 loss also reduces mitochondrial ROS, increases cytosolic GSK3β, promotes β-catenin degradation, and reduces cell proliferation and invasion.\",\n      \"method\": \"OMA1 KO in OS cells, xenograft mouse models, Western blot, co-IP for p53-Parkin, mitophagy assays, GSK3β/β-catenin pathway analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with in vivo validation and multiple molecular pathway readouts; single lab\",\n      \"pmids\": [\"39487118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under mitochondrial dysfunction; non-imported preproteins accumulate at the ER, inducing an unfolded protein response.\",\n      \"method\": \"In vitro cleavage assay, mass spectrometry-based proteomics, OMA1 KO, DNAJC15 KO, protein import assays, OXPHOS biogenesis measurements, ER stress readouts\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro cleavage plus in vivo KO genetics with proteomic validation and multiple orthogonal functional readouts\",\n      \"pmids\": [\"41760807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OMA1 cleaves the membrane-anchored IMS protein AIFM1 under stress conditions (with slower kinetics than OPA1 cleavage), causing dislocation of AIFM1 from the inner mitochondrial membrane, reduced interaction with OXPHOS subunits, decreased respiratory activity, and impaired cell growth. Under steady state, AIFM1 safeguards mitochondrial proteome by mediating import of respiratory complex I subunits via TIM23.\",\n      \"method\": \"In vitro and in vivo multiproteomic and biochemical approaches, OMA1 KO, AIFM1 cleavage site mapping, co-IP for OXPHOS interactions, oxygen consumption assays, protein import assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro cleavage plus in vivo KO with proteomic and functional validation across multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"41876740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A fluorescence-based direct activity assay for OMA1 was developed using an 8-amino-acid peptide derived from the S1 OMA1 cleavage site in OPA1, flanked by a fluorophore and quencher. This assay measures OMA1 enzymatic activity quantitatively in whole cell lysates.\",\n      \"method\": \"Fluorescent peptide substrate assay, whole cell lysate, validation against OMA1-depleted controls\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with validated peptide substrate; single lab\",\n      \"pmids\": [\"30926535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A conserved cysteine residue (C403 in mouse OMA1, corresponding to the IMS-exposed redox-sensing switch) is required for proper OMA1-mediated stress responses including mitochondrial fission and apoptosis. Prime-edited C403A mutant sarcoma cells show impaired mitochondrial stress responses, resistance to apoptosis, enhanced mitochondrial DNA release, and altered tumor immunogenicity.\",\n      \"method\": \"Prime editing (C403A mutation), mitochondrial morphology, ATP production, apoptosis assays, mtDNA release measurement, syngeneic tumor models with immune readouts\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — precise site-directed mutation via prime editing with in vitro and in vivo functional validation; single lab\",\n      \"pmids\": [\"37024121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Leptin promotes OMA1 ubiquitination and proteasomal degradation via GSK3 phosphorylation (inhibition), thereby preventing OMA1-mediated cleavage of L-OPA1 and maintaining mitochondrial fusion and integrity in MSCs. Proteasome inhibitor MG132 and GSK3 inhibitor SB216763 prevent leptin-induced OMA1 degradation.\",\n      \"method\": \"siRNA, inhibitor treatments (MG132, SB216763), OMA1 ubiquitination assay, Western blot for OMA1/OPA1, mitochondrial morphology imaging\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic approaches with ubiquitination assay; single lab\",\n      \"pmids\": [\"29748581\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OMA1 is a stress-activated ATP-independent zinc metalloprotease embedded in the mitochondrial inner membrane that, upon stress stimuli (loss of membrane potential, oxidative stress, proteotoxic insults), undergoes autocatalytic activation and cleaves multiple substrates including OPA1 (abolishing inner membrane fusion and triggering fragmentation), DELE1 (releasing it to the cytosol to activate the HRI–eIF2α–ATF4 integrated stress response), PINK1 (routing it to degradation on intact mitochondria), DNAJC15 (limiting OXPHOS biogenesis), and AIFM1 (reducing respiratory activity); its activity is regulated by IMS-exposed disulfide bonds (Cys272/Cys332), an N-terminal stress-sensor domain, cardiolipin binding (modulated by prohibitin), and ubiquitin-proteasome-mediated degradation (regulated by GSK3), and it acts in concert with Parkin to safeguard mitochondrial fusion and genome integrity under physiological conditions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OMA1 is a stress-activated, ATP-independent zinc metallopeptidase of the mitochondrial inner membrane that serves as a central proteolytic relay coupling mitochondrial stress to organelle morphology, bioenergetics, and cytosolic signaling [#0, #5]. First identified in yeast as a membrane-embedded metallopeptidase that degrades misfolded inner-membrane proteins redundantly with the m-AAA protease [#0], OMA1 was established in mammalian cells as the protease responsible for stress-induced cleavage of OPA1: upon loss of membrane potential, oxidative stress, or impaired mitochondrial activity, OMA1 converts long OPA1 to short isoforms, abolishing inner-membrane fusion and driving fragmentation [#1, #2, #4]. OMA1 is constitutively active but its proteolytic activity is strongly enhanced by diverse stress insults through an N-terminal stress-sensor domain and an autocatalytic turnover that renders the response reversible [#5]; its activity is further tuned by IMS-exposed redox-sensing cysteines that form a structural disulfide [#12, #29], by cardiolipin binding stabilized by prohibitin [#11], and by GSK3-dependent ubiquitin-proteasome degradation [#30]. Beyond OPA1, OMA1 cleaves DELE1 to release a cytosolic fragment that activates the HRI\\u2013eIF2\\u03b1\\u2013ATF4 integrated stress response, transmitting mitochondrial stress to the cytosol [#13, #18]; it degrades PINK1 when import arrest fails, acting antagonistically to TOM7 and TIM23 to gate PINK1 accumulation on damaged mitochondria [#10, #20]; it cleaves the chaperone DNAJC15 to limit OXPHOS biogenesis [#26] and the IMS protein AIFM1 to reduce respiratory activity [#27]; and it clears protein import intermediates stalled in the translocases for downstream VCP/proteasome degradation [#21]. Through OPA1 processing OMA1 governs mitochondrial dynamics in response to membrane potential and is required for apoptotic cristae remodeling and cytochrome c release downstream of Bax/Bak [#6, #17], with whole-animal consequences for metabolic homeostasis [#3] and a synergistic role with Parkin in safeguarding mitochondrial structure and genome integrity [#23].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the founding biochemical identity of OMA1 as a membrane-embedded, ATP-independent metallopeptidase performing inner-membrane protein quality control, answering what kind of enzyme it is.\",\n      \"evidence\": \"Genetic identification in yeast with in vitro proteolytic assays, cleavage-site mapping, and topology/fractionation\",\n      \"pmids\": [\"12963738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No mammalian substrates identified\", \"Physiological triggers of activity not yet defined\", \"Stress-sensing mechanism unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined OMA1's signature mammalian function by showing it mediates stress-induced cleavage of OPA1 distinct from constitutive YME1L processing, linking the protease to mitochondrial fusion control.\",\n      \"evidence\": \"siRNA knockdown, membrane-potential dissipation, fusion and apoptosis assays, plus parallel m-AAA genetic perturbations in cells and mice\",\n      \"pmids\": [\"20038677\", \"20038678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activation mechanism of OMA1 under stress not resolved\", \"Cleavage site on OPA1 not mapped at this stage\", \"Reversibility of the response unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed the OMA1\\u2013OPA1 axis is physiologically required in vivo for metabolic homeostasis, moving the system from cell biology to organismal relevance.\",\n      \"evidence\": \"Oma1 knockout mice with metabolic phenotyping, high-fat and cold-shock challenges, and tissue OPA1 Western blots\",\n      \"pmids\": [\"22433842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions not dissected\", \"Molecular link between OPA1 processing and energy expenditure incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved OMA1 activation logic and its role in apoptosis and disease stress, establishing an N-terminal stress-sensor domain, autocatalytic reversible turnover, and activation downstream of Bax/Bak and p53.\",\n      \"evidence\": \"Domain mutagenesis, pulse-chase turnover, YME1L/OMA1 double-KO morphology/cristae EM, inducible apoptosis systems, ischemic AKI models, and cisplatin/p53 manipulation\",\n      \"pmids\": [\"24550258\", \"24616225\", \"25275009\", \"24671334\", \"25112877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise biochemical trigger sensed by the N-terminal domain unknown\", \"How p53 and Bax/Bak signals reach OMA1 not mechanistically linked\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered the molecular regulators of OMA1 stability and activity\\u2014redox-sensing cysteines, cardiolipin/prohibitin, and conformational oligomer changes\\u2014explaining how the protease is tuned.\",\n      \"evidence\": \"Cysteine mutagenesis (Cys272/Cys332) with redox-state assays, OMA1 cardiolipin-binding domain deletion in prohibitin-KO neurons, C-terminal mutagenesis with in-gel activity assays, and a fluorescent peptide activity assay\",\n      \"pmids\": [\"31044600\", \"31819158\", \"24648523\", \"30926535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream redox source coupling to the disulfide not defined\", \"Structural model of the active oligomer lacking\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed OMA1 as a regulator of PINK1 fate, cleaving PINK1 that fails to arrest at the outer membrane and gating Parkinson's-relevant mitophagy signaling.\",\n      \"evidence\": \"PINK1 mutagenesis, Tom7 knockout, OMA1 KO/knockdown with PINK1 accumulation and autophosphorylation assays\",\n      \"pmids\": [\"30733118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PINK1 cleavage site not mapped here\", \"Selectivity of OMA1 for stalled versus arrested PINK1 incompletely defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established OMA1 as a cytosolic stress transmitter by identifying DELE1 as a substrate whose cleaved fragment activates HRI and the integrated stress response.\",\n      \"evidence\": \"Genome-wide CRISPRi screen with OMA1/DELE1/HRI knockouts, DELE1 cleavage and eIF2\\u03b1/ATF4 readouts, DELE1\\u2013HRI co-IP, and fractionation\",\n      \"pmids\": [\"32132707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DELE1 cleavage site and OMA1 recognition determinants not defined\", \"Kinetics relative to OPA1 processing unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected OMA1 activation to mitochondrial cristae disease genes and metabolic state, showing CHCHD2/10 loss and p32/C1QBP ablation activate OMA1-dependent OPA1 cleavage.\",\n      \"evidence\": \"CHCHD2/10 double-KO and C10 knock-in mice with cristae EM, and p32/C1QBP KO with morphology and oxygen consumption assays\",\n      \"pmids\": [\"32338760\", \"32606429\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which these proteins restrain OMA1 unknown\", \"Direct versus indirect regulation not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified an OPA1-independent structural role for OMA1 at the MICOS complex and clarified its requirement for membrane-potential-dependent fragmentation.\",\n      \"evidence\": \"Co-IP and proximity ligation with MIC60, OMA1 KO with MICOS stability/bioenergetic readouts and intermembrane bridge rescue, plus TMRE/morphology in OMA1 and DRP1 KO cells\",\n      \"pmids\": [\"33644718\", \"27858084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MICOS association regulates OMA1 protease activity unclear\", \"Single-lab MICOS interaction without broad replication\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated in vivo that OMA1 mediates a dual local (fragmentation) and global (integrated stress response) protective program in CHCHD10 myopathy, and that a redox-sensing cysteine is functionally required.\",\n      \"evidence\": \"CHCHD10 G58R knock-in crossed to OMA1 KO with OPA1/DELE1/ATF4 readouts, and prime-edited C403A sarcoma cells with stress-response and tumor immunogenicity assays\",\n      \"pmids\": [\"35700042\", \"37024121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Balance between protective and deleterious OMA1 output not fully parsed\", \"How C403 oxidation status is set in vivo unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded OMA1 regulation of PINK1 import (via TIM23 antagonism) and uncovered an OPA1/DELE1-independent metabolic role in protecting against DNA damage.\",\n      \"evidence\": \"Co-IP/MS with TIM23 knockdown and PINK1 mutant rescue, and a metabolism-focused CRISPR screen with OMA1 KO and OXPHOS-inhibitor rescue of DNA damage sensitivity\",\n      \"pmids\": [\"37160114\", \"37002921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate underlying the metabolic/DNA-damage protection not identified\", \"How OMA1 controls glycolysis-OXPHOS balance mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened the OMA1 substrate and partner repertoire (stalled import intermediates, HSPA9) and established its synergy with Parkin in safeguarding mitochondrial structure and genome integrity.\",\n      \"evidence\": \"Translocase clogging model with VCP/proteasome inhibitors, OMA1\\u2013HSPA9 co-IP/MS with cGAS-STING readouts in glioblastoma, OMA1 KO osteosarcoma with PINK1/Parkin/p53/GSK3\\u03b2 analysis, and a 18-genotype Parkin/OMA1 mouse epistasis study\",\n      \"pmids\": [\"38530280\", \"38604814\", \"39487118\", \"39972141\", \"39312414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus stress-relayed nature of several substrate cleavages not fully separated\", \"Tumor-context interactions (HSPA9, p53-Parkin) from single labs\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the substrate spectrum to bioenergetic regulators by showing OMA1 cleaves DNAJC15 (limiting OXPHOS biogenesis) and AIFM1 (reducing respiratory activity), defining OMA1 as a tuner of respiratory chain biogenesis.\",\n      \"evidence\": \"In vitro cleavage assays with proteomics, OMA1/DNAJC15/AIFM1 knockouts, AIFM1 cleavage-site mapping, protein import and oxygen consumption assays\",\n      \"pmids\": [\"41760807\", \"41876740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy and kinetics among OMA1 substrates under a given stress not unified\", \"Physiological conditions selectively engaging each substrate undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single protease achieves substrate selectivity and ordered cleavage among OPA1, DELE1, PINK1, DNAJC15, and AIFM1, and what high-resolution structural state defines its stress-activated active oligomer.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of active OMA1 oligomer\", \"Substrate prioritization rules unknown\", \"Integration of redox, cardiolipin, and ubiquitin inputs into a unified activation model lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 5, 10, 13, 21, 26, 27]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 28]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5, 12, 24, 29]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 4, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 4, 16, 17]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 13, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 7, 25]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 21, 26, 27]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 20, 22, 25]}\n    ],\n    \"complexes\": [\"MICOS\"],\n    \"partners\": [\"OPA1\", \"DELE1\", \"PINK1\", \"MIC60\", \"HSPA9\", \"AFG3L2\", \"AIFM1\", \"DNAJC15\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}