{"gene":"OMA1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2003,"finding":"OMA1 (Oma1) is a novel conserved metallopeptidase embedded in the mitochondrial inner membrane that degrades misfolded membrane proteins (e.g., a misfolded derivative of Oxa1) in an ATP-independent manner, with its proteolytic center exposed to the matrix side; it was identified as a component of the mitochondrial inner membrane quality control system overlapping with the m-AAA protease.","method":"Biochemical fractionation, in vitro protease assays, cleavage-site mapping of Oxa1 substrate in yeast","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro assay with substrate cleavage-site mapping and topology determination; foundational discovery paper","pmids":["12963738"],"is_preprint":false},{"year":2009,"finding":"OMA1 mediates stress-induced (loss of membrane potential or ATP) proteolytic cleavage of OPA1 at the S1 site in mammalian cells, converting long OPA1 isoforms to short isoforms and inhibiting mitochondrial fusion; siRNA knockdown of OMA1 inhibits this inducible cleavage, retains fusion competence, and slows apoptosis. OMA1 itself is normally processed from 60 kDa to 40 kDa, and loss of membrane potential causes 60-kDa OMA1 to accumulate, suggesting OMA1 activity is attenuated by proteolytic degradation.","method":"siRNA knockdown, Western blot for OPA1 isoforms, live-cell imaging of mitochondrial morphology, CCCP/oligomycin treatment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, replicated across two independent labs in the same year (PMID 20038677 and 20038678)","pmids":["20038677","20038678"],"is_preprint":false},{"year":2009,"finding":"Two classes of metallopeptidases regulate OPA1 cleavage in the mitochondrial inner membrane: isoenzymes of the m-AAA protease (paraplegin, AFG3L1, AFG3L2) for constitutive processing, and the ATP-independent OMA1 for stress-induced processing. Loss of AFG3L2 or mitochondrial DNA depletion induces OPA1 processing specifically by OMA1, linking distinct peptidases to constitutive versus induced OPA1 cleavage.","method":"Knockout/knockdown of AFG3L1/2, dominant-negative AFG3L2 expression, siRNA, Western blot for OPA1 isoforms, electron microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple KO/KD combinations and orthogonal methods","pmids":["20038678"],"is_preprint":false},{"year":2012,"finding":"In vivo, OMA1 deficiency in mice prevents stress-induced OPA1 proteolytic inactivation, causing a persistent mitochondrial fusion/fission imbalance that results in obesity, hepatic steatosis, decreased energy expenditure, and impaired thermogenesis, establishing OMA1 as essential for metabolic homeostasis via OPA1 regulation.","method":"Oma1 knockout mice, metabolic phenotyping, Western blot for OPA1 isoforms, transcriptional profiling, high-fat diet challenge","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — whole-animal KO with comprehensive metabolic and molecular phenotyping","pmids":["22433842"],"is_preprint":false},{"year":2014,"finding":"YME1L and OMA1 cleave OPA1 at two distinct sites (S2 and S1, respectively) to balance mitochondrial fusion and fission. Long OPA1 forms are sufficient for mitochondrial fusion; short OPA1 forms (generated by OMA1) promote fission and partially colocalize with ER-mitochondria contact sites and the mitochondrial fission machinery. Deletion of OMA1 rescued mitochondrial tubulation, cristae morphogenesis, and apoptotic resistance in YME1L-null cells.","method":"YME1L/OMA1 double knockout cells, mitochondrial morphology imaging, electron microscopy, apoptosis assays, expression of GTPase-inactive short OPA1","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with double-KO and expression rescue; replicated in same lab with prior work","pmids":["24616225"],"is_preprint":false},{"year":2014,"finding":"OMA1 is constitutively active but undergoes strongly enhanced proteolytic activity in response to various stress insults (mitochondrial depolarization, heat, oxidative stress). An N-terminal stress-sensor domain (present only in higher eukaryotes) modulates OMA1 activation. OMA1 activation is coupled to its own autocatalytic degradation initiating from both termini, ensuring reversibility of the stress response and allowing OPA1-mediated fusion to resume upon stress alleviation.","method":"OMA1 truncation/domain mutant analysis, in-cell stress assays, Western blot for OMA1 and OPA1 isoforms, pulse-chase degradation experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis combined with functional proteolysis assays and multiple stress conditions","pmids":["24550258"],"is_preprint":false},{"year":2014,"finding":"Oligomerized Bax and Bak activate OMA1 in a Bax/Bak-dependent fashion during apoptosis; activated OMA1 then cleaves OPA1, which is critical for mitochondrial cristae remodeling. Knockdown or knockout of OMA1 attenuates cytochrome c release, placing OMA1 downstream of Bax/Bak oligomerization in the apoptotic pathway.","method":"Inducible Bim/tBid expression cell lines, OMA1 siRNA/KO, cytochrome c release assays, Western blot for OPA1 isoforms","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — defined epistasis with Bax/Bak upstream; KO with quantitative cytochrome c release readout","pmids":["25275009"],"is_preprint":false},{"year":2014,"finding":"OMA1-mediated OPA1 proteolysis plays a critical role in mitochondrial fragmentation and apoptosis during ischemic acute kidney injury. OMA1 knockdown in renal tubular cells suppressed OPA1 cleavage, mitochondrial fragmentation, cytochrome c release, and apoptosis; OMA1-deficient mice were protected from ischemic AKI with better renal function and less tubular damage.","method":"OMA1 siRNA knockdown in proximal tubular cells, OMA1 knockout mice, ischemia-reperfusion model, Western blot, mitochondrial morphology imaging, renal function assays","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 — both in vitro KD and in vivo KO with consistent phenotypes","pmids":["24671334"],"is_preprint":false},{"year":2014,"finding":"Stress-triggered activation of OMA1 (Oma1) involves conformational changes within its homo-oligomeric complex associated with C-terminal residues. Substitutions in the conserved C-terminal region impair formation of the labile proteolytically active complex in response to stress stimuli. OMA1 genetically interacts with other inner membrane-bound quality control proteases in yeast.","method":"Oma1 C-terminal mutagenesis in yeast, native gel electrophoresis of Oma1 complexes, protease activity assays, genetic interaction screens","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis with biochemical complex analysis, single lab","pmids":["24648523"],"is_preprint":false},{"year":2019,"finding":"PINK1 import into depolarized mitochondria can be cleaved and degraded by the OMA1 protease when PINK1 fails to arrest at the outer mitochondrial membrane. Tom7 and OMA1 exert opposing ('tug-of-war') effects on PINK1 accumulation: deletion of Tom7 allows PINK1 import into depolarized mitochondria where it is cleaved by OMA1, while OMA1 suppression rescues defective import arrest seen with certain Parkinson's disease PINK1 mutations.","method":"Tom7/OMA1 siRNA and KO, PINK1 import assays, PINK1 mutant rescue experiments, Western blot for PINK1 cleavage","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple KO conditions and disease-relevant rescue experiments","pmids":["30733118"],"is_preprint":false},{"year":2019,"finding":"Prohibitin (PHB1/PHB2) promotes OMA1 turnover in neurons, effectively decreasing the pool of active OMA1. OMA1 binds to cardiolipin (CL), a major mitochondrial phospholipid, and CL binding promotes OMA1 turnover; deletion of the CL-binding domain of OMA1 decreases its turnover rate. This PHB-mediated CL stabilization regulates OMA1 activity and downstream cytochrome c release.","method":"PHB2 KO neurons, OMA1 domain deletion mutants, cardiolipin-binding assays, OMA1 turnover pulse-chase experiments, cytochrome c release assays, caspase activation","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis combined with lipid-binding assays and functional turnover measurements","pmids":["31819158"],"is_preprint":false},{"year":2019,"finding":"Oma1 is a redox-dependent protein existing in a semi-oxidized state. Two IMS-exposed conserved cysteine residues (Cys272 and Cys332) form a disulfide bond that plays a structural role influencing conformational stability and proteolytic activity of the Oma1 oligomeric complex. Reduction/oxidation of these residues dynamically tunes Oma1 activity and stability in both yeast and mammalian mitochondria.","method":"Cysteine mutagenesis, redox state analysis by alkylation/gel-shift, in vitro substrate engagement assays, genetic validation in yeast","journal":"Antioxidants & redox signaling","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with biochemical redox characterization and functional substrate assay, cross-species validation","pmids":["31044600"],"is_preprint":false},{"year":2020,"finding":"Mitochondrial stress activates OMA1-dependent cleavage of DELE1, releasing a short DELE1 fragment that accumulates in the cytosol where it interacts with and activates the eIF2α kinase HRI, thereby phosphorylating eIF2α and inducing ATF4 translation—constituting the OMA1-DELE1-HRI pathway that relays mitochondrial stress to the integrated stress response.","method":"Genome-wide CRISPRi screen, OMA1/DELE1/HRI knockdown, DELE1 cleavage assays, co-immunoprecipitation of DELE1 with HRI, eIF2α phosphorylation measurement, ATF4 reporter assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen plus orthogonal KD, co-IP, and functional readouts; replicated in companion paper","pmids":["32132707"],"is_preprint":false},{"year":2020,"finding":"Loss of both CHCHD2 and CHCHD10 activates OMA1, which cleaves L-OPA1, causing disrupted mitochondrial cristae. OMA1 activation similarly occurs in affected tissues of mutant CHCHD10 knock-in mice. Partial functional redundancy between CHCHD2 and CHCHD10 was demonstrated using OMA1 activation as a functional assay.","method":"CHCHD2/CHCHD10 double-knockout mice, CHCHD10 knock-in mice, OMA1 activity/OPA1 cleavage assays, electron microscopy, cardiomyopathy phenotyping","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple KO/KI mouse models with OMA1-dependent molecular and ultrastructural readouts","pmids":["32338760"],"is_preprint":false},{"year":2021,"finding":"OMA1 associates dynamically with the MICOS complex via the subunit MIC60, independently of OPA1. This OMA1-MICOS association is required for stability of MICOS and intermembrane contacts, as well as for optimal bioenergetic output and apoptosis. Loss of OMA1 disrupts these activities, which can be alleviated by a MICOS-emulating intermembrane bridge.","method":"Co-immunoprecipitation of OMA1 with MICOS subunits, OMA1 KO cells, bioenergetics assays, synthetic rescue with intermembrane bridge construct","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 3/2 — reciprocal co-IP with functional follow-up, single lab","pmids":["33644718"],"is_preprint":false},{"year":2022,"finding":"In CHCHD10 mitochondrial myopathy, OMA1 mediates a coordinated local and global stress response: locally, OMA1 drives mitochondrial fragmentation; globally, OMA1 cleaves DELE1 to activate the integrated stress response. OMA1-dependent survival was essential for neonatal survival in CHCHD10-KI mice conditionally under inner mitochondrial membrane stress.","method":"CHCHD10 knock-in mouse model, OMA1 KO crosses, DELE1 cleavage assays, mitochondrial morphology, survival analysis, isoform profiling","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with orthogonal molecular and morphological readouts","pmids":["35700042"],"is_preprint":false},{"year":2023,"finding":"TIM23 forms a physical complex with PINK1 and facilitates PINK1 accumulation by protecting it from OMA1-mediated degradation upon mitochondrial depolarization. Inactivation of OMA1 enhances PINK1 accumulation and compensates for TIM23 downregulation, and rescues defects in pathogenic PINK1 mutants that fail to interact with TIM23.","method":"Mass spectrometry of PINK1 co-immunoprecipitates, TIM23 knockdown, OMA1 KO, PINK1 autophosphorylation assays, PINK1 mutant rescue experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — MS-based interaction discovery plus genetic epistasis with PINK1 mutant rescue","pmids":["37160114"],"is_preprint":false},{"year":2023,"finding":"Mitochondrial cysteine 403 of OMA1 constitutes a redox-sensing site in mammalian cells. Prime editing of OMA1 C403A in mouse sarcoma cells impaired mitochondrial stress responses including ATP production, mitochondrial fission, and apoptosis, and enhanced mitochondrial DNA release, demonstrating a functional redox switch.","method":"Prime editing (C403A mutation), mitochondrial stress assays, mitochondrial DNA release measurement, apoptosis assays, immunocompetent tumor models","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 1 — precise in-cell mutagenesis with multiple functional readouts, single lab","pmids":["37024121"],"is_preprint":false},{"year":2023,"finding":"OMA1 protects against DNA damage-induced apoptosis through metabolic control of glycolysis rather than through OPA1 or DELE1 processing. OMA1-deficient cells show reduced glycolysis and accumulate OXPHOS proteins upon DNA damage; OXPHOS inhibition restores glycolysis and resistance to DNA damage.","method":"CRISPR screen (metabolism-focused), OMA1 KO cells, metabolic flux assays, OXPHOS inhibitor rescue, apoptosis assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR screen with mechanistic metabolic follow-up, single lab","pmids":["37002921"],"is_preprint":false},{"year":2024,"finding":"OMA1 cleaves arrested import intermediates in the mitochondrial translocase upon mitochondrial membrane depolarization in human cells, releasing the stalled protein fragment from the translocase channel. The released fragment is subsequently cleared in the cytosol by VCP/p97 and the proteasome.","method":"Translocase clogging cell model, OMA1 KO/KD, Western blot for cleavage fragments, VCP/proteasome inhibitors","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — defined substrate cleavage assay combined with genetic KO and pharmacological epistasis","pmids":["38530280"],"is_preprint":false},{"year":2024,"finding":"OMA1-dependent OPA1 processing is sensitive to both mitochondrial membrane potential depolarization and oxidative stress in neuronal cells; oxidative stress is necessary for depolarization-induced OMA1-mediated proteolysis. OMA1 KO cells show exacerbated acute mitochondrial fragmentation but better restorative fusion after stress due to preserved L-OPA1.","method":"OMA1 KO HT22 cells, mitochondrial morphology imaging, ROS measurement, oxygen-glucose deprivation/reoxygenation model, OPA1 isoform Western blot","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — KO with multiple stress paradigms, single lab","pmids":["39312414"],"is_preprint":false},{"year":2025,"finding":"Parkin (ubiquitin E3 ligase) and OMA1 (metalloprotease) constitute a dual regulatory system that safeguards mitochondrial structure and genome via 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 whole-body and tissue-specific KO and mutant mice, mitochondrial morphology analysis, untargeted metabolomics, RNA sequencing","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — systematic genetic epistasis across 18 mouse models with comprehensive molecular phenotyping","pmids":["39972141"],"is_preprint":false},{"year":2026,"finding":"OMA1 cleaves AIFM1 (AIF/apoptosis-inducing factor) in the intermembrane space under mitochondrial stress conditions, with slower kinetics than OPA1 cleavage. This OMA1-mediated AIFM1 dislocation from the inner membrane reduces AIFM1 interactions with OXPHOS subunits, decreasing respiratory activity and impairing cell growth. Under steady-state conditions, AIFM1 broadly mediates import of respiratory complex I subunits via the TIM23 complex.","method":"In vitro and in vivo multiproteomic approaches, biochemical cleavage assays, OMA1 KO, co-immunoprecipitation of AIFM1 with OXPHOS subunits, respiratory activity measurement, mitochondrial protein import assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro cleavage reconstitution plus multiproteomic and genetic validation","pmids":["41876740"],"is_preprint":false},{"year":2026,"finding":"OMA1 cleaves the mitochondrial chaperone DNAJC15, promoting its degradation by the m-AAA protease AFG3L2 under cellular stress. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction; non-imported preproteins accumulate at the ER, inducing an unfolded protein response.","method":"OMA1 KO, DNAJC15 cleavage assays, m-AAA protease interaction experiments, mitochondrial protein import assays, OXPHOS biogenesis quantification, ER stress reporters","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — substrate cleavage reconstitution with downstream import and ER stress functional validation","pmids":["41760807"],"is_preprint":false},{"year":2018,"finding":"Leptin-mediated protection of mitochondrial integrity in mesenchymal stem cells requires GSK3 phosphorylation as a prerequisite for ubiquitination-dependent proteasomal degradation of OMA1, thereby attenuating OMA1-mediated OPA1 cleavage. The proteasome inhibitor MG132 prevented leptin-induced OMA1 degradation, and GSK3 inhibitor (SB216763) also reduced OMA1 levels.","method":"Leptin treatment of hMSCs, MG132/GSK3 inhibitor treatment, OMA1/OPA1 Western blot, OPA1 siRNA rescue, mitochondrial morphology imaging","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological inhibitors with Western blot readouts, single lab","pmids":["29748581"],"is_preprint":false},{"year":2019,"finding":"OMA1 links mitochondrial protein quality control to TOR signaling in yeast: inactivation of Oma1 leads to enhanced ROS production during logarithmic growth and reduced stress signaling via the TORC1-Rim15-Msn2/Msn4 axis. Pharmacological or genetic ROS prevention in Oma1-deficient cells restores defective TOR signaling.","method":"Oma1 KO yeast, ROS measurement, genetic epistasis with TORC1 pathway components, pharmacological ROS inhibition","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with orthogonal metabolic and signaling readouts in yeast ortholog","pmids":["27325672"],"is_preprint":false},{"year":2024,"finding":"OMA1 competitively binds to HSPA9 in glioblastoma cells, inducing mitophagy and promoting cGAS-STING activation through increased mitochondrial DNA release, which upregulates PD-L1 transcription and contributes to immune evasion.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, OMA1 KD, cGAS-STING pathway assays, PD-L1 measurement","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP/MS with functional KD, single lab","pmids":["38604814"],"is_preprint":false}],"current_model":"OMA1 is a mitochondrial inner membrane zinc metalloprotease that functions as a stress sensor: under basal conditions it is largely dormant, but upon mitochondrial stress (loss of membrane potential, oxidative stress, protein misfolding, apoptotic signals) OMA1 undergoes conformational activation—regulated by redox-sensitive disulfide bonds (Cys272/Cys332), cardiolipin binding, and prohibitin scaffolding—and cleaves multiple substrates including OPA1 (inhibiting inner membrane fusion and driving fragmentation), DELE1 (releasing a cytosolic fragment that activates the eIF2α kinase HRI to trigger the integrated stress response), AIFM1 (reducing OXPHOS activity), DNAJC15 (restricting mitochondrial protein import), and arrested import intermediates; OMA1 activation is coupled to its own autocatalytic degradation (ensuring reversibility), is positioned downstream of Bax/Bak oligomerization in apoptosis and upstream of PINK1/Parkin-mediated mitophagy, and acts in concert with Parkin to maintain mitochondrial fusion and genome integrity under physiological conditions."},"narrative":{"teleology":[{"year":2003,"claim":"The foundational question of whether mitochondria possess an ATP-independent inner membrane quality control protease was answered by identification of Oma1 as a metallopeptidase that degrades misfolded membrane proteins like Oxa1 derivatives, establishing a new proteolytic pathway distinct from m-AAA protease function.","evidence":"Biochemical fractionation, in vitro protease assays, and cleavage-site mapping of Oxa1 substrate in yeast","pmids":["12963738"],"confidence":"High","gaps":["Mammalian substrate specificity unknown","No structural information on OMA1","Relationship to mitochondrial dynamics not yet explored"]},{"year":2009,"claim":"The critical question of which protease mediates stress-induced OPA1 processing was resolved: OMA1 cleaves OPA1 at the S1 site upon loss of membrane potential, converting long fusion-competent OPA1 to short forms and inhibiting mitochondrial fusion, while constitutive OPA1 processing depends on m-AAA proteases—establishing OMA1 as the stress-responsive arm of OPA1 regulation.","evidence":"siRNA knockdown in mammalian cells, OPA1 isoform Western blot, mitochondrial morphology imaging, CCCP/oligomycin treatment, replicated across two independent laboratories","pmids":["20038677","20038678"],"confidence":"High","gaps":["Mechanism of OMA1 activation by stress unknown","In vivo physiological relevance not yet tested","Whether OMA1 has substrates beyond OPA1 unclear"]},{"year":2012,"claim":"The physiological relevance of OMA1 was established in vivo: OMA1-knockout mice showed that loss of stress-induced OPA1 processing causes persistent mitochondrial hyperfusion leading to obesity, hepatic steatosis, and impaired thermogenesis, demonstrating OMA1 is essential for metabolic homeostasis.","evidence":"Oma1 knockout mice with comprehensive metabolic phenotyping, high-fat diet challenge, OPA1 isoform analysis","pmids":["22433842"],"confidence":"High","gaps":["Whether metabolic phenotype is entirely OPA1-dependent or involves other substrates unknown","Tissue-specific requirements of OMA1 not dissected"]},{"year":2014,"claim":"Multiple advances resolved how OMA1 is activated and regulated, and positioned it in the apoptotic cascade: OMA1 possesses an N-terminal stress-sensor domain and undergoes autocatalytic self-degradation ensuring reversibility; its C-terminal domain mediates stress-responsive oligomeric conformational changes; Bax/Bak oligomerization activates OMA1 upstream of cristae remodeling and cytochrome c release; and OMA1-generated short OPA1 forms promote fission at ER-mitochondria contact sites.","evidence":"Domain mutagenesis, native gel electrophoresis, pulse-chase degradation, inducible Bim/tBid expression, OMA1 KO/KD with cytochrome c release assays, YME1L/OMA1 double-knockout epistasis, electron microscopy, ischemia-reperfusion kidney injury model","pmids":["24550258","24648523","25275009","24616225","24671334"],"confidence":"High","gaps":["Molecular details of how Bax/Bak signal reaches OMA1 unclear","Whether autocatalytic degradation occurs in trans or cis unknown","Structural basis of stress-sensor domain function unresolved"]},{"year":2019,"claim":"Three regulatory layers of OMA1 were uncovered: OMA1 activity is tuned by redox-sensitive IMS-exposed disulfide bonds (Cys272/Cys332); prohibitin scaffolds and cardiolipin binding promote OMA1 turnover to limit its activity; and OMA1 degrades imported PINK1 in depolarized mitochondria, opposing Tom7-mediated PINK1 stabilization—linking OMA1 to PINK1/Parkin mitophagy signaling.","evidence":"Cysteine mutagenesis with redox state analysis in yeast and mammalian cells; PHB2-KO neurons with cardiolipin-binding domain deletions and turnover assays; Tom7/OMA1 KO epistasis with PINK1 import and Parkinson's-relevant mutant rescue","pmids":["31044600","31819158","30733118"],"confidence":"High","gaps":["How cardiolipin binding mechanistically promotes OMA1 turnover is unclear","Relative contribution of redox versus depolarization sensing in vivo not quantified","Whether OMA1-PINK1 regulation is tissue-specific unknown"]},{"year":2020,"claim":"A genome-wide screen revealed that OMA1 relays mitochondrial stress to the cytosol by cleaving DELE1, whose released fragment activates the eIF2α kinase HRI to induce the integrated stress response and ATF4 translation—establishing the OMA1-DELE1-HRI pathway as a mitochondria-to-nucleus stress signaling axis.","evidence":"Genome-wide CRISPRi screen, OMA1/DELE1/HRI knockdown, DELE1-HRI co-immunoprecipitation, eIF2α phosphorylation and ATF4 reporter assays","pmids":["32132707"],"confidence":"High","gaps":["Full spectrum of ISR target genes activated by this pathway not catalogued","Whether OMA1-DELE1-HRI operates in all tissues equally unknown","Structural basis of DELE1 cleavage site recognition unresolved"]},{"year":2022,"claim":"The in vivo survival function of OMA1's dual signaling was demonstrated: in CHCHD10 mitochondrial myopathy mice, OMA1 coordinates both local fragmentation and global ISR activation via DELE1, and OMA1-dependent responses are essential for neonatal survival under inner membrane stress.","evidence":"CHCHD10 knock-in mouse model crossed with OMA1 KO, DELE1 cleavage assays, survival analysis, mitochondrial morphology","pmids":["35700042"],"confidence":"High","gaps":["Whether pharmacological OMA1 modulation can rescue CHCHD10 disease unknown","Relative contribution of OPA1 versus DELE1 cleavage to survival not separated"]},{"year":2023,"claim":"Additional regulatory and functional dimensions were defined: mammalian Cys403 acts as a redox switch controlling OMA1 stress responses; TIM23 physically protects PINK1 from OMA1-mediated degradation; and OMA1 protects against DNA damage-induced apoptosis through metabolic control of glycolysis independent of OPA1 or DELE1.","evidence":"Prime editing of C403A in mouse cells with mitochondrial stress/apoptosis assays; PINK1 co-IP mass spectrometry with TIM23 KD and OMA1 KO epistasis; CRISPR metabolism screen with metabolic flux analysis in OMA1-KO cells","pmids":["37024121","37160114","37002921"],"confidence":"Medium","gaps":["Whether C403 redox sensing is mechanistically linked to the Cys272/Cys332 disulfide is unknown","Glycolysis-regulatory substrate of OMA1 not identified","Structural basis of TIM23-PINK1 protection from OMA1 unclear"]},{"year":2024,"claim":"OMA1's substrate repertoire was expanded to include arrested translocase import intermediates, which OMA1 cleaves upon depolarization to unclog the TIM23 channel, with released fragments cleared by cytosolic VCP/p97 and the proteasome—revealing OMA1 as a translocase rescue factor.","evidence":"Translocase clogging cell model, OMA1 KO/KD, cleavage fragment analysis, VCP/proteasome inhibitor epistasis","pmids":["38530280"],"confidence":"High","gaps":["How OMA1 accesses substrates stuck in the translocase channel is structurally unresolved","Scope of physiological import intermediates cleaved by OMA1 not determined"]},{"year":2025,"claim":"Systematic genetic epistasis across 18 mouse models revealed that Parkin and OMA1 constitute a dual regulatory system safeguarding mitochondrial fusion and genome integrity through MFN1 and OPA1 respectively; combined loss causes severe organismal defects including premature death and innate immune activation, while individual loss is tolerated.","evidence":"18 single/double/triple whole-body and tissue-specific KO mice, metabolomics, RNA sequencing","pmids":["39972141"],"confidence":"High","gaps":["Whether Parkin-OMA1 cooperation involves direct physical interaction unknown","Mechanism linking combined loss to innate immune activation not fully defined"]},{"year":2026,"claim":"Two new OMA1 substrates were identified that expand its role beyond dynamics: OMA1 cleaves AIFM1 in the IMS with slower kinetics than OPA1, reducing OXPHOS by dislocating AIFM1 from respiratory complexes; and OMA1 cleaves the mitochondrial chaperone DNAJC15, whose subsequent degradation by AFG3L2 restricts protein import and OXPHOS biogenesis under stress, with non-imported preproteins triggering ER UPR.","evidence":"In vitro cleavage reconstitution, multiproteomic approaches, OMA1 KO, co-IP of AIFM1 with OXPHOS subunits, mitochondrial import assays, ER stress reporters","pmids":["41876740","41760807"],"confidence":"High","gaps":["Complete substrate degradome of OMA1 not yet defined","How OMA1 achieves differential cleavage kinetics between substrates is structurally unclear","Whether AIFM1 and DNAJC15 cleavage are relevant in vivo in specific tissues not tested"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of OMA1 and how it achieves substrate selectivity, the full in vivo substrate repertoire, whether the glycolysis-protective function involves an unidentified substrate, and whether pharmacological modulation of OMA1 is therapeutically tractable in mitochondrial diseases or neurodegeneration.","evidence":"Open question based on gaps across the literature","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of OMA1 exists","Complete degradome not catalogued by unbiased proteomics","Therapeutic targeting not explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4,5,6,12,19,22,23]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,22,23]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5,11,17]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,5,10,14]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,7,22]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,12,15,17]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,4,14,21]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,19,23]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,18]}],"complexes":["OMA1 homo-oligomeric complex","OMA1-MICOS complex"],"partners":["OPA1","DELE1","PINK1","AIFM1","DNAJC15","MIC60","PHB2","HSPA9"],"other_free_text":[]},"mechanistic_narrative":"OMA1 is a mitochondrial inner membrane zinc metalloprotease that functions as a stress-responsive quality control hub, integrating signals from membrane depolarization, oxidative stress, and protein misfolding to remodel mitochondrial dynamics, cristae architecture, bioenergetics, and protein import. Under basal conditions OMA1 is largely quiescent, but upon stress it undergoes conformational activation—regulated by redox-sensitive disulfide bonds (Cys272/Cys332 and Cys403), cardiolipin binding, and prohibitin-mediated turnover—and cleaves key substrates including OPA1 at the S1 site (driving mitochondrial fragmentation and cytochrome c release during apoptosis), DELE1 (activating the HRI-eIF2α integrated stress response), AIFM1 (reducing OXPHOS capacity), DNAJC15 (restricting mitochondrial protein import), and arrested translocase intermediates, while also degrading misfolded inner membrane proteins [PMID:12963738, PMID:20038677, PMID:32132707, PMID:41876740, PMID:41760807, PMID:38530280]. OMA1 activation is coupled to its own autocatalytic degradation, ensuring reversibility of the stress response, and is positioned downstream of Bax/Bak oligomerization in apoptosis and upstream of PINK1 stabilization in mitophagy, with OMA1-mediated PINK1 degradation counterbalanced by TIM23-dependent protection [PMID:24550258, PMID:25275009, PMID:30733118, PMID:37160114]. OMA1 cooperates with Parkin to maintain mitochondrial fusion and genome integrity under physiological conditions; combined loss of both causes severe organismal phenotypes including premature death and innate immune activation, while individual loss of OMA1 in mice causes obesity and impaired thermogenesis through persistent OPA1-dependent hyperfusion [PMID:39972141, PMID:22433842]."},"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":644,"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":504,"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":476,"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":413,"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":275,"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":225,"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":181,"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":152,"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":138,"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":125,"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":107,"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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Cells","date":"2025-06-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.23.660251","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.30.621162","title":"H<sub>2</sub>S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.30.621162","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.05.606704","title":"Mfn2 induces NCLX-mediated calcium release from 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protease.\",\n      \"method\": \"Biochemical fractionation, in vitro protease assays, cleavage-site mapping of Oxa1 substrate in yeast\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro assay with substrate cleavage-site mapping and topology determination; foundational discovery paper\",\n      \"pmids\": [\"12963738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"OMA1 mediates stress-induced (loss of membrane potential or ATP) proteolytic cleavage of OPA1 at the S1 site in mammalian cells, converting long OPA1 isoforms to short isoforms and inhibiting mitochondrial fusion; siRNA knockdown of OMA1 inhibits this inducible cleavage, retains fusion competence, and slows apoptosis. OMA1 itself is normally processed from 60 kDa to 40 kDa, and loss of membrane potential causes 60-kDa OMA1 to accumulate, suggesting OMA1 activity is attenuated by proteolytic degradation.\",\n      \"method\": \"siRNA knockdown, Western blot for OPA1 isoforms, live-cell imaging of mitochondrial morphology, CCCP/oligomycin treatment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, replicated across two independent labs in the same year (PMID 20038677 and 20038678)\",\n      \"pmids\": [\"20038677\", \"20038678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Two classes of metallopeptidases regulate OPA1 cleavage in the mitochondrial inner membrane: isoenzymes of the m-AAA protease (paraplegin, AFG3L1, AFG3L2) for constitutive processing, and the ATP-independent OMA1 for stress-induced processing. Loss of AFG3L2 or mitochondrial DNA depletion induces OPA1 processing specifically by OMA1, linking distinct peptidases to constitutive versus induced OPA1 cleavage.\",\n      \"method\": \"Knockout/knockdown of AFG3L1/2, dominant-negative AFG3L2 expression, siRNA, Western blot for OPA1 isoforms, electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple KO/KD combinations and orthogonal methods\",\n      \"pmids\": [\"20038678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In vivo, OMA1 deficiency in mice prevents stress-induced OPA1 proteolytic inactivation, causing a persistent mitochondrial fusion/fission imbalance that results in obesity, hepatic steatosis, decreased energy expenditure, and impaired thermogenesis, establishing OMA1 as essential for metabolic homeostasis via OPA1 regulation.\",\n      \"method\": \"Oma1 knockout mice, metabolic phenotyping, Western blot for OPA1 isoforms, transcriptional profiling, high-fat diet challenge\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — whole-animal KO with comprehensive metabolic and molecular phenotyping\",\n      \"pmids\": [\"22433842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"YME1L and OMA1 cleave OPA1 at two distinct sites (S2 and S1, respectively) to balance mitochondrial fusion and fission. Long OPA1 forms are sufficient for mitochondrial fusion; short OPA1 forms (generated by OMA1) promote fission and partially colocalize with ER-mitochondria contact sites and the mitochondrial fission machinery. Deletion of OMA1 rescued mitochondrial tubulation, cristae morphogenesis, and apoptotic resistance in YME1L-null cells.\",\n      \"method\": \"YME1L/OMA1 double knockout cells, mitochondrial morphology imaging, electron microscopy, apoptosis assays, expression of GTPase-inactive short OPA1\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with double-KO and expression rescue; replicated in same lab with prior work\",\n      \"pmids\": [\"24616225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OMA1 is constitutively active but undergoes strongly enhanced proteolytic activity in response to various stress insults (mitochondrial depolarization, heat, oxidative stress). An N-terminal stress-sensor domain (present only in higher eukaryotes) modulates OMA1 activation. OMA1 activation is coupled to its own autocatalytic degradation initiating from both termini, ensuring reversibility of the stress response and allowing OPA1-mediated fusion to resume upon stress alleviation.\",\n      \"method\": \"OMA1 truncation/domain mutant analysis, in-cell stress assays, Western blot for OMA1 and OPA1 isoforms, pulse-chase degradation experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis combined with functional proteolysis assays and multiple stress conditions\",\n      \"pmids\": [\"24550258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Oligomerized Bax and Bak activate OMA1 in a Bax/Bak-dependent fashion during apoptosis; activated OMA1 then cleaves OPA1, which is critical for mitochondrial cristae remodeling. Knockdown or knockout of OMA1 attenuates cytochrome c release, placing OMA1 downstream of Bax/Bak oligomerization in the apoptotic pathway.\",\n      \"method\": \"Inducible Bim/tBid expression cell lines, OMA1 siRNA/KO, cytochrome c release assays, Western blot for OPA1 isoforms\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined epistasis with Bax/Bak upstream; KO with quantitative cytochrome c release readout\",\n      \"pmids\": [\"25275009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OMA1-mediated OPA1 proteolysis plays a critical role in mitochondrial fragmentation and apoptosis during ischemic acute kidney injury. OMA1 knockdown in renal tubular cells suppressed OPA1 cleavage, mitochondrial fragmentation, cytochrome c release, and apoptosis; OMA1-deficient mice were protected from ischemic AKI with better renal function and less tubular damage.\",\n      \"method\": \"OMA1 siRNA knockdown in proximal tubular cells, OMA1 knockout mice, ischemia-reperfusion model, Western blot, mitochondrial morphology imaging, renal function assays\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — both in vitro KD and in vivo KO with consistent phenotypes\",\n      \"pmids\": [\"24671334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Stress-triggered activation of OMA1 (Oma1) involves conformational changes within its homo-oligomeric complex associated with C-terminal residues. Substitutions in the conserved C-terminal region impair formation of the labile proteolytically active complex in response to stress stimuli. OMA1 genetically interacts with other inner membrane-bound quality control proteases in yeast.\",\n      \"method\": \"Oma1 C-terminal mutagenesis in yeast, native gel electrophoresis of Oma1 complexes, protease activity assays, genetic interaction screens\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with biochemical complex analysis, single lab\",\n      \"pmids\": [\"24648523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PINK1 import into depolarized mitochondria can be cleaved and degraded by the OMA1 protease when PINK1 fails to arrest at the outer mitochondrial membrane. Tom7 and OMA1 exert opposing ('tug-of-war') effects on PINK1 accumulation: deletion of Tom7 allows PINK1 import into depolarized mitochondria where it is cleaved by OMA1, while OMA1 suppression rescues defective import arrest seen with certain Parkinson's disease PINK1 mutations.\",\n      \"method\": \"Tom7/OMA1 siRNA and KO, PINK1 import assays, PINK1 mutant rescue experiments, Western blot for PINK1 cleavage\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple KO conditions and disease-relevant rescue experiments\",\n      \"pmids\": [\"30733118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Prohibitin (PHB1/PHB2) promotes OMA1 turnover in neurons, effectively decreasing the pool of active OMA1. OMA1 binds to cardiolipin (CL), a major mitochondrial phospholipid, and CL binding promotes OMA1 turnover; deletion of the CL-binding domain of OMA1 decreases its turnover rate. This PHB-mediated CL stabilization regulates OMA1 activity and downstream cytochrome c release.\",\n      \"method\": \"PHB2 KO neurons, OMA1 domain deletion mutants, cardiolipin-binding assays, OMA1 turnover pulse-chase experiments, cytochrome c release assays, caspase activation\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis combined with lipid-binding assays and functional turnover measurements\",\n      \"pmids\": [\"31819158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oma1 is a redox-dependent protein existing in a semi-oxidized state. Two IMS-exposed conserved cysteine residues (Cys272 and Cys332) form a disulfide bond that plays a structural role influencing conformational stability and proteolytic activity of the Oma1 oligomeric complex. Reduction/oxidation of these residues dynamically tunes Oma1 activity and stability in both yeast and mammalian mitochondria.\",\n      \"method\": \"Cysteine mutagenesis, redox state analysis by alkylation/gel-shift, in vitro substrate engagement assays, genetic validation in yeast\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with biochemical redox characterization and functional substrate assay, cross-species validation\",\n      \"pmids\": [\"31044600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mitochondrial stress activates OMA1-dependent cleavage of DELE1, releasing a short DELE1 fragment that accumulates in the cytosol where it interacts with and activates the eIF2α kinase HRI, thereby phosphorylating eIF2α and inducing ATF4 translation—constituting the OMA1-DELE1-HRI pathway that relays mitochondrial stress to the integrated stress response.\",\n      \"method\": \"Genome-wide CRISPRi screen, OMA1/DELE1/HRI knockdown, DELE1 cleavage assays, co-immunoprecipitation of DELE1 with HRI, eIF2α phosphorylation measurement, ATF4 reporter assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen plus orthogonal KD, co-IP, and functional readouts; replicated in companion paper\",\n      \"pmids\": [\"32132707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of both CHCHD2 and CHCHD10 activates OMA1, which cleaves L-OPA1, causing disrupted mitochondrial cristae. OMA1 activation similarly occurs in affected tissues of mutant CHCHD10 knock-in mice. Partial functional redundancy between CHCHD2 and CHCHD10 was demonstrated using OMA1 activation as a functional assay.\",\n      \"method\": \"CHCHD2/CHCHD10 double-knockout mice, CHCHD10 knock-in mice, OMA1 activity/OPA1 cleavage assays, electron microscopy, cardiomyopathy phenotyping\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple KO/KI mouse models with OMA1-dependent molecular and ultrastructural readouts\",\n      \"pmids\": [\"32338760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OMA1 associates dynamically with the MICOS complex via the subunit MIC60, independently of OPA1. This OMA1-MICOS association is required for stability of MICOS and intermembrane contacts, as well as for optimal bioenergetic output and apoptosis. Loss of OMA1 disrupts these activities, which can be alleviated by a MICOS-emulating intermembrane bridge.\",\n      \"method\": \"Co-immunoprecipitation of OMA1 with MICOS subunits, OMA1 KO cells, bioenergetics assays, synthetic rescue with intermembrane bridge construct\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3/2 — reciprocal co-IP with functional follow-up, single lab\",\n      \"pmids\": [\"33644718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In CHCHD10 mitochondrial myopathy, OMA1 mediates a coordinated local and global stress response: locally, OMA1 drives mitochondrial fragmentation; globally, OMA1 cleaves DELE1 to activate the integrated stress response. OMA1-dependent survival was essential for neonatal survival in CHCHD10-KI mice conditionally under inner mitochondrial membrane stress.\",\n      \"method\": \"CHCHD10 knock-in mouse model, OMA1 KO crosses, DELE1 cleavage assays, mitochondrial morphology, survival analysis, isoform profiling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with orthogonal molecular and morphological readouts\",\n      \"pmids\": [\"35700042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TIM23 forms a physical complex with PINK1 and facilitates PINK1 accumulation by protecting it from OMA1-mediated degradation upon mitochondrial depolarization. Inactivation of OMA1 enhances PINK1 accumulation and compensates for TIM23 downregulation, and rescues defects in pathogenic PINK1 mutants that fail to interact with TIM23.\",\n      \"method\": \"Mass spectrometry of PINK1 co-immunoprecipitates, TIM23 knockdown, OMA1 KO, PINK1 autophosphorylation assays, PINK1 mutant rescue experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-based interaction discovery plus genetic epistasis with PINK1 mutant rescue\",\n      \"pmids\": [\"37160114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mitochondrial cysteine 403 of OMA1 constitutes a redox-sensing site in mammalian cells. Prime editing of OMA1 C403A in mouse sarcoma cells impaired mitochondrial stress responses including ATP production, mitochondrial fission, and apoptosis, and enhanced mitochondrial DNA release, demonstrating a functional redox switch.\",\n      \"method\": \"Prime editing (C403A mutation), mitochondrial stress assays, mitochondrial DNA release measurement, apoptosis assays, immunocompetent tumor models\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — precise in-cell mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"37024121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OMA1 protects against DNA damage-induced apoptosis through metabolic control of glycolysis rather than through OPA1 or DELE1 processing. OMA1-deficient cells show reduced glycolysis and accumulate OXPHOS proteins upon DNA damage; OXPHOS inhibition restores glycolysis and resistance to DNA damage.\",\n      \"method\": \"CRISPR screen (metabolism-focused), OMA1 KO cells, metabolic flux assays, OXPHOS inhibitor rescue, apoptosis assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen with mechanistic metabolic follow-up, single lab\",\n      \"pmids\": [\"37002921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OMA1 cleaves arrested import intermediates in the mitochondrial translocase upon mitochondrial membrane depolarization in human cells, releasing the stalled protein fragment from the translocase channel. The released fragment is subsequently cleared in the cytosol by VCP/p97 and the proteasome.\",\n      \"method\": \"Translocase clogging cell model, OMA1 KO/KD, Western blot for cleavage fragments, VCP/proteasome inhibitors\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined substrate cleavage assay combined with genetic KO and pharmacological epistasis\",\n      \"pmids\": [\"38530280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OMA1-dependent OPA1 processing is sensitive to both mitochondrial membrane potential depolarization and oxidative stress in neuronal cells; oxidative stress is necessary for depolarization-induced OMA1-mediated proteolysis. OMA1 KO cells show exacerbated acute mitochondrial fragmentation but better restorative fusion after stress due to preserved L-OPA1.\",\n      \"method\": \"OMA1 KO HT22 cells, mitochondrial morphology imaging, ROS measurement, oxygen-glucose deprivation/reoxygenation model, OPA1 isoform Western blot\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple stress paradigms, single lab\",\n      \"pmids\": [\"39312414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Parkin (ubiquitin E3 ligase) and OMA1 (metalloprotease) constitute a dual regulatory system that safeguards mitochondrial structure and genome via 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 whole-body and tissue-specific KO and mutant mice, mitochondrial morphology analysis, untargeted metabolomics, RNA sequencing\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic genetic epistasis across 18 mouse models with comprehensive molecular phenotyping\",\n      \"pmids\": [\"39972141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OMA1 cleaves AIFM1 (AIF/apoptosis-inducing factor) in the intermembrane space under mitochondrial stress conditions, with slower kinetics than OPA1 cleavage. This OMA1-mediated AIFM1 dislocation from the inner membrane reduces AIFM1 interactions with OXPHOS subunits, decreasing respiratory activity and impairing cell growth. Under steady-state conditions, AIFM1 broadly mediates import of respiratory complex I subunits via the TIM23 complex.\",\n      \"method\": \"In vitro and in vivo multiproteomic approaches, biochemical cleavage assays, OMA1 KO, co-immunoprecipitation of AIFM1 with OXPHOS subunits, respiratory activity measurement, mitochondrial protein import assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage reconstitution plus multiproteomic and genetic validation\",\n      \"pmids\": [\"41876740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OMA1 cleaves the mitochondrial chaperone DNAJC15, promoting its degradation by the m-AAA protease AFG3L2 under cellular stress. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction; non-imported preproteins accumulate at the ER, inducing an unfolded protein response.\",\n      \"method\": \"OMA1 KO, DNAJC15 cleavage assays, m-AAA protease interaction experiments, mitochondrial protein import assays, OXPHOS biogenesis quantification, ER stress reporters\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — substrate cleavage reconstitution with downstream import and ER stress functional validation\",\n      \"pmids\": [\"41760807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Leptin-mediated protection of mitochondrial integrity in mesenchymal stem cells requires GSK3 phosphorylation as a prerequisite for ubiquitination-dependent proteasomal degradation of OMA1, thereby attenuating OMA1-mediated OPA1 cleavage. The proteasome inhibitor MG132 prevented leptin-induced OMA1 degradation, and GSK3 inhibitor (SB216763) also reduced OMA1 levels.\",\n      \"method\": \"Leptin treatment of hMSCs, MG132/GSK3 inhibitor treatment, OMA1/OPA1 Western blot, OPA1 siRNA rescue, mitochondrial morphology imaging\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological inhibitors with Western blot readouts, single lab\",\n      \"pmids\": [\"29748581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OMA1 links mitochondrial protein quality control to TOR signaling in yeast: inactivation of Oma1 leads to enhanced ROS production during logarithmic growth and reduced stress signaling via the TORC1-Rim15-Msn2/Msn4 axis. Pharmacological or genetic ROS prevention in Oma1-deficient cells restores defective TOR signaling.\",\n      \"method\": \"Oma1 KO yeast, ROS measurement, genetic epistasis with TORC1 pathway components, pharmacological ROS inhibition\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with orthogonal metabolic and signaling readouts in yeast ortholog\",\n      \"pmids\": [\"27325672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OMA1 competitively binds to HSPA9 in glioblastoma cells, inducing mitophagy and promoting cGAS-STING activation through increased mitochondrial DNA release, which upregulates PD-L1 transcription and contributes to immune evasion.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, OMA1 KD, cGAS-STING pathway assays, PD-L1 measurement\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP/MS with functional KD, single lab\",\n      \"pmids\": [\"38604814\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OMA1 is a mitochondrial inner membrane zinc metalloprotease that functions as a stress sensor: under basal conditions it is largely dormant, but upon mitochondrial stress (loss of membrane potential, oxidative stress, protein misfolding, apoptotic signals) OMA1 undergoes conformational activation—regulated by redox-sensitive disulfide bonds (Cys272/Cys332), cardiolipin binding, and prohibitin scaffolding—and cleaves multiple substrates including OPA1 (inhibiting inner membrane fusion and driving fragmentation), DELE1 (releasing a cytosolic fragment that activates the eIF2α kinase HRI to trigger the integrated stress response), AIFM1 (reducing OXPHOS activity), DNAJC15 (restricting mitochondrial protein import), and arrested import intermediates; OMA1 activation is coupled to its own autocatalytic degradation (ensuring reversibility), is positioned downstream of Bax/Bak oligomerization in apoptosis and upstream of PINK1/Parkin-mediated mitophagy, and acts in concert with Parkin to maintain mitochondrial fusion and genome integrity under physiological conditions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OMA1 is a mitochondrial inner membrane zinc metalloprotease that functions as a stress-responsive quality control hub, integrating signals from membrane depolarization, oxidative stress, and protein misfolding to remodel mitochondrial dynamics, cristae architecture, bioenergetics, and protein import. Under basal conditions OMA1 is largely quiescent, but upon stress it undergoes conformational activation—regulated by redox-sensitive disulfide bonds (Cys272/Cys332 and Cys403), cardiolipin binding, and prohibitin-mediated turnover—and cleaves key substrates including OPA1 at the S1 site (driving mitochondrial fragmentation and cytochrome c release during apoptosis), DELE1 (activating the HRI-eIF2α integrated stress response), AIFM1 (reducing OXPHOS capacity), DNAJC15 (restricting mitochondrial protein import), and arrested translocase intermediates, while also degrading misfolded inner membrane proteins [PMID:12963738, PMID:20038677, PMID:32132707, PMID:41876740, PMID:41760807, PMID:38530280]. OMA1 activation is coupled to its own autocatalytic degradation, ensuring reversibility of the stress response, and is positioned downstream of Bax/Bak oligomerization in apoptosis and upstream of PINK1 stabilization in mitophagy, with OMA1-mediated PINK1 degradation counterbalanced by TIM23-dependent protection [PMID:24550258, PMID:25275009, PMID:30733118, PMID:37160114]. OMA1 cooperates with Parkin to maintain mitochondrial fusion and genome integrity under physiological conditions; combined loss of both causes severe organismal phenotypes including premature death and innate immune activation, while individual loss of OMA1 in mice causes obesity and impaired thermogenesis through persistent OPA1-dependent hyperfusion [PMID:39972141, PMID:22433842].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"The foundational question of whether mitochondria possess an ATP-independent inner membrane quality control protease was answered by identification of Oma1 as a metallopeptidase that degrades misfolded membrane proteins like Oxa1 derivatives, establishing a new proteolytic pathway distinct from m-AAA protease function.\",\n      \"evidence\": \"Biochemical fractionation, in vitro protease assays, and cleavage-site mapping of Oxa1 substrate in yeast\",\n      \"pmids\": [\"12963738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian substrate specificity unknown\", \"No structural information on OMA1\", \"Relationship to mitochondrial dynamics not yet explored\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The critical question of which protease mediates stress-induced OPA1 processing was resolved: OMA1 cleaves OPA1 at the S1 site upon loss of membrane potential, converting long fusion-competent OPA1 to short forms and inhibiting mitochondrial fusion, while constitutive OPA1 processing depends on m-AAA proteases—establishing OMA1 as the stress-responsive arm of OPA1 regulation.\",\n      \"evidence\": \"siRNA knockdown in mammalian cells, OPA1 isoform Western blot, mitochondrial morphology imaging, CCCP/oligomycin treatment, replicated across two independent laboratories\",\n      \"pmids\": [\"20038677\", \"20038678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of OMA1 activation by stress unknown\", \"In vivo physiological relevance not yet tested\", \"Whether OMA1 has substrates beyond OPA1 unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The physiological relevance of OMA1 was established in vivo: OMA1-knockout mice showed that loss of stress-induced OPA1 processing causes persistent mitochondrial hyperfusion leading to obesity, hepatic steatosis, and impaired thermogenesis, demonstrating OMA1 is essential for metabolic homeostasis.\",\n      \"evidence\": \"Oma1 knockout mice with comprehensive metabolic phenotyping, high-fat diet challenge, OPA1 isoform analysis\",\n      \"pmids\": [\"22433842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether metabolic phenotype is entirely OPA1-dependent or involves other substrates unknown\", \"Tissue-specific requirements of OMA1 not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Multiple advances resolved how OMA1 is activated and regulated, and positioned it in the apoptotic cascade: OMA1 possesses an N-terminal stress-sensor domain and undergoes autocatalytic self-degradation ensuring reversibility; its C-terminal domain mediates stress-responsive oligomeric conformational changes; Bax/Bak oligomerization activates OMA1 upstream of cristae remodeling and cytochrome c release; and OMA1-generated short OPA1 forms promote fission at ER-mitochondria contact sites.\",\n      \"evidence\": \"Domain mutagenesis, native gel electrophoresis, pulse-chase degradation, inducible Bim/tBid expression, OMA1 KO/KD with cytochrome c release assays, YME1L/OMA1 double-knockout epistasis, electron microscopy, ischemia-reperfusion kidney injury model\",\n      \"pmids\": [\"24550258\", \"24648523\", \"25275009\", \"24616225\", \"24671334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular details of how Bax/Bak signal reaches OMA1 unclear\", \"Whether autocatalytic degradation occurs in trans or cis unknown\", \"Structural basis of stress-sensor domain function unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Three regulatory layers of OMA1 were uncovered: OMA1 activity is tuned by redox-sensitive IMS-exposed disulfide bonds (Cys272/Cys332); prohibitin scaffolds and cardiolipin binding promote OMA1 turnover to limit its activity; and OMA1 degrades imported PINK1 in depolarized mitochondria, opposing Tom7-mediated PINK1 stabilization—linking OMA1 to PINK1/Parkin mitophagy signaling.\",\n      \"evidence\": \"Cysteine mutagenesis with redox state analysis in yeast and mammalian cells; PHB2-KO neurons with cardiolipin-binding domain deletions and turnover assays; Tom7/OMA1 KO epistasis with PINK1 import and Parkinson's-relevant mutant rescue\",\n      \"pmids\": [\"31044600\", \"31819158\", \"30733118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cardiolipin binding mechanistically promotes OMA1 turnover is unclear\", \"Relative contribution of redox versus depolarization sensing in vivo not quantified\", \"Whether OMA1-PINK1 regulation is tissue-specific unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A genome-wide screen revealed that OMA1 relays mitochondrial stress to the cytosol by cleaving DELE1, whose released fragment activates the eIF2α kinase HRI to induce the integrated stress response and ATF4 translation—establishing the OMA1-DELE1-HRI pathway as a mitochondria-to-nucleus stress signaling axis.\",\n      \"evidence\": \"Genome-wide CRISPRi screen, OMA1/DELE1/HRI knockdown, DELE1-HRI co-immunoprecipitation, eIF2α phosphorylation and ATF4 reporter assays\",\n      \"pmids\": [\"32132707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full spectrum of ISR target genes activated by this pathway not catalogued\", \"Whether OMA1-DELE1-HRI operates in all tissues equally unknown\", \"Structural basis of DELE1 cleavage site recognition unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The in vivo survival function of OMA1's dual signaling was demonstrated: in CHCHD10 mitochondrial myopathy mice, OMA1 coordinates both local fragmentation and global ISR activation via DELE1, and OMA1-dependent responses are essential for neonatal survival under inner membrane stress.\",\n      \"evidence\": \"CHCHD10 knock-in mouse model crossed with OMA1 KO, DELE1 cleavage assays, survival analysis, mitochondrial morphology\",\n      \"pmids\": [\"35700042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether pharmacological OMA1 modulation can rescue CHCHD10 disease unknown\", \"Relative contribution of OPA1 versus DELE1 cleavage to survival not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Additional regulatory and functional dimensions were defined: mammalian Cys403 acts as a redox switch controlling OMA1 stress responses; TIM23 physically protects PINK1 from OMA1-mediated degradation; and OMA1 protects against DNA damage-induced apoptosis through metabolic control of glycolysis independent of OPA1 or DELE1.\",\n      \"evidence\": \"Prime editing of C403A in mouse cells with mitochondrial stress/apoptosis assays; PINK1 co-IP mass spectrometry with TIM23 KD and OMA1 KO epistasis; CRISPR metabolism screen with metabolic flux analysis in OMA1-KO cells\",\n      \"pmids\": [\"37024121\", \"37160114\", \"37002921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether C403 redox sensing is mechanistically linked to the Cys272/Cys332 disulfide is unknown\", \"Glycolysis-regulatory substrate of OMA1 not identified\", \"Structural basis of TIM23-PINK1 protection from OMA1 unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"OMA1's substrate repertoire was expanded to include arrested translocase import intermediates, which OMA1 cleaves upon depolarization to unclog the TIM23 channel, with released fragments cleared by cytosolic VCP/p97 and the proteasome—revealing OMA1 as a translocase rescue factor.\",\n      \"evidence\": \"Translocase clogging cell model, OMA1 KO/KD, cleavage fragment analysis, VCP/proteasome inhibitor epistasis\",\n      \"pmids\": [\"38530280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How OMA1 accesses substrates stuck in the translocase channel is structurally unresolved\", \"Scope of physiological import intermediates cleaved by OMA1 not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Systematic genetic epistasis across 18 mouse models revealed that Parkin and OMA1 constitute a dual regulatory system safeguarding mitochondrial fusion and genome integrity through MFN1 and OPA1 respectively; combined loss causes severe organismal defects including premature death and innate immune activation, while individual loss is tolerated.\",\n      \"evidence\": \"18 single/double/triple whole-body and tissue-specific KO mice, metabolomics, RNA sequencing\",\n      \"pmids\": [\"39972141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Parkin-OMA1 cooperation involves direct physical interaction unknown\", \"Mechanism linking combined loss to innate immune activation not fully defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Two new OMA1 substrates were identified that expand its role beyond dynamics: OMA1 cleaves AIFM1 in the IMS with slower kinetics than OPA1, reducing OXPHOS by dislocating AIFM1 from respiratory complexes; and OMA1 cleaves the mitochondrial chaperone DNAJC15, whose subsequent degradation by AFG3L2 restricts protein import and OXPHOS biogenesis under stress, with non-imported preproteins triggering ER UPR.\",\n      \"evidence\": \"In vitro cleavage reconstitution, multiproteomic approaches, OMA1 KO, co-IP of AIFM1 with OXPHOS subunits, mitochondrial import assays, ER stress reporters\",\n      \"pmids\": [\"41876740\", \"41760807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Complete substrate degradome of OMA1 not yet defined\", \"How OMA1 achieves differential cleavage kinetics between substrates is structurally unclear\", \"Whether AIFM1 and DNAJC15 cleavage are relevant in vivo in specific tissues not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of OMA1 and how it achieves substrate selectivity, the full in vivo substrate repertoire, whether the glycolysis-protective function involves an unidentified substrate, and whether pharmacological modulation of OMA1 is therapeutically tractable in mitochondrial diseases or neurodegeneration.\",\n      \"evidence\": \"Open question based on gaps across the literature\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of OMA1 exists\", \"Complete degradome not catalogued by unbiased proteomics\", \"Therapeutic targeting not explored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4, 5, 6, 12, 19, 22, 23]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 22, 23]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5, 11, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 5, 10, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 7, 22]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 12, 15, 17]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 4, 14, 21]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 19, 23]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 18]}\n    ],\n    \"complexes\": [\n      \"OMA1 homo-oligomeric complex\",\n      \"OMA1-MICOS complex\"\n    ],\n    \"partners\": [\n      \"OPA1\",\n      \"DELE1\",\n      \"PINK1\",\n      \"AIFM1\",\n      \"DNAJC15\",\n      \"MIC60\",\n      \"PHB2\",\n      \"HSPA9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}