| 2003 |
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. |
Genetic identification in yeast, in vitro proteolytic assays, cleavage-site mapping, topology/fractionation experiments |
The Journal of biological chemistry |
High |
12963738
|
| 2009 |
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. |
siRNA knockdown, Western blot, mitochondrial membrane potential dissipation (CCCP/oligomycin), fluorescence microscopy for fusion competence, apoptosis assays |
The Journal of cell biology |
High |
20038677
|
| 2009 |
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. |
Mouse knockout/knockdown of m-AAA subunits, dominant-negative AFG3L2 expression, mtDNA depletion, siRNA against OMA1, Western blot for OPA1 isoforms |
The Journal of cell biology |
High |
20038678
|
| 2012 |
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. |
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 |
The EMBO journal |
High |
22433842
|
| 2014 |
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. |
Double/single KO cell lines (YME1L, OMA1, or both), mitochondrial morphology imaging, cristae EM, OPA1 isoform Western blot, apoptosis assays, colocalization microscopy |
The Journal of cell biology |
High |
24616225
|
| 2014 |
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. |
Mutagenesis of OMA1 stress-sensor domain, Western blot for OMA1 and OPA1 isoforms under diverse stress conditions, pulse-chase for OMA1 turnover |
The EMBO journal |
High |
24550258
|
| 2014 |
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. |
Inducible Bim/tBid expression cell lines, Bax/Bak knockout, OMA1 siRNA and CRISPR KO, Western blot for OPA1 processing, cytochrome c release assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
25275009
|
| 2014 |
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. |
OMA1 siRNA in renal proximal tubular cells, OMA1 KO mice, renal ischemia-reperfusion model, OPA1 Western blot, cytochrome c release, mitochondrial morphology imaging |
American journal of physiology. Renal physiology |
High |
24671334
|
| 2014 |
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. |
siRNA against OMA1 and p53, p53 cDNA reconstitution, Western blot for OMA1/OPA1, immunofluorescence for mitochondrial morphology, apoptosis assays |
The Journal of biological chemistry |
Medium |
25112877
|
| 2016 |
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. |
Yeast genetics, OMA1 C-terminal mutagenesis, in-gel activity assays, stress treatments, Western blot |
The Journal of biological chemistry |
Medium |
24648523
|
| 2019 |
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. |
PINK1 mutagenesis, Tom7 KO, OMA1 KO/knockdown, PINK1 accumulation and autophosphorylation assays, mitochondrial depolarization |
Molecular cell |
High |
30733118
|
| 2019 |
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. |
PHB KO neurons, OMA1 CL-binding domain deletion, CL-binding assay, OMA1 turnover measurement, cytochrome c release assay, caspase 9 activation |
Cell death and differentiation |
Medium |
31819158
|
| 2019 |
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. |
Biochemical redox state analysis (alkylation/shift assays), cysteine mutagenesis (Cys272, Cys332), in vitro substrate engagement under redox conditions, yeast and mammalian systems |
Antioxidants & redox signaling |
High |
31044600
|
| 2020 |
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. |
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 |
Nature |
High |
32132707
|
| 2020 |
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. |
CHCHD2/10 double KO and C10 KI mice, OMA1 activation assay (L-OPA1 cleavage as readout), EM for cristae ultrastructure |
Human molecular genetics |
Medium |
32338760
|
| 2020 |
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. |
p32/C1QBP knockout, OPA1 Western blot, mitochondrial morphology imaging, oxygen consumption assay |
Scientific reports |
Medium |
32606429
|
| 2021 |
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. |
Co-IP, proximity ligation, OMA1 KO, MICOS subunit knockdown, MICOS stability assays, oxygen consumption, apoptosis assays, intermembrane bridge rescue |
iScience |
Medium |
33644718
|
| 2021 |
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. |
OMA1 KO cells, DRP1 KO cells, TMRE flow cytometry, mitochondrial morphology confocal imaging, CCCP/oligomycin/ρ0 cell treatments |
Cellular and molecular life sciences : CMLS |
Medium |
27858084
|
| 2022 |
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. |
CHCHD10 G58R knock-in mice, OMA1 KO cross, DELE1 cleavage Western blot, OPA1 processing, ATF4 pathway readouts, mitochondrial morphology EM, isoform switch analysis |
The Journal of clinical investigation |
High |
35700042
|
| 2023 |
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. |
CRISPR screen (metabolism-focused), OMA1 KO, chemotherapeutic DNA damage, glycolysis and OXPHOS measurements, OXPHOS inhibitor rescue |
Cell reports |
Medium |
37002921
|
| 2023 |
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. |
Co-IP/mass spectrometry, TIM23 KD, OMA1 KO, PINK1 accumulation and autophosphorylation assays, pathogenic PINK1 mutant complementation |
Cell reports |
High |
37160114
|
| 2024 |
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. |
Translocase clogging model in human cells, OMA1 KO/knockdown, OPA1 processing as activation control, proteasome and VCP inhibitors, Western blot for cleavage fragments |
The Journal of cell biology |
Medium |
38530280
|
| 2024 |
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. |
Co-IP, mass spectrometry, Western blot, OMA1 KD/OE, mitophagy assays, cGAS-STING pathway readouts, immunofluorescence |
Journal for immunotherapy of cancer |
Medium |
38604814
|
| 2024 |
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. |
18 single/double/triple KO and mutant mouse models, systematic mitochondrial morphology analysis, untargeted metabolomics, RNA sequencing |
Nature |
High |
39972141
|
| 2024 |
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. |
OMA1 KO HT22 cells, ROS induction/scavenging, mitochondrial morphology assays, OGD/R model, membrane potential measurements |
FASEB journal |
Medium |
39312414
|
| 2024 |
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. |
OMA1 KO in OS cells, xenograft mouse models, Western blot, co-IP for p53-Parkin, mitophagy assays, GSK3β/β-catenin pathway analysis |
Cell death & disease |
Medium |
39487118
|
| 2025 |
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. |
In vitro cleavage assay, mass spectrometry-based proteomics, OMA1 KO, DNAJC15 KO, protein import assays, OXPHOS biogenesis measurements, ER stress readouts |
Nature structural & molecular biology |
High |
41760807
|
| 2026 |
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. |
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 |
The EMBO journal |
High |
41876740
|
| 2019 |
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. |
Fluorescent peptide substrate assay, whole cell lysate, validation against OMA1-depleted controls |
Mitochondrion |
Medium |
30926535
|
| 2022 |
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. |
Prime editing (C403A mutation), mitochondrial morphology, ATP production, apoptosis assays, mtDNA release measurement, syngeneic tumor models with immune readouts |
Life science alliance |
Medium |
37024121
|
| 2018 |
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. |
siRNA, inhibitor treatments (MG132, SB216763), OMA1 ubiquitination assay, Western blot for OMA1/OPA1, mitochondrial morphology imaging |
Cell death & disease |
Medium |
29748581
|