OMA1 is an ATP-independent zinc metalloendopeptidase of the M48 family that is anchored in the mitochondrial inner membrane by a single transmembrane helix, with its HExxH catalytic domain facing the intermembrane space. It is largely latent in healthy mitochondria and is activated by membrane depolarization, ATP depletion, oxidative and proteotoxic stress, and Bax/Bak activation during apoptosis; activation involves self-cleavage, which also drives its turnover. Active OMA1 cleaves the long, fusion-competent forms of the dynamin-like GTPase OPA1 at the S1 site, which inhibits inner-membrane fusion, fragments the mitochondrial network and remodels cristae. It also cleaves DELE1; the released DELE1 fragment travels to the cytosol and activates the eIF2alpha kinase HRI (EIF2AK1), triggering the integrated stress response. Other reported substrates include UQCC3, YME1L1 and PINK1. The yeast ortholog Oma1 degrades misfolded inner-membrane proteins, indicating an ancestral role in inner-membrane protein quality control.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002024 diet induced thermogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Thermogenic and energy-balance defects are whole-animal phenotypes of Oma1-knockout mice, secondary to altered OPA1 processing. Reason: These rows are transferred from mouse Oma1, where knockout mice gain adipose mass, have decreased energy expenditure and impaired thermogenesis [PMID:22433842]. The same paper attributes the phenotype to loss of OMA1-dependent OPA1 inactivation. OMA1 does not perform any step of thermogenesis or energy homeostasis; it processes an inner-membrane GTPase, and the organismal outcome is a downstream consequence of disturbed mitochondrial dynamics. Under the participation test (CLAUDE.md "Do not add what curators deliberately declined to add"), necessity evidence of this kind does not establish involvement. The claim is not false for the mouse knockout, so these rows are marked as over-annotation rather than removed. Supporting Evidence: PMID:22433842 Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis PMID:22433842 we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1) |
| GO:0002024 diet induced thermogenesis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Thermogenic and energy-balance defects are whole-animal phenotypes of Oma1-knockout mice, secondary to altered OPA1 processing. Reason: These rows are transferred from mouse Oma1, where knockout mice gain adipose mass, have decreased energy expenditure and impaired thermogenesis [PMID:22433842]. The same paper attributes the phenotype to loss of OMA1-dependent OPA1 inactivation. OMA1 does not perform any step of thermogenesis or energy homeostasis; it processes an inner-membrane GTPase, and the organismal outcome is a downstream consequence of disturbed mitochondrial dynamics. Under the participation test (CLAUDE.md "Do not add what curators deliberately declined to add"), necessity evidence of this kind does not establish involvement. The claim is not false for the mouse knockout, so these rows are marked as over-annotation rather than removed. Supporting Evidence: PMID:22433842 Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis PMID:22433842 we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1) |
| GO:0004222 metalloendopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: OMA1 is an ATP-independent M48-family zinc metalloendopeptidase that cleaves OPA1, DELE1 and other inner-membrane substrates in human cells. Reason: Accepted as the core activity. Knockdown of OMA1 in mammalian cells abolishes stress-induced OPA1 cleavage [PMID:20038677], OMA1 knockdown or knockout blocks OPA1 cleavage during Bax/Bak-dependent apoptosis [PMID:25275009], and two independent genetic screens showed that OMA1 is required for stress-induced DELE1 cleavage [PMID:32132706, PMID:32132707]. The protein carries the M48 HExxH zinc-binding motif with the annotated catalytic Glu328. The IBA places this activity at a deep PANTHER node (PTN000506393) shared with yeast, plant and bacterial M48 members; human OMA1 sits inside that clade (PTHR22726:SF1), so the inherited activity is not in doubt. The endopeptidase term is as specific as GO allows (EC 3.4.24.-, no substrate-specific child term). Supporting Evidence: PMID:20038677 we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1 PMID:32132707 OMA1 knockdown dramatically reduced DELE1S levels and blocked ATF4 induction (Fig. 3f, Extended Data Fig. 2f) suggesting that OMA1 cleaves DELE1, which is necessary for ATF4 induction. file:human/OMA1/OMA1-uniprot.txt CC -!- SIMILARITY: Belongs to the peptidase M48 family. |
| GO:0004222 metalloendopeptidase activity | IDA PMID:25275009 Activation of mitochondrial protease OMA1 by Bax and Bak pro... | ACCEPT | Summary: OMA1 is an ATP-independent M48-family zinc metalloendopeptidase that cleaves OPA1, DELE1 and other inner-membrane substrates in human cells. Reason: Accepted as the core activity. Knockdown of OMA1 in mammalian cells abolishes stress-induced OPA1 cleavage [PMID:20038677], OMA1 knockdown or knockout blocks OPA1 cleavage during Bax/Bak-dependent apoptosis [PMID:25275009], and two independent genetic screens showed that OMA1 is required for stress-induced DELE1 cleavage [PMID:32132706, PMID:32132707]. The protein carries the M48 HExxH zinc-binding motif with the annotated catalytic Glu328. The IBA places this activity at a deep PANTHER node (PTN000506393) shared with yeast, plant and bacterial M48 members; human OMA1 sits inside that clade (PTHR22726:SF1), so the inherited activity is not in doubt. The endopeptidase term is as specific as GO allows (EC 3.4.24.-, no substrate-specific child term). Supporting Evidence: PMID:25275009 Activated OMA1 cleaved the dynamin-like GTPase, optical nerve atrophy 1, an event that is critical for remodeling of mitochondrial cristae. Knockdown or knockout of OMA1 in these cells attenuated cytochrome c release. |
| GO:0004222 metalloendopeptidase activity | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: OMA1 is an ATP-independent M48-family zinc metalloendopeptidase that cleaves OPA1, DELE1 and other inner-membrane substrates in human cells. Reason: Accepted as the core activity. Knockdown of OMA1 in mammalian cells abolishes stress-induced OPA1 cleavage [PMID:20038677], OMA1 knockdown or knockout blocks OPA1 cleavage during Bax/Bak-dependent apoptosis [PMID:25275009], and two independent genetic screens showed that OMA1 is required for stress-induced DELE1 cleavage [PMID:32132706, PMID:32132707]. The protein carries the M48 HExxH zinc-binding motif with the annotated catalytic Glu328. The IBA places this activity at a deep PANTHER node (PTN000506393) shared with yeast, plant and bacterial M48 members; human OMA1 sits inside that clade (PTHR22726:SF1), so the inherited activity is not in doubt. The endopeptidase term is as specific as GO allows (EC 3.4.24.-, no substrate-specific child term). Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. |
| GO:0004222 metalloendopeptidase activity | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: OMA1 is an ATP-independent M48-family zinc metalloendopeptidase that cleaves OPA1, DELE1 and other inner-membrane substrates in human cells. Reason: Accepted as the core activity. Knockdown of OMA1 in mammalian cells abolishes stress-induced OPA1 cleavage [PMID:20038677], OMA1 knockdown or knockout blocks OPA1 cleavage during Bax/Bak-dependent apoptosis [PMID:25275009], and two independent genetic screens showed that OMA1 is required for stress-induced DELE1 cleavage [PMID:32132706, PMID:32132707]. The protein carries the M48 HExxH zinc-binding motif with the annotated catalytic Glu328. The IBA places this activity at a deep PANTHER node (PTN000506393) shared with yeast, plant and bacterial M48 members; human OMA1 sits inside that clade (PTHR22726:SF1), so the inherited activity is not in doubt. The endopeptidase term is as specific as GO allows (EC 3.4.24.-, no substrate-specific child term). Supporting Evidence: PMID:32132707 OMA1 knockdown dramatically reduced DELE1S levels and blocked ATF4 induction (Fig. 3f, Extended Data Fig. 2f) suggesting that OMA1 cleaves DELE1, which is necessary for ATF4 induction. PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0004222 metalloendopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: OMA1 is an ATP-independent M48-family zinc metalloendopeptidase that cleaves OPA1, DELE1 and other inner-membrane substrates in human cells. Reason: Accepted as the core activity. Knockdown of OMA1 in mammalian cells abolishes stress-induced OPA1 cleavage [PMID:20038677], OMA1 knockdown or knockout blocks OPA1 cleavage during Bax/Bak-dependent apoptosis [PMID:25275009], and two independent genetic screens showed that OMA1 is required for stress-induced DELE1 cleavage [PMID:32132706, PMID:32132707]. The protein carries the M48 HExxH zinc-binding motif with the annotated catalytic Glu328. The IBA places this activity at a deep PANTHER node (PTN000506393) shared with yeast, plant and bacterial M48 members; human OMA1 sits inside that clade (PTHR22726:SF1), so the inherited activity is not in doubt. The endopeptidase term is as specific as GO allows (EC 3.4.24.-, no substrate-specific child term). Supporting Evidence: PMID:20038677 we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1 PMID:32132707 OMA1 knockdown dramatically reduced DELE1S levels and blocked ATF4 induction (Fig. 3f, Extended Data Fig. 2f) suggesting that OMA1 cleaves DELE1, which is necessary for ATF4 induction. file:human/OMA1/OMA1-uniprot.txt CC -!- SIMILARITY: Belongs to the peptidase M48 family. |
| GO:0004222 metalloendopeptidase activity | IMP PMID:20038677 Inducible proteolytic inactivation of OPA1 mediated by the O... | ACCEPT | Summary: OMA1 is an ATP-independent M48-family zinc metalloendopeptidase that cleaves OPA1, DELE1 and other inner-membrane substrates in human cells. Reason: Accepted as the core activity. Knockdown of OMA1 in mammalian cells abolishes stress-induced OPA1 cleavage [PMID:20038677], OMA1 knockdown or knockout blocks OPA1 cleavage during Bax/Bak-dependent apoptosis [PMID:25275009], and two independent genetic screens showed that OMA1 is required for stress-induced DELE1 cleavage [PMID:32132706, PMID:32132707]. The protein carries the M48 HExxH zinc-binding motif with the annotated catalytic Glu328. The IBA places this activity at a deep PANTHER node (PTN000506393) shared with yeast, plant and bacterial M48 members; human OMA1 sits inside that clade (PTHR22726:SF1), so the inherited activity is not in doubt. The endopeptidase term is as specific as GO allows (EC 3.4.24.-, no substrate-specific child term). Supporting Evidence: PMID:20038677 we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1 PMID:20038677 OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function |
| GO:0004222 metalloendopeptidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: OMA1 is an ATP-independent M48-family zinc metalloendopeptidase that cleaves OPA1, DELE1 and other inner-membrane substrates in human cells. Reason: Accepted as the core activity. Knockdown of OMA1 in mammalian cells abolishes stress-induced OPA1 cleavage [PMID:20038677], OMA1 knockdown or knockout blocks OPA1 cleavage during Bax/Bak-dependent apoptosis [PMID:25275009], and two independent genetic screens showed that OMA1 is required for stress-induced DELE1 cleavage [PMID:32132706, PMID:32132707]. The protein carries the M48 HExxH zinc-binding motif with the annotated catalytic Glu328. The IBA places this activity at a deep PANTHER node (PTN000506393) shared with yeast, plant and bacterial M48 members; human OMA1 sits inside that clade (PTHR22726:SF1), so the inherited activity is not in doubt. The endopeptidase term is as specific as GO allows (EC 3.4.24.-, no substrate-specific child term). Supporting Evidence: PMID:20038677 we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1 PMID:32132707 OMA1 knockdown dramatically reduced DELE1S levels and blocked ATF4 induction (Fig. 3f, Extended Data Fig. 2f) suggesting that OMA1 cleaves DELE1, which is necessary for ATF4 induction. file:human/OMA1/OMA1-uniprot.txt CC -!- SIMILARITY: Belongs to the peptidase M48 family. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | MODIFY | Summary: Mitochondrial localization is correct but the evidence supports the more specific inner-membrane location. Reason: OMA1 is an integral protein of the mitochondrial inner membrane: in vitro imported OMA1 resists carbonate extraction [PMID:20038677] and its substrates OPA1 and DELE1 are inner-membrane proteins. "Mitochondrion" is true but less specific than the evidence allows; replace with mitochondrial inner membrane (GO:0005743), which this gene already carries by IDA, IBA and TAS. Proposed replacements: mitochondrial inner membrane Supporting Evidence: PMID:34800366 We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | MODIFY | Summary: Mitochondrial localization is correct but the evidence supports the more specific inner-membrane location. Reason: OMA1 is an integral protein of the mitochondrial inner membrane: in vitro imported OMA1 resists carbonate extraction [PMID:20038677] and its substrates OPA1 and DELE1 are inner-membrane proteins. "Mitochondrion" is true but less specific than the evidence allows; replace with mitochondrial inner membrane (GO:0005743), which this gene already carries by IDA, IBA and TAS. Proposed replacements: mitochondrial inner membrane Supporting Evidence: PMID:20038677 both 40- and 60-kD OMA1 proteins were pelleted, showing that these are integral membrane proteins Reactome:R-HSA-8867344 Mitochondrial metalloendopeptidase OMA1 (OMA1) is part of the quality control system in the inner membrane of mitochondria. |
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: OMA1 is an integral inner-membrane protease; this is the compartment in which it acts. Reason: Accepted. Mammalian OMA1 is an integral membrane protein of mitochondria [PMID:20038677], and its substrates (OPA1, DELE1, UQCC3, YME1L1) are inner-membrane proteins. The yeast ortholog Oma1 is likewise an integral inner-membrane protease [PMID:12963738], and the IBA node (PTN000506394) covering the eukaryotic OMA1 clade, including the human protein, is consistent with this being an ancestral location. Supporting Evidence: PMID:12963738 Both peptidases are integral parts of the inner membrane and mediate the proteolytic breakdown of a misfolded derivative of the polytopic inner membrane protein Oxa1. PMID:20038677 both 40- and 60-kD OMA1 proteins were pelleted, showing that these are integral membrane proteins |
| GO:0005743 mitochondrial inner membrane | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: OMA1 is an integral inner-membrane protease; this is the compartment in which it acts. Reason: Accepted. Mammalian OMA1 is an integral membrane protein of mitochondria [PMID:20038677], and its substrates (OPA1, DELE1, UQCC3, YME1L1) are inner-membrane proteins. The yeast ortholog Oma1 is likewise an integral inner-membrane protease [PMID:12963738], and the IBA node (PTN000506394) covering the eukaryotic OMA1 clade, including the human protein, is consistent with this being an ancestral location. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. PMID:20038677 both 40- and 60-kD OMA1 proteins were pelleted, showing that these are integral membrane proteins |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | Summary: OMA1 is an integral inner-membrane protease; this is the compartment in which it acts. Reason: Accepted. Mammalian OMA1 is an integral membrane protein of mitochondria [PMID:20038677], and its substrates (OPA1, DELE1, UQCC3, YME1L1) are inner-membrane proteins. The yeast ortholog Oma1 is likewise an integral inner-membrane protease [PMID:12963738], and the IBA node (PTN000506394) covering the eukaryotic OMA1 clade, including the human protein, is consistent with this being an ancestral location. Supporting Evidence: PMID:20038677 both 40- and 60-kD OMA1 proteins were pelleted, showing that these are integral membrane proteins |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: OMA1 is an integral inner-membrane protease; this is the compartment in which it acts. Reason: Accepted. Mammalian OMA1 is an integral membrane protein of mitochondria [PMID:20038677], and its substrates (OPA1, DELE1, UQCC3, YME1L1) are inner-membrane proteins. The yeast ortholog Oma1 is likewise an integral inner-membrane protease [PMID:12963738], and the IBA node (PTN000506394) covering the eukaryotic OMA1 clade, including the human protein, is consistent with this being an ancestral location. Supporting Evidence: PMID:20038677 both 40- and 60-kD OMA1 proteins were pelleted, showing that these are integral membrane proteins |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-8867344 | ACCEPT | Summary: OMA1 is an integral inner-membrane protease; this is the compartment in which it acts. Reason: Accepted. Mammalian OMA1 is an integral membrane protein of mitochondria [PMID:20038677], and its substrates (OPA1, DELE1, UQCC3, YME1L1) are inner-membrane proteins. The yeast ortholog Oma1 is likewise an integral inner-membrane protease [PMID:12963738], and the IBA node (PTN000506394) covering the eukaryotic OMA1 clade, including the human protein, is consistent with this being an ancestral location. Supporting Evidence: Reactome:R-HSA-8867344 Mitochondrial metalloendopeptidase OMA1 (OMA1) is part of the quality control system in the inner membrane of mitochondria. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9840408 | ACCEPT | Summary: OMA1 is an integral inner-membrane protease; this is the compartment in which it acts. Reason: Accepted. Mammalian OMA1 is an integral membrane protein of mitochondria [PMID:20038677], and its substrates (OPA1, DELE1, UQCC3, YME1L1) are inner-membrane proteins. The yeast ortholog Oma1 is likewise an integral inner-membrane protease [PMID:12963738], and the IBA node (PTN000506394) covering the eukaryotic OMA1 clade, including the human protein, is consistent with this being an ancestral location. Supporting Evidence: Reactome:R-HSA-9840408 Upon mitochondrial stress, import of DELE1 into the matrix is blocked and OMA1 at the inner membrane cleaves the N-terminal region of DELE1 |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9840564 | ACCEPT | Summary: OMA1 is an integral inner-membrane protease; this is the compartment in which it acts. Reason: Accepted. Mammalian OMA1 is an integral membrane protein of mitochondria [PMID:20038677], and its substrates (OPA1, DELE1, UQCC3, YME1L1) are inner-membrane proteins. The yeast ortholog Oma1 is likewise an integral inner-membrane protease [PMID:12963738], and the IBA node (PTN000506394) covering the eukaryotic OMA1 clade, including the human protein, is consistent with this being an ancestral location. Supporting Evidence: Reactome:R-HSA-9840564 Depletion of ATP and depolarization of the mitochondrial inner membrane cause degradation of YME1L1 by OMA1 |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | KEEP AS NON CORE | Summary: The catalytic domain of OMA1 faces the intermembrane space, where its OPA1 and DELE1 cleavage sites are accessible, but the protein itself is anchored in the inner membrane. Reason: Kept as non-core. UniProt models the region C-terminal to the single transmembrane helix (including the HExxH catalytic motif) as intermembrane-space-facing, by similarity to mouse Oma1, and Reactome describes OMA1 at the inner membrane cleaving the N-terminal region of DELE1. The IDA row therefore records where the active site works. Mitochondrial inner membrane (GO:0005743) remains the primary location for the protein; this term is compatible with it rather than a replacement. The yeast ortholog was reported to expose its proteolytic centre to the matrix [PMID:12963738], so the IMS orientation should not be propagated beyond mammals without topology data. Supporting Evidence: file:human/OMA1/OMA1-uniprot.txt /note="Mitochondrial intermembrane" Reactome:R-HSA-9840408 Upon mitochondrial stress, import of DELE1 into the matrix is blocked and OMA1 at the inner membrane cleaves the N-terminal region of DELE1 |
| GO:0005758 mitochondrial intermembrane space | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | KEEP AS NON CORE | Summary: The catalytic domain of OMA1 faces the intermembrane space, where its OPA1 and DELE1 cleavage sites are accessible, but the protein itself is anchored in the inner membrane. Reason: Kept as non-core. UniProt models the region C-terminal to the single transmembrane helix (including the HExxH catalytic motif) as intermembrane-space-facing, by similarity to mouse Oma1, and Reactome describes OMA1 at the inner membrane cleaving the N-terminal region of DELE1. The IDA row therefore records where the active site works. Mitochondrial inner membrane (GO:0005743) remains the primary location for the protein; this term is compatible with it rather than a replacement. The yeast ortholog was reported to expose its proteolytic centre to the matrix [PMID:12963738], so the IMS orientation should not be propagated beyond mammals without topology data. Supporting Evidence: file:human/OMA1/OMA1-uniprot.txt /note="Mitochondrial intermembrane" Reactome:R-HSA-9840408 Upon mitochondrial stress, import of DELE1 into the matrix is blocked and OMA1 at the inner membrane cleaves the N-terminal region of DELE1 |
| GO:0006006 glucose metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Glucose metabolic process (IEA), transferred from mouse Oma1, annotated from the metabolic phenotype of the knockout (PMID:22433842). Reason: The row is transferred from mouse Oma1, annotated from the knockout phenotype: Oma1-deficient mice show altered blood parameters and marked changes in the expression of genes of lipid and glucose metabolic pathways (PMID:22433842). The claim therefore has an experimental basis. These metabolic changes are tissue-level consequences of disturbed mitochondrial quality control, not evidence that the protease takes part in glucose metabolism itself. The term over-reads the phenotype rather than being unsupported, so it is marked as an over-annotation instead of removed. Supporting Evidence: PMID:22433842 ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters |
| GO:0006006 glucose metabolic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Glucose metabolic process (ISS), inferred from mouse Oma1, annotated from the metabolic phenotype of the knockout (PMID:22433842). Reason: The row is inferred from mouse Oma1, annotated from the knockout phenotype: Oma1-deficient mice show altered blood parameters and marked changes in the expression of genes of lipid and glucose metabolic pathways (PMID:22433842). The claim therefore has an experimental basis. These metabolic changes are tissue-level consequences of disturbed mitochondrial quality control, not evidence that the protease takes part in glucose metabolism itself. The term over-reads the phenotype rather than being unsupported, so it is marked as an over-annotation instead of removed. Supporting Evidence: PMID:22433842 ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | MODIFY | Summary: Correct but uninformative; OMA1 performs regulated cleavage of mitochondrial inner-membrane proteins. Reason: OMA1 is a metalloendopeptidase, so proteolysis is true. The more specific process supported by experiment is mitochondrial protein processing (GO:0034982), a descendant of proteolysis that the gene already carries by IDA and IMP (OPA1, UQCC3, DELE1 cleavage) [PMID:20038677, PMID:25605331, PMID:32132707]. Proposed replacements: mitochondrial protein processing Supporting Evidence: PMID:20038677 we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1 PMID:25605331 We also demonstrated that the OMA1 metalloprotease cleaves C11orf83 in response to mitochondrial depolarization PMID:32132707 OMA1 knockdown dramatically reduced DELE1S levels and blocked ATF4 induction (Fig. 3f, Extended Data Fig. 2f) suggesting that OMA1 cleaves DELE1, which is necessary for ATF4 induction. |
| GO:0006515 protein quality control | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Degradation of misfolded inner-membrane proteins is established for yeast Oma1 and inherited by the eukaryotic OMA1 clade; in human cells the best-studied OMA1 cleavages are regulatory rather than clearance of misfolded proteins. Reason: GO:0006515 is the breakdown of misfolded or attenuated proteins. Yeast Oma1 degrades a misfolded Oxa1 derivative in the inner membrane [PMID:12963738], and the PAINT node PTN000506394, which spans yeast and human OMA1, carries this term; there is no evidence that the human protein has lost the activity, so the IBA is retained. The human IMP rests on Head et al., whose own framing is organelle-level quality control (inactivating OPA1 so damaged fragments cannot fuse again) rather than clearance of a misfolded substrate [PMID:20038677]. OMA1 also degrades YME1L1 and PINK1 under stress. The term holds but is peripheral to the regulatory OPA1/DELE1 processing that defines the human protein, so both rows are kept as non-core. Supporting Evidence: PMID:12963738 Both peptidases are integral parts of the inner membrane and mediate the proteolytic breakdown of a misfolded derivative of the polytopic inner membrane protein Oxa1. PMID:12963738 These results identify Oma1 as a novel component of the quality control system in the inner membrane of mitochondria. |
| GO:0006515 protein quality control | IMP PMID:20038677 Inducible proteolytic inactivation of OPA1 mediated by the O... | KEEP AS NON CORE | Summary: Degradation of misfolded inner-membrane proteins is established for yeast Oma1 and inherited by the eukaryotic OMA1 clade; in human cells the best-studied OMA1 cleavages are regulatory rather than clearance of misfolded proteins. Reason: GO:0006515 is the breakdown of misfolded or attenuated proteins. Yeast Oma1 degrades a misfolded Oxa1 derivative in the inner membrane [PMID:12963738], and the PAINT node PTN000506394, which spans yeast and human OMA1, carries this term; there is no evidence that the human protein has lost the activity, so the IBA is retained. The human IMP rests on Head et al., whose own framing is organelle-level quality control (inactivating OPA1 so damaged fragments cannot fuse again) rather than clearance of a misfolded substrate [PMID:20038677]. OMA1 also degrades YME1L1 and PINK1 under stress. The term holds but is peripheral to the regulatory OPA1/DELE1 processing that defines the human protein, so both rows are kept as non-core. Supporting Evidence: PMID:20038677 Inducible cleavage provides a mechanism for quality control because proteolytic inactivation of OPA1 promotes selective removal of defective mitochondrial fragments by preventing their fusion with the mitochondrial network PMID:20038677 we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1 |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Lipid metabolic process (IEA), transferred from mouse Oma1, annotated from the metabolic phenotype of the knockout (PMID:22433842). Reason: The row is transferred from mouse Oma1, annotated from the knockout phenotype: Oma1-deficient mice show altered blood parameters and marked changes in the expression of genes of lipid and glucose metabolic pathways (PMID:22433842). The claim therefore has an experimental basis. These metabolic changes are tissue-level consequences of disturbed mitochondrial quality control, not evidence that the protease takes part in lipid metabolism itself. The term over-reads the phenotype rather than being unsupported, so it is marked as an over-annotation instead of removed. Supporting Evidence: PMID:22433842 ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters |
| GO:0006629 lipid metabolic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Lipid metabolic process (ISS), inferred from mouse Oma1, annotated from the metabolic phenotype of the knockout (PMID:22433842). Reason: The row is inferred from mouse Oma1, annotated from the knockout phenotype: Oma1-deficient mice show altered blood parameters and marked changes in the expression of genes of lipid and glucose metabolic pathways (PMID:22433842). The claim therefore has an experimental basis. These metabolic changes are tissue-level consequences of disturbed mitochondrial quality control, not evidence that the protease takes part in lipid metabolism itself. The term over-reads the phenotype rather than being unsupported, so it is marked as an over-annotation instead of removed. Supporting Evidence: PMID:22433842 ablation of OMA1 in mice results in marked transcriptional changes in genes of lipid and glucose metabolic pathways and substantial alterations in circulating blood parameters |
| GO:0010637 negative regulation of mitochondrial fusion | IEA GO_REF:0000107 | ACCEPT | Summary: Stress-activated OMA1 converts fusion-competent long OPA1 to short forms, inhibiting inner-membrane fusion. Reason: Core process. OMA1 knockdown inhibits inducible OPA1 cleavage and helps retain fusion competence [PMID:20038677]; Oma1-null mice lose stress-induced OPA1 inactivation [PMID:22433842]. Reconstitution shows that excess short OPA1 inhibits fusion [PMID:31922487]. OMA1 acts on the fusion machinery, so regulation (not participation) is the right relationship. Supporting Evidence: PMID:22433842 we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1) PMID:20038677 OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function |
| GO:0010637 negative regulation of mitochondrial fusion | IMP PMID:20038677 Inducible proteolytic inactivation of OPA1 mediated by the O... | ACCEPT | Summary: Stress-activated OMA1 converts fusion-competent long OPA1 to short forms, inhibiting inner-membrane fusion. Reason: Core process. OMA1 knockdown inhibits inducible OPA1 cleavage and helps retain fusion competence [PMID:20038677]; Oma1-null mice lose stress-induced OPA1 inactivation [PMID:22433842]. Reconstitution shows that excess short OPA1 inhibits fusion [PMID:31922487]. OMA1 acts on the fusion machinery, so regulation (not participation) is the right relationship. Supporting Evidence: PMID:20038677 OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function PMID:31922487 we found that excess levels of s-Opa1 inhibit fusion activity |
| GO:0010637 negative regulation of mitochondrial fusion | ISS GO_REF:0000024 | ACCEPT | Summary: Stress-activated OMA1 converts fusion-competent long OPA1 to short forms, inhibiting inner-membrane fusion. Reason: Core process. OMA1 knockdown inhibits inducible OPA1 cleavage and helps retain fusion competence [PMID:20038677]; Oma1-null mice lose stress-induced OPA1 inactivation [PMID:22433842]. Reconstitution shows that excess short OPA1 inhibits fusion [PMID:31922487]. OMA1 acts on the fusion machinery, so regulation (not participation) is the right relationship. Supporting Evidence: PMID:22433842 we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1) PMID:20038677 OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function |
| GO:0016540 protein autoprocessing | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: OMA1 cleaves itself after import and upon stress; this autocatalytic processing controls its activation and turnover. Reason: Autoprocessing has been shown in mammalian cells: OMA1 "undergoes pre-activating proteolytic and auto-proteolytic cleavage after mitochondrial import" [PMID:29545505], and UniProt records stress-induced autocatalytic cleavage at both ends, by similarity to mouse Oma1. This is the sanctioned case in which the substrate does the cleaving (GO:0016540 under proteolysis). Mouse Oma1 is in the same PANTHER subfamily (PTHR22726:SF1), so the transfer is sound. The term is retained but is a regulatory feature, not the core function. Supporting Evidence: PMID:29545505 OMA1 is a zinc metallopeptidase of the inner mitochondrial membrane that undergoes pre-activating proteolytic and auto-proteolytic cleavage after mitochondrial import. file:human/OMA1/OMA1-uniprot.txt CC -!- PTM: Autocatalytically cleaved in response to mitochondrial |
| GO:0016540 protein autoprocessing | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: OMA1 cleaves itself after import and upon stress; this autocatalytic processing controls its activation and turnover. Reason: Autoprocessing has been shown in mammalian cells: OMA1 "undergoes pre-activating proteolytic and auto-proteolytic cleavage after mitochondrial import" [PMID:29545505], and UniProt records stress-induced autocatalytic cleavage at both ends, by similarity to mouse Oma1. This is the sanctioned case in which the substrate does the cleaving (GO:0016540 under proteolysis). Mouse Oma1 is in the same PANTHER subfamily (PTHR22726:SF1), so the transfer is sound. The term is retained but is a regulatory feature, not the core function. Supporting Evidence: PMID:29545505 OMA1 is a zinc metallopeptidase of the inner mitochondrial membrane that undergoes pre-activating proteolytic and auto-proteolytic cleavage after mitochondrial import. file:human/OMA1/OMA1-uniprot.txt CC -!- PTM: Autocatalytically cleaved in response to mitochondrial |
| GO:0031638 zymogen activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Autocatalytic cleavage converts OMA1 to its stress-active short form. Reason: UniProt (by similarity to mouse Oma1, same PANTHER subfamily SF1) states that OMA1 protease activity is activated upon autocatalytic cleavage after mitochondrial depolarization, and a human-cell study describes pre-activating and auto-proteolytic cleavage of OMA1 [PMID:29545505]. Because OMA1 cleaves itself, it performs the zymogen-activation step and passes the participation test. Note that the N-terminal pre-activating cleavage is attributed to AFG3L2, and the C-terminal self-cleavage also drives turnover, so activation and degradation are coupled. Retained as non-core regulation of its own activity. Supporting Evidence: file:human/OMA1/OMA1-uniprot.txt CC -!- ACTIVITY REGULATION: Protease activity is activated upon autocatalytic PMID:29545505 OMA1 is a zinc metallopeptidase of the inner mitochondrial membrane that undergoes pre-activating proteolytic and auto-proteolytic cleavage after mitochondrial import. |
| GO:0031638 zymogen activation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Autocatalytic cleavage converts OMA1 to its stress-active short form. Reason: UniProt (by similarity to mouse Oma1, same PANTHER subfamily SF1) states that OMA1 protease activity is activated upon autocatalytic cleavage after mitochondrial depolarization, and a human-cell study describes pre-activating and auto-proteolytic cleavage of OMA1 [PMID:29545505]. Because OMA1 cleaves itself, it performs the zymogen-activation step and passes the participation test. Note that the N-terminal pre-activating cleavage is attributed to AFG3L2, and the C-terminal self-cleavage also drives turnover, so activation and degradation are coupled. Retained as non-core regulation of its own activity. Supporting Evidence: file:human/OMA1/OMA1-uniprot.txt CC -!- ACTIVITY REGULATION: Protease activity is activated upon autocatalytic PMID:29545505 OMA1 is a zinc metallopeptidase of the inner mitochondrial membrane that undergoes pre-activating proteolytic and auto-proteolytic cleavage after mitochondrial import. |
| GO:0031966 mitochondrial membrane | IDA PMID:20038677 Inducible proteolytic inactivation of OPA1 mediated by the O... | MODIFY | Summary: Mitochondrial membrane is correct but general; the same paper and later work place OMA1 in the inner membrane. Reason: Head et al. showed that imported OMA1 is carbonate-resistant, i.e. an integral mitochondrial membrane protein [PMID:20038677]. Its substrates and later fractionation place it in the inner membrane (UniProt location ECO:0000269|PubMed:32132707). Replace with mitochondrial inner membrane (GO:0005743), which the gene already carries. Proposed replacements: mitochondrial inner membrane Supporting Evidence: PMID:20038677 both 40- and 60-kD OMA1 proteins were pelleted, showing that these are integral membrane proteins Reactome:R-HSA-8867344 Mitochondrial metalloendopeptidase OMA1 (OMA1) is part of the quality control system in the inner membrane of mitochondria. |
| GO:0033108 mitochondrial respiratory chain complex assembly | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: OMA1 has no demonstrated role as a respiratory chain assembly factor; supercomplex instability in its absence is an indirect effect. Reason: The transferred annotation rests on mouse Oma1 data summarised by UniProt as "Required for the stability of the respiratory supercomplexes" (by similarity). Required-for-stability is necessity evidence and does not show that OMA1 aggregates or bonds components of respiratory complexes. A plausible indirect route is altered OPA1-dependent cristae structure, or turnover of assembly factors such as UQCC3, an OMA1 substrate [PMID:25605331]. No direct assembly activity is known, so the term is marked as over-annotation rather than removed. Supporting Evidence: file:human/OMA1/OMA1-uniprot.txt Required for the stability of the respiratory supercomplexes PMID:25605331 We also demonstrated that the OMA1 metalloprotease cleaves C11orf83 in response to mitochondrial depolarization |
| GO:0033108 mitochondrial respiratory chain complex assembly | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: OMA1 has no demonstrated role as a respiratory chain assembly factor; supercomplex instability in its absence is an indirect effect. Reason: The transferred annotation rests on mouse Oma1 data summarised by UniProt as "Required for the stability of the respiratory supercomplexes" (by similarity). Required-for-stability is necessity evidence and does not show that OMA1 aggregates or bonds components of respiratory complexes. A plausible indirect route is altered OPA1-dependent cristae structure, or turnover of assembly factors such as UQCC3, an OMA1 substrate [PMID:25605331]. No direct assembly activity is known, so the term is marked as over-annotation rather than removed. Supporting Evidence: file:human/OMA1/OMA1-uniprot.txt Required for the stability of the respiratory supercomplexes PMID:25605331 We also demonstrated that the OMA1 metalloprotease cleaves C11orf83 in response to mitochondrial depolarization |
| GO:0033554 cellular response to stress | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | MODIFY | Summary: True but general; the specific stress pathway in which OMA1 acts is integrated stress response signaling via DELE1 and HRI. Reason: Both Nature studies show that OMA1 is activated by mitochondrial stress and cleaves DELE1, whose short form activates HRI [PMID:32132706, PMID:32132707]. Integrated stress response signaling (GO:0140467) is a descendant of cellular response to stress and is already annotated from the same papers, so it replaces this general term. Proposed replacements: integrated stress response signaling Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0033554 cellular response to stress | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | MODIFY | Summary: True but general; the specific stress pathway in which OMA1 acts is integrated stress response signaling via DELE1 and HRI. Reason: Both Nature studies show that OMA1 is activated by mitochondrial stress and cleaves DELE1, whose short form activates HRI [PMID:32132706, PMID:32132707]. Integrated stress response signaling (GO:0140467) is a descendant of cellular response to stress and is already annotated from the same papers, so it replaces this general term. Proposed replacements: integrated stress response signaling Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:0034982 mitochondrial protein processing | IDA PMID:25275009 Activation of mitochondrial protease OMA1 by Bax and Bak pro... | ACCEPT | Summary: OMA1 proteolytically processes mitochondrial inner-membrane proteins: OPA1 at the S1 site, DELE1, UQCC3. Reason: Core process. OMA1 cleaves OPA1 in mammalian cells [PMID:20038677, PMID:25275009], cleaves UQCC3 (C11orf83) upon depolarization [PMID:25605331], and is required for DELE1 cleavage [PMID:32132707]. GO:0034982 is the most specific process term for peptide cleavage of mitochondrial proteins. Supporting Evidence: PMID:25275009 Activated OMA1 cleaved the dynamin-like GTPase, optical nerve atrophy 1, an event that is critical for remodeling of mitochondrial cristae. Knockdown or knockout of OMA1 in these cells attenuated cytochrome c release. |
| GO:0034982 mitochondrial protein processing | IEA GO_REF:0000107 | ACCEPT | Summary: OMA1 proteolytically processes mitochondrial inner-membrane proteins: OPA1 at the S1 site, DELE1, UQCC3. Reason: Core process. OMA1 cleaves OPA1 in mammalian cells [PMID:20038677, PMID:25275009], cleaves UQCC3 (C11orf83) upon depolarization [PMID:25605331], and is required for DELE1 cleavage [PMID:32132707]. GO:0034982 is the most specific process term for peptide cleavage of mitochondrial proteins. Supporting Evidence: PMID:20038677 we show that this inducible cleavage is mediated by a zinc metalloprotease called OMA1 PMID:32132707 OMA1 knockdown dramatically reduced DELE1S levels and blocked ATF4 induction (Fig. 3f, Extended Data Fig. 2f) suggesting that OMA1 cleaves DELE1, which is necessary for ATF4 induction. |
| GO:0034982 mitochondrial protein processing | IMP PMID:25605331 C11orf83, a mitochondrial cardiolipin-binding protein involv... | ACCEPT | Summary: OMA1 proteolytically processes mitochondrial inner-membrane proteins: OPA1 at the S1 site, DELE1, UQCC3. Reason: Core process. OMA1 cleaves OPA1 in mammalian cells [PMID:20038677, PMID:25275009], cleaves UQCC3 (C11orf83) upon depolarization [PMID:25605331], and is required for DELE1 cleavage [PMID:32132707]. GO:0034982 is the most specific process term for peptide cleavage of mitochondrial proteins. Supporting Evidence: PMID:25605331 We also demonstrated that the OMA1 metalloprotease cleaves C11orf83 in response to mitochondrial depolarization |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:25275009 Activation of mitochondrial protease OMA1 by Bax and Bak pro... | KEEP AS NON CORE | Summary: Bax/Bak-activated OMA1 cleaves OPA1 and promotes cristae remodelling and cytochrome c release during intrinsic apoptosis. Reason: In inducible Bim/tBid cell lines OMA1 was activated in a Bax/Bak-dependent manner, and knockdown or knockout of OMA1 attenuated cytochrome c release [PMID:25275009]; OMA1 siRNA also slowed apoptosis [PMID:20038677]. OMA1 performs a specific upstream proteolytic step, so the regulatory term is defensible, but it is a context-specific output of OPA1 processing, not the core function. Supporting Evidence: PMID:25275009 Activated OMA1 cleaved the dynamin-like GTPase, optical nerve atrophy 1, an event that is critical for remodeling of mitochondrial cristae. Knockdown or knockout of OMA1 in these cells attenuated cytochrome c release. PMID:20038677 OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function |
| GO:0097009 energy homeostasis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Thermogenic and energy-balance defects are whole-animal phenotypes of Oma1-knockout mice, secondary to altered OPA1 processing. Reason: These rows are transferred from mouse Oma1, where knockout mice gain adipose mass, have decreased energy expenditure and impaired thermogenesis [PMID:22433842]. The same paper attributes the phenotype to loss of OMA1-dependent OPA1 inactivation. OMA1 does not perform any step of thermogenesis or energy homeostasis; it processes an inner-membrane GTPase, and the organismal outcome is a downstream consequence of disturbed mitochondrial dynamics. Under the participation test (CLAUDE.md "Do not add what curators deliberately declined to add"), necessity evidence of this kind does not establish involvement. The claim is not false for the mouse knockout, so these rows are marked as over-annotation rather than removed. Supporting Evidence: PMID:22433842 Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis PMID:22433842 we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1) |
| GO:0097009 energy homeostasis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Thermogenic and energy-balance defects are whole-animal phenotypes of Oma1-knockout mice, secondary to altered OPA1 processing. Reason: These rows are transferred from mouse Oma1, where knockout mice gain adipose mass, have decreased energy expenditure and impaired thermogenesis [PMID:22433842]. The same paper attributes the phenotype to loss of OMA1-dependent OPA1 inactivation. OMA1 does not perform any step of thermogenesis or energy homeostasis; it processes an inner-membrane GTPase, and the organismal outcome is a downstream consequence of disturbed mitochondrial dynamics. Under the participation test (CLAUDE.md "Do not add what curators deliberately declined to add"), necessity evidence of this kind does not establish involvement. The claim is not false for the mouse knockout, so these rows are marked as over-annotation rather than removed. Supporting Evidence: PMID:22433842 Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis PMID:22433842 we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1) |
| GO:0120162 positive regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Thermogenic and energy-balance defects are whole-animal phenotypes of Oma1-knockout mice, secondary to altered OPA1 processing. Reason: These rows are transferred from mouse Oma1, where knockout mice gain adipose mass, have decreased energy expenditure and impaired thermogenesis [PMID:22433842]. The same paper attributes the phenotype to loss of OMA1-dependent OPA1 inactivation. OMA1 does not perform any step of thermogenesis or energy homeostasis; it processes an inner-membrane GTPase, and the organismal outcome is a downstream consequence of disturbed mitochondrial dynamics. Under the participation test (CLAUDE.md "Do not add what curators deliberately declined to add"), necessity evidence of this kind does not establish involvement. The claim is not false for the mouse knockout, so these rows are marked as over-annotation rather than removed. Supporting Evidence: PMID:22433842 Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis PMID:22433842 we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1) |
| GO:0120162 positive regulation of cold-induced thermogenesis | ISS PMID:22433842 Loss of mitochondrial protease OMA1 alters processing of the... | MARK AS OVER ANNOTATED | Summary: Thermogenic and energy-balance defects are whole-animal phenotypes of Oma1-knockout mice, secondary to altered OPA1 processing. Reason: These rows are transferred from mouse Oma1, where knockout mice gain adipose mass, have decreased energy expenditure and impaired thermogenesis [PMID:22433842]. The same paper attributes the phenotype to loss of OMA1-dependent OPA1 inactivation. OMA1 does not perform any step of thermogenesis or energy homeostasis; it processes an inner-membrane GTPase, and the organismal outcome is a downstream consequence of disturbed mitochondrial dynamics. Under the participation test (CLAUDE.md "Do not add what curators deliberately declined to add"), necessity evidence of this kind does not establish involvement. The claim is not false for the mouse knockout, so these rows are marked as over-annotation rather than removed. Supporting Evidence: PMID:22433842 Oma1-mutant mice exhibit an increase in body weight due to increased adipose mass, hepatic steatosis, decreased energy expenditure and impaired thermogenenesis PMID:22433842 we provide in vivo evidence that the ATP-independent metalloprotease OMA1 plays an essential role in the proteolytic inactivation of the dynamin-related GTPase OPA1 (optic atrophy 1) |
| GO:0140467 integrated stress response signaling | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: OMA1 is the stress-activated protease that cleaves DELE1, the first step of the mitochondrial OMA1-DELE1-HRI integrated stress response relay. Reason: Core process. Two independent genome-wide screens placed OMA1 upstream of DELE1 and HRI; OMA1 cleaves DELE1, whose short form reaches the cytosol and activates HRI [PMID:32132706, PMID:32132707]. OMA1 carries out a signalling step (signal-generating proteolysis), so it participates in the process rather than being merely required for it. Supporting Evidence: PMID:32132706 Mechanistically, stress-induced activation of OMA1 causes DELE1 to be cleaved into a short form that accumulates in the cytosol, where it binds to and activates HRI via its C-terminal portion. PMID:32132706 We show that the mitochondrial protease OMA1 and the poorly characterized protein DELE1, together with HRI, constitute the missing pathway that is triggered by mitochondrial stress. |
| GO:0140467 integrated stress response signaling | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: OMA1 is the stress-activated protease that cleaves DELE1, the first step of the mitochondrial OMA1-DELE1-HRI integrated stress response relay. Reason: Core process. Two independent genome-wide screens placed OMA1 upstream of DELE1 and HRI; OMA1 cleaves DELE1, whose short form reaches the cytosol and activates HRI [PMID:32132706, PMID:32132707]. OMA1 carries out a signalling step (signal-generating proteolysis), so it participates in the process rather than being merely required for it. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. PMID:32132707 OMA1 knockdown dramatically reduced DELE1S levels and blocked ATF4 induction (Fig. 3f, Extended Data Fig. 2f) suggesting that OMA1 cleaves DELE1, which is necessary for ATF4 induction. |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132706 A pathway coordinated by DELE1 relays mitochondrial stress t... | ACCEPT | Summary: OMA1-mediated DELE1 cleavage is the upstream step that activates the eIF2alpha kinase HRI (EIF2AK1). Reason: Core process and the most specific ISR branch. The OMA1-DELE1 relay specifically activates HRI, not the other eIF2alpha kinases [PMID:32132706, PMID:32132707]. OMA1 generates the signal (S-DELE1) and so participates in HRI-mediated signaling. The process is accepted alongside its parent GO:0140467. Supporting Evidence: PMID:32132706 We show that the mitochondrial protease OMA1 and the poorly characterized protein DELE1, together with HRI, constitute the missing pathway that is triggered by mitochondrial stress. |
| GO:0140468 HRI-mediated signaling | IDA PMID:32132707 Mitochondrial stress is relayed to the cytosol by an OMA1-DE... | ACCEPT | Summary: OMA1-mediated DELE1 cleavage is the upstream step that activates the eIF2alpha kinase HRI (EIF2AK1). Reason: Core process and the most specific ISR branch. The OMA1-DELE1 relay specifically activates HRI, not the other eIF2alpha kinases [PMID:32132706, PMID:32132707]. OMA1 generates the signal (S-DELE1) and so participates in HRI-mediated signaling. The process is accepted alongside its parent GO:0140467. Supporting Evidence: PMID:32132707 Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it interacts with HRI and activates the eIF2Ξ± kinase activity of HRI. |
| GO:1903850 regulation of cristae formation | IDA PMID:25275009 Activation of mitochondrial protease OMA1 by Bax and Bak pro... | KEEP AS NON CORE | Summary: OMA1-mediated OPA1 cleavage remodels mitochondrial cristae during apoptosis. Reason: Jiang et al. report that activated OMA1 cleaves OPA1, "an event that is critical for remodeling of mitochondrial cristae" [PMID:25275009]. OMA1 acts through OPA1, so a regulatory term is appropriate. It is kept as non-core because cristae remodelling is a consequence of the core OPA1-processing activity in a specific apoptotic context. Supporting Evidence: PMID:25275009 Activated OMA1 cleaved the dynamin-like GTPase, optical nerve atrophy 1, an event that is critical for remodeling of mitochondrial cristae. Knockdown or knockout of OMA1 in these cells attenuated cytochrome c release. |
| GO:1990627 mitochondrial inner membrane fusion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: OMA1 does not perform inner-membrane fusion; it regulates fusion by processing OPA1, and the documented effect of stress-activated OMA1 is inhibition of fusion. Reason: The membrane-fusion machinery is OPA1 (with cardiolipin). OMA1 generates short OPA1, and reconstitution shows that stoichiometric short OPA1 cooperates with long OPA1 in pore opening while excess short OPA1 inhibits fusion [PMID:31922487]. That study used purified OPA1 forms without OMA1, so it does not show that OMA1 participates in fusion. In cells, OMA1 knockdown preserves fusion competence [PMID:20038677], which is the basis for the accepted negative regulation of mitochondrial fusion (GO:0010637). Any constitutive contribution of OMA1 to the S-OPA1 pool would at most be regulation of fusion. Participation in fusion is therefore an over-annotation. Supporting Evidence: PMID:31922487 stoichiometric levels of the processed, short form of Opa1 (s-Opa1) work together with l-Opa1 to mediate efficient and fast membrane pore opening PMID:20038677 OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function |
| GO:1990627 mitochondrial inner membrane fusion | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: OMA1 does not perform inner-membrane fusion; it regulates fusion by processing OPA1, and the documented effect of stress-activated OMA1 is inhibition of fusion. Reason: The membrane-fusion machinery is OPA1 (with cardiolipin). OMA1 generates short OPA1, and reconstitution shows that stoichiometric short OPA1 cooperates with long OPA1 in pore opening while excess short OPA1 inhibits fusion [PMID:31922487]. That study used purified OPA1 forms without OMA1, so it does not show that OMA1 participates in fusion. In cells, OMA1 knockdown preserves fusion competence [PMID:20038677], which is the basis for the accepted negative regulation of mitochondrial fusion (GO:0010637). Any constitutive contribution of OMA1 to the S-OPA1 pool would at most be regulation of fusion. Participation in fusion is therefore an over-annotation. Supporting Evidence: PMID:31922487 stoichiometric levels of the processed, short form of Opa1 (s-Opa1) work together with l-Opa1 to mediate efficient and fast membrane pore opening PMID:20038677 OMA1 small interfering RNA inhibits inducible cleavage, helps retain fusion competence, and slows the onset of apoptosis, showing that OMA1 controls OPA1 cleavage and function |
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Download this section (compressed HTML)Q: How does OMA1 sense distinct stresses (depolarization, ROS, ATP loss, proteotoxicity) at the molecular level, and is the stress-sensor region the common input?
Q: Does human OMA1 retain the ancestral role of the yeast enzyme in degrading misfolded inner-membrane proteins, or is its substrate set limited to regulatory targets such as OPA1 and DELE1?
Q: Does constitutive OMA1 activity contribute to the short-OPA1 pool needed for efficient fusion under basal conditions, or is that pool generated only by YME1L1?
Experiment: Reconstitute purified human OMA1 (wild type and E328Q) in proteoliposomes with OPA1 and DELE1 to measure direct cleavage, cleavage-site specificity and lipid (cardiolipin) dependence.
Experiment: Proteomic substrate trapping with catalytically inactive OMA1 in OMA1-null human cells under depolarization, to define the full stress-dependent substrate repertoire and test for misfolded-protein clearance.
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