Bnip3 (BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; Nip3) is an atypical BH3-only member of the BCL-2 family and the paralog of BNIP3L/NIX. It is a 187-residue tail-anchored membrane protein. Its C-terminal transmembrane helix inserts it into the mitochondrial outer membrane, and a smaller pool into the endoplasmic reticulum; the same helix drives homodimerization. The cytosolic N-terminal region carries an LC3-interacting region (LIR), whose binding to LC3B and GABARAP-family proteins is enhanced by phosphorylation of flanking serines. Through it, Bnip3 acts as a selective autophagy receptor that delivers mitochondria to autophagosomes (mitophagy); overexpressed BNIP3 can also target ER for autophagy (ER-phagy) in human cells. Bnip3 is induced by HIF-1 under hypoxia and other stresses. With NIX it limits mitochondrial mass: Bnip3-null mouse liver accumulates dysfunctional mitochondria and develops steatosis, and Bnip3 or Nix deletion rescues the excessive mitophagy and lethality of Fbxl4-null mice. Basal levels are kept low by SCF(FBXL4)/PPTC7-dependent ubiquitination. Bnip3 also inhibits OPA1-mediated fusion and takes part in Mieap-dependent intramitochondrial quality control. When overexpressed, or under some stresses such as post-ischaemic myocardium or nitric-oxide-treated macrophages, it promotes mitochondrial, often necrosis-like cell death.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000423 mitophagy | IBA GO_REF:0000033 | ACCEPT | Summary: Bnip3 mediates selective autophagy of mitochondria, acting as an LC3/GABARAP-binding receptor in the mitochondrial outer membrane. Reason: Core process. LIR-dependent mitophagy is shown directly, and Bnip3-null mouse liver accumulates mitochondrial mass. Bnip3 deletion also rescues the hyperactive mitophagy of Fbxl4-/- mice. The IBA (PTN001032684, Bilateria) agrees with fly BNIP3 and worm DCT-1 evidence. Supporting Evidence: PMID:23209295 The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. PMID:22547685 These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver PMID:36896912 Fbxl4-/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4-/- mice. |
| GO:0000423 mitophagy | IEA GO_REF:0000107 | ACCEPT | Summary: Bnip3 mediates selective autophagy of mitochondria, acting as an LC3/GABARAP-binding receptor in the mitochondrial outer membrane. Reason: Core process. LIR-dependent mitophagy is shown directly, and Bnip3-null mouse liver accumulates mitochondrial mass. Bnip3 deletion also rescues the hyperactive mitophagy of Fbxl4-/- mice. The IBA (PTN001032684, Bilateria) agrees with fly BNIP3 and worm DCT-1 evidence. Supporting Evidence: PMID:23209295 The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. PMID:22547685 These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver PMID:36896912 Fbxl4-/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4-/- mice. |
| GO:0000423 mitophagy | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 mediates selective autophagy of mitochondria, acting as an LC3/GABARAP-binding receptor in the mitochondrial outer membrane. Reason: Core process. LIR-dependent mitophagy is shown directly, and Bnip3-null mouse liver accumulates mitochondrial mass. Bnip3 deletion also rescues the hyperactive mitophagy of Fbxl4-/- mice. The IBA (PTN001032684, Bilateria) agrees with fly BNIP3 and worm DCT-1 evidence. Supporting Evidence: PMID:23209295 The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. PMID:22547685 These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver PMID:36896912 Fbxl4-/- mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4-/- mice. |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | ACCEPT | Summary: Bnip3 is a HIF-1 target induced by hypoxia, and it mediates hypoxia-induced autophagy. Reason: Well-supported effector role in the hypoxia response. The HRE in the mouse Bnip3 promoter is required for its induction. Supporting Evidence: PMID:19273585 the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy PMID:16954213 Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction |
| GO:0001666 response to hypoxia | ISO GO_REF:0000096 | ACCEPT | Summary: Bnip3 is a HIF-1 target induced by hypoxia, and it mediates hypoxia-induced autophagy. Reason: Well-supported effector role in the hypoxia response. The HRE in the mouse Bnip3 promoter is required for its induction. Supporting Evidence: PMID:19273585 the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy PMID:16954213 Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction |
| GO:0001666 response to hypoxia | ISS GO_REF:0000024 | ACCEPT | Summary: Bnip3 is a HIF-1 target induced by hypoxia, and it mediates hypoxia-induced autophagy. Reason: Well-supported effector role in the hypoxia response. The HRE in the mouse Bnip3 promoter is required for its induction. Supporting Evidence: PMID:19273585 the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy PMID:16954213 Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear BNIP3 has been reported in some cell types, for example glioma and some tumour cells. Reason: A minor, cell-type-specific location that is not the site of the core receptor function. The IBA (PTN001032684) is seeded only by vertebrate BNIP3/BNIP3L/rat Bnip3, so a Bilateria-level placement of a nuclear location is generous. |
| GO:0005634 nucleus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nuclear BNIP3 has been reported in some cell types, for example glioma and some tumour cells. Reason: A minor, cell-type-specific location that is not the site of the core receptor function. The IBA (PTN001032684) is seeded only by vertebrate BNIP3/BNIP3L/rat Bnip3, so a Bilateria-level placement of a nuclear location is generous. |
| GO:0005634 nucleus | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Nuclear BNIP3 has been reported in some cell types, for example glioma and some tumour cells. Reason: A minor, cell-type-specific location that is not the site of the core receptor function. The IBA (PTN001032684) is seeded only by vertebrate BNIP3/BNIP3L/rat Bnip3, so a Bilateria-level placement of a nuclear location is generous. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nuclear BNIP3 has been reported in some cell types, for example glioma and some tumour cells. Reason: A minor, cell-type-specific location that is not the site of the core receptor function. The IBA (PTN001032684) is seeded only by vertebrate BNIP3/BNIP3L/rat Bnip3, so a Bilateria-level placement of a nuclear location is generous. |
| GO:0005635 nuclear envelope | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear envelope localization of NIP3 was seen mainly on co-expression with adenovirus E1B 19K. Reason: A minor and partly artefactual location: UniProt records the shift to the nuclear envelope on co-expression with E1B-19K. The nuclear envelope is continuous with the ER, where an endogenous Bnip3 pool does reside. Not a core location. Supporting Evidence: file:mouse/Bnip3/Bnip3-uniprot.txt Coexpression with the EIB 19-kDa protein results in a shift in NIP3 localization pattern to the nuclear envelope PMID:22505714 In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). |
| GO:0005635 nuclear envelope | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nuclear envelope localization of NIP3 was seen mainly on co-expression with adenovirus E1B 19K. Reason: A minor and partly artefactual location: UniProt records the shift to the nuclear envelope on co-expression with E1B-19K. The nuclear envelope is continuous with the ER, where an endogenous Bnip3 pool does reside. Not a core location. Supporting Evidence: file:mouse/Bnip3/Bnip3-uniprot.txt Coexpression with the EIB 19-kDa protein results in a shift in NIP3 localization pattern to the nuclear envelope PMID:22505714 In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). |
| GO:0005635 nuclear envelope | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Nuclear envelope localization of NIP3 was seen mainly on co-expression with adenovirus E1B 19K. Reason: A minor and partly artefactual location: UniProt records the shift to the nuclear envelope on co-expression with E1B-19K. The nuclear envelope is continuous with the ER, where an endogenous Bnip3 pool does reside. Not a core location. Supporting Evidence: file:mouse/Bnip3/Bnip3-uniprot.txt Coexpression with the EIB 19-kDa protein results in a shift in NIP3 localization pattern to the nuclear envelope PMID:22505714 In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). |
| GO:0005635 nuclear envelope | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nuclear envelope localization of NIP3 was seen mainly on co-expression with adenovirus E1B 19K. Reason: A minor and partly artefactual location: UniProt records the shift to the nuclear envelope on co-expression with E1B-19K. The nuclear envelope is continuous with the ER, where an endogenous Bnip3 pool does reside. Not a core location. Supporting Evidence: file:mouse/Bnip3/Bnip3-uniprot.txt Coexpression with the EIB 19-kDa protein results in a shift in NIP3 localization pattern to the nuclear envelope PMID:22505714 In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). |
| GO:0005654 nucleoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nucleoplasmic BNIP3 is reported in some cell types (rat-sourced transfer). Reason: A minor, cell-type-specific location that is not the site of the core function. |
| GO:0005654 nucleoplasm | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Nucleoplasmic BNIP3 is reported in some cell types (rat-sourced transfer). Reason: A minor, cell-type-specific location that is not the site of the core function. |
| GO:0005654 nucleoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Nucleoplasmic BNIP3 is reported in some cell types (rat-sourced transfer). Reason: A minor, cell-type-specific location that is not the site of the core function. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | ACCEPT | Summary: Bnip3 is a cytoplasmic organelle-membrane protein, with its N-terminal domain facing the cytosol. Reason: Correct, broad location. Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. |
| GO:0005737 cytoplasm | ISO GO_REF:0000096 | ACCEPT | Summary: Bnip3 is a cytoplasmic organelle-membrane protein, with its N-terminal domain facing the cytosol. Reason: Correct, broad location. Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Bnip3 is a cytoplasmic organelle-membrane protein, with its N-terminal domain facing the cytosol. Reason: Correct, broad location. Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. |
| GO:0005739 mitochondrion | HDA PMID:14651853 Integrated analysis of protein composition, tissue diversity... | ACCEPT | Summary: Bnip3 was detected in the mouse mitochondrial proteome (brain, heart, kidney, liver). Reason: A high-throughput localization consistent with extensive targeted evidence. GO:0005741 is the more specific location. Supporting Evidence: PMID:14651853 we performed a proteomic survey of mitochondria from mouse brain, heart, kidney, and liver PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Bnip3 is a mitochondrial protein. It is found in the mouse mitochondrial proteome and is anchored in the outer membrane by its C-terminal TM helix. Reason: Correct. GO:0005741 is the more specific location. Supporting Evidence: PMID:9396766 Nip3 is expressed in mitochondria and a mutant (Nip3(163)) lacking the putative transmembrane domain and COOH terminus does not dimerize or localize to mitochondria. PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. |
| GO:0005739 mitochondrion | ISO GO_REF:0000008 | ACCEPT | Summary: Bnip3 is a mitochondrial protein. It is found in the mouse mitochondrial proteome and is anchored in the outer membrane by its C-terminal TM helix. Reason: Correct. GO:0005741 is the more specific location. Supporting Evidence: PMID:9396766 Nip3 is expressed in mitochondria and a mutant (Nip3(163)) lacking the putative transmembrane domain and COOH terminus does not dimerize or localize to mitochondria. PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. |
| GO:0005739 mitochondrion | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 is a mitochondrial protein. It is found in the mouse mitochondrial proteome and is anchored in the outer membrane by its C-terminal TM helix. Reason: Correct. GO:0005741 is the more specific location. Supporting Evidence: PMID:9396766 Nip3 is expressed in mitochondria and a mutant (Nip3(163)) lacking the putative transmembrane domain and COOH terminus does not dimerize or localize to mitochondria. PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: Bnip3 is a mitochondrial protein. It is found in the mouse mitochondrial proteome and is anchored in the outer membrane by its C-terminal TM helix. Reason: Correct. GO:0005741 is the more specific location. Supporting Evidence: PMID:9396766 Nip3 is expressed in mitochondria and a mutant (Nip3(163)) lacking the putative transmembrane domain and COOH terminus does not dimerize or localize to mitochondria. PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. |
| GO:0005740 mitochondrial envelope | IEA GO_REF:0000002 | ACCEPT | Summary: Bnip3 is an integral mitochondrial outer membrane protein. Reason: Correct but less specific than GO:0005741. Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. |
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Bnip3 is a tail-anchored mitochondrial outer membrane protein with its N terminus (LIR, BH3) in the cytosol. Reason: Primary functional location. Consistent with the IBA (PTN001032684). Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. file:mouse/Bnip3/Bnip3-uniprot.txt Mitochondrion outer membrane {ECO:0000250}; Single-pass membrane protein |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Bnip3 is a tail-anchored mitochondrial outer membrane protein with its N terminus (LIR, BH3) in the cytosol. Reason: Primary functional location. Consistent with the IBA (PTN001032684). Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. file:mouse/Bnip3/Bnip3-uniprot.txt Mitochondrion outer membrane {ECO:0000250}; Single-pass membrane protein |
| GO:0005741 mitochondrial outer membrane | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 is a tail-anchored mitochondrial outer membrane protein with its N terminus (LIR, BH3) in the cytosol. Reason: Primary functional location. Consistent with the IBA (PTN001032684). Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. file:mouse/Bnip3/Bnip3-uniprot.txt Mitochondrion outer membrane {ECO:0000250}; Single-pass membrane protein |
| GO:0005741 mitochondrial outer membrane | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 is a tail-anchored mitochondrial outer membrane protein with its N terminus (LIR, BH3) in the cytosol. Reason: Primary functional location. Consistent with the IBA (PTN001032684). Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. file:mouse/Bnip3/Bnip3-uniprot.txt Mitochondrion outer membrane {ECO:0000250}; Single-pass membrane protein |
| GO:0005741 mitochondrial outer membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Bnip3 is a tail-anchored mitochondrial outer membrane protein with its N terminus (LIR, BH3) in the cytosol. Reason: Primary functional location. Consistent with the IBA (PTN001032684). Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. PMID:22547685 BNip3 localizes to the outer mitochondrial membrane, where it functions in mitophagy and mitochondrial dynamics. file:mouse/Bnip3/Bnip3-uniprot.txt Mitochondrion outer membrane {ECO:0000250}; Single-pass membrane protein |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: An endogenous Bnip3 pool resides in the ER, where it can drive ER-phagy. Reason: Supported by direct evidence (PMID:22505714) and the IBA. Supporting Evidence: PMID:22505714 In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: An endogenous Bnip3 pool resides in the ER membrane, where it can drive ER-phagy. Reason: Supported by direct evidence (PMID:22505714) and the IBA. Supporting Evidence: PMID:22505714 In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). PMID:22505714 We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000107 | ACCEPT | Summary: An endogenous Bnip3 pool resides in the ER membrane, where it can drive ER-phagy. Reason: Supported by direct evidence (PMID:22505714) and the IBA. Supporting Evidence: PMID:22505714 In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). PMID:22505714 We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. |
| GO:0005789 endoplasmic reticulum membrane | ISO GO_REF:0000119 | ACCEPT | Summary: An endogenous Bnip3 pool resides in the ER membrane, where it can drive ER-phagy. Reason: Supported by direct evidence (PMID:22505714) and the IBA. Supporting Evidence: PMID:22505714 In addition, we discovered that endogenous Bnip3 is localized to both mitochondria and the endoplasmic reticulum (ER). PMID:22505714 We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. |
| GO:0006915 apoptotic process | ISO PMID:7954800 Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a com... | KEEP AS NON CORE | Summary: Bnip3 (Nip3) was identified as an E1B-19K/BCL2-interacting protein and can promote cell death when overexpressed. Reason: Cell death roles are real but context-dependent and secondary to the receptor function. The cited paper (PMID:7954800) shows the E1B-19K/BCL2 interaction rather than a death phenotype; pro-death activity is from later work. Supporting Evidence: PMID:7954800 We have isolated cDNAs for three different proteins, designated Nip1, Nip2, and Nip3, that interact with the 19 kDa protein. PMID:9396766 In conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can overcome Bcl-2 suppression. |
| GO:0009617 response to bacterium | IEP PMID:23012479 Impact of lactobacilli on orally acquired listeriosis. | MARK AS OVER ANNOTATED | Summary: Expression-based annotation from an intestinal transcriptomic study of Listeria infection in gnotobiotic mice. Reason: IEP from a genome-wide expression survey. A change in Bnip3 transcript level during infection does not show that Bnip3 does any of the work of an antibacterial response, and nothing else links Bnip3 to bacterial defence. Supporting Evidence: PMID:23012479 A whole genome intestinal transcriptomic analysis revealed that each Lactobacillus changes expression of a specific subset of genes during infection |
| GO:0010637 negative regulation of mitochondrial fusion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BNIP3 binds OPA1 and inhibits OPA1-mediated fusion, which leads to fragmentation. Reason: Mechanistically specific and experimentally supported in the human/rodent source, but secondary to the receptor role. Supporting Evidence: PMID:20436456 Fission is due to inhibition of Opa1-mediated fusion and is counteracted by Opa1 in an Mfn1-dependent manner. |
| GO:0010637 negative regulation of mitochondrial fusion | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: BNIP3 binds OPA1 and inhibits OPA1-mediated fusion, which leads to fragmentation. Reason: Mechanistically specific and experimentally supported in the human/rodent source, but secondary to the receptor role. Supporting Evidence: PMID:20436456 Fission is due to inhibition of Opa1-mediated fusion and is counteracted by Opa1 in an Mfn1-dependent manner. |
| GO:0010659 cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: In mouse, Bnip3 contributes to cardiomyocyte death after ischaemia/reperfusion, and forced cardiac expression causes apoptosis. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium PMID:17909626 Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice |
| GO:0010659 cardiac muscle cell apoptotic process | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: In mouse, Bnip3 contributes to cardiomyocyte death after ischaemia/reperfusion, and forced cardiac expression causes apoptosis. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium PMID:17909626 Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice |
| GO:0010666 positive regulation of cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: In mouse, Bnip3 promotes cardiomyocyte apoptosis after ischaemia/reperfusion. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium PMID:17909626 Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice |
| GO:0010666 positive regulation of cardiac muscle cell apoptotic process | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: In mouse, Bnip3 promotes cardiomyocyte apoptosis after ischaemia/reperfusion. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium PMID:17909626 Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice |
| GO:0010917 negative regulation of mitochondrial membrane potential | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BNIP3 overexpression causes PT pore opening and loss of mitochondrial membrane potential. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0010917 negative regulation of mitochondrial membrane potential | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: BNIP3 overexpression causes PT pore opening and loss of mitochondrial membrane potential. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0014069 postsynaptic density | IDA PMID:17114649 Qualitative and quantitative analyses of protein phosphoryla... | MARK AS OVER ANNOTATED | Summary: Bnip3 phosphopeptides were detected in mouse synaptosomal preparations. Reason: A large-scale phosphoproteomic survey of synaptosomes, which contain mitochondria. Detection in this fraction is consistent with Bnip3's mitochondrial location and does not show that it is a postsynaptic density component; no targeted study places Bnip3 at the PSD. Supporting Evidence: PMID:17114649 we isolated and identified 974 unique phosphorylation sites on 499 proteins |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Bnip3 is an integral membrane protein (single C-terminal TM helix). Reason: Correct, broad location. Supporting Evidence: file:mouse/Bnip3/Bnip3-uniprot.txt Mitochondrion outer membrane {ECO:0000250}; Single-pass membrane protein |
| GO:0016239 positive regulation of macroautophagy | ISO GO_REF:0000008 | ACCEPT | Summary: HIF-induced BNIP3, redundantly with BNIP3L, is required for hypoxia-induced autophagy. Reason: Directly supported (human ortholog source, PMID:19273585). Bnip3 also induces autophagy in rodent cells. Supporting Evidence: PMID:19273585 the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy PMID:19273585 Herein, we propose a model in which the atypical BH3 domains of hypoxia-induced BNIP3/BNIP3L have been designed to induce autophagy by disrupting the Bcl-2-Beclin1 complex without inducing cell death. PMID:22505714 Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. |
| GO:0021987 cerebral cortex development | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred developmental annotation (rat). Reason: Ortholog-transferred developmental process. Bnip3 has no established direct role in this developmental program. Any phenotype is most plausibly secondary to its effects on mitochondrial turnover and cell death. |
| GO:0030425 dendrite | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Dendritic localization transferred from rat. Reason: Plausible cell-type-specific location (mitochondria/ER in dendrites), not informative about the core function. |
| GO:0030425 dendrite | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Dendritic localization transferred from rat. Reason: Plausible cell-type-specific location (mitochondria/ER in dendrites), not informative about the core function. |
| GO:0030425 dendrite | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Dendritic localization transferred from rat. Reason: Plausible cell-type-specific location (mitochondria/ER in dendrites), not informative about the core function. |
| GO:0031966 mitochondrial membrane | IDA PMID:10891486 BNIP3 and genetic control of necrosis-like cell death throug... | ACCEPT | Summary: Endogenous BNIP3 associates loosely with mitochondrial membranes and integrates fully into the outer membrane upon death induction. Reason: Correct. GO:0005741 is more specific. Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Bnip3 is an integral mitochondrial (outer) membrane protein. Reason: Correct. GO:0005741 is more specific. Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. |
| GO:0031966 mitochondrial membrane | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 is an integral mitochondrial (outer) membrane protein. Reason: Correct. GO:0005741 is more specific. Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. |
| GO:0031966 mitochondrial membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Bnip3 is an integral mitochondrial (outer) membrane protein. Reason: Correct. GO:0005741 is more specific. Supporting Evidence: PMID:10891486 We report that endogenous BNIP3 is loosely associated with mitochondrial membrane in normal tissue but fully integrates into the mitochondrial outer membrane with the N terminus in the cytoplasm and the C terminus in the membrane during induction of cell death. |
| GO:0035694 mitochondrial protein catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BNIP3, with NIX, mediates Mieap/SPATA18-induced accumulation of lysosomal proteins within mitochondria (MALM). Reason: A genuine, distinct mitochondrial quality-control function, but less established than receptor-mediated mitophagy. Supporting Evidence: PMID:22292033 These results suggest that two mitochondrial outer membrane proteins, BNIP3 and NIX, mediate MALM in order to maintain mitochondrial integrity. file:mouse/Bnip3/Bnip3-uniprot.txt participates in mitochondrial protein catabolic process (also named MALM) |
| GO:0035694 mitochondrial protein catabolic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: BNIP3, with NIX, mediates Mieap/SPATA18-induced accumulation of lysosomal proteins within mitochondria (MALM). Reason: A genuine, distinct mitochondrial quality-control function, but less established than receptor-mediated mitophagy. Supporting Evidence: PMID:22292033 These results suggest that two mitochondrial outer membrane proteins, BNIP3 and NIX, mediate MALM in order to maintain mitochondrial integrity. file:mouse/Bnip3/Bnip3-uniprot.txt participates in mitochondrial protein catabolic process (also named MALM) |
| GO:0035694 mitochondrial protein catabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: BNIP3, with NIX, mediates Mieap/SPATA18-induced accumulation of lysosomal proteins within mitochondria (MALM). Reason: A genuine, distinct mitochondrial quality-control function, but less established than receptor-mediated mitophagy. Supporting Evidence: PMID:22292033 These results suggest that two mitochondrial outer membrane proteins, BNIP3 and NIX, mediate MALM in order to maintain mitochondrial integrity. file:mouse/Bnip3/Bnip3-uniprot.txt participates in mitochondrial protein catabolic process (also named MALM) |
| GO:0042802 identical protein binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Bnip3 self-associates into SDS-resistant homodimers through its TM helix. Reason: Self-association is real and needed for both autophagy induction and pro-death activity. It is a structural property rather than the core activity. The more specific term, protein homodimerization activity (GO:0042803), is also annotated. Supporting Evidence: PMID:22505714 Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. PMID:9396766 Nip3 is detected as both a 60- and 30-kD protein in vivo and in vitro and exhibits strong homologous interaction in a yeast two-hybrid system indicating that it can homodimerize. |
| GO:0042802 identical protein binding | IPI PMID:22044588 p53-TIGAR axis attenuates mitophagy to exacerbate cardiac da... | KEEP AS NON CORE | Summary: Bnip3 dimer detection in mouse ischaemic heart (the IPI WITH is Bnip3 itself). Reason: Only the abstract is available. The paper reports Bnip3 'activation' in ischaemic myocardium, plausibly scored as the SDS-resistant dimer. Self-association is real but structural; GO:0042803 is the more informative term. Supporting Evidence: PMID:22044588 ROS production was elevated and followed by Bnip3 activation which is an initiator of mitophagy PMID:9396766 Nip3 is detected as both a 60- and 30-kD protein in vivo and in vitro and exhibits strong homologous interaction in a yeast two-hybrid system indicating that it can homodimerize. |
| GO:0042802 identical protein binding | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Bnip3 self-associates into SDS-resistant homodimers through its TM helix. Reason: Self-association is real and needed for both autophagy induction and pro-death activity. It is a structural property rather than the core activity. The more specific term, protein homodimerization activity (GO:0042803), is also annotated. Supporting Evidence: PMID:22505714 Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. PMID:9396766 Nip3 is detected as both a 60- and 30-kD protein in vivo and in vitro and exhibits strong homologous interaction in a yeast two-hybrid system indicating that it can homodimerize. |
| GO:0042802 identical protein binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Bnip3 self-associates into SDS-resistant homodimers through its TM helix. Reason: Self-association is real and needed for both autophagy induction and pro-death activity. It is a structural property rather than the core activity. The more specific term, protein homodimerization activity (GO:0042803), is also annotated. Supporting Evidence: PMID:22505714 Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. PMID:9396766 Nip3 is detected as both a 60- and 30-kD protein in vivo and in vitro and exhibits strong homologous interaction in a yeast two-hybrid system indicating that it can homodimerize. |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: Bnip3 homodimerizes through its C-terminal TM helix, which is required for autophagy induction. Reason: Directly shown and functionally required. Supporting Evidence: PMID:9396766 Nip3 is detected as both a 60- and 30-kD protein in vivo and in vitro and exhibits strong homologous interaction in a yeast two-hybrid system indicating that it can homodimerize. PMID:22505714 Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. |
| GO:0042803 protein homodimerization activity | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 homodimerizes through its C-terminal TM helix, which is required for autophagy induction. Reason: Directly shown and functionally required. Supporting Evidence: PMID:9396766 Nip3 is detected as both a 60- and 30-kD protein in vivo and in vitro and exhibits strong homologous interaction in a yeast two-hybrid system indicating that it can homodimerize. PMID:22505714 Bnip3 contains a C-terminal transmembrane domain that is essential for homodimerization and proapoptotic function. In this study, we show that homodimerization of Bnip3 is also a requirement for induction of autophagy. |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Bnip3 can promote apoptotic and necrosis-like death, as seen in the post-infarct mouse heart and in overexpression studies. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:9396766 In conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can overcome Bcl-2 suppression. PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium PMID:10891486 We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Bnip3 can promote apoptotic and necrosis-like death, as seen in the post-infarct mouse heart and in overexpression studies. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:9396766 In conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can overcome Bcl-2 suppression. PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium PMID:10891486 We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction. |
| GO:0043065 positive regulation of apoptotic process | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Bnip3 can promote apoptotic and necrosis-like death, as seen in the post-infarct mouse heart and in overexpression studies. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:9396766 In conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can overcome Bcl-2 suppression. PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium PMID:10891486 We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction. |
| GO:0043065 positive regulation of apoptotic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Bnip3 can promote apoptotic and necrosis-like death, as seen in the post-infarct mouse heart and in overexpression studies. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:9396766 In conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can overcome Bcl-2 suppression. PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium PMID:10891486 We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction. |
| GO:0043065 positive regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Bnip3 can promote apoptotic and necrosis-like death, as seen in the post-infarct mouse heart and in overexpression studies. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:9396766 In conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can overcome Bcl-2 suppression. PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium PMID:10891486 We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction. |
| GO:0043068 positive regulation of programmed cell death | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Bnip3 promotes mitochondrial, PT-pore-dependent cell death when overexpressed. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:10891486 We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction. |
| GO:0043068 positive regulation of programmed cell death | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Bnip3 promotes mitochondrial, PT-pore-dependent cell death when overexpressed. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:10891486 We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction. |
| GO:0043069 negative regulation of programmed cell death | ISO GO_REF:0000008 | KEEP AS NON CORE | Summary: Ablation of BNIP3/BNIP3L triggers cell death under hypoxia, and BNIP3-induced mitophagy can be pro-survival. Reason: Supported by genetic evidence in the human source. Cell-fate roles are context-dependent and secondary. Supporting Evidence: PMID:19273585 In addition, the ablation of BNIP3 and/or BNIP3L triggers cell death, and BNIP3 and BNIP3L are crucial for hypoxia-induced autophagy. |
| GO:0043243 positive regulation of protein-containing complex disassembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The BNIP3-OPA1 interaction disrupts OPA1 complexes. Reason: An experimentally supported mechanistic detail, but secondary. Supporting Evidence: PMID:20436456 Bnip3-Opa1 interaction is necessary to trigger Opa1 complex disruption in a Bax- and/or Bak-dependent manner, ultimately leading to apoptosis. |
| GO:0043243 positive regulation of protein-containing complex disassembly | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: The BNIP3-OPA1 interaction disrupts OPA1 complexes. Reason: An experimentally supported mechanistic detail, but secondary. Supporting Evidence: PMID:20436456 Bnip3-Opa1 interaction is necessary to trigger Opa1 complex disruption in a Bax- and/or Bak-dependent manner, ultimately leading to apoptosis. |
| GO:0043653 mitochondrial fragmentation involved in apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: BNIP3 binding to OPA1 promotes mitochondrial fragmentation and apoptosis. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. The IBA node (PTN001032684, Bilateria) for this term is seeded only by human BNIP3, so its deep placement rests on mammalian data. Supporting Evidence: PMID:20436456 We show that Bnip3 interacts with Opa1, leading to mitochondrial fragmentation and apoptosis. PMID:20436456 Fission is due to inhibition of Opa1-mediated fusion and is counteracted by Opa1 in an Mfn1-dependent manner. |
| GO:0043653 mitochondrial fragmentation involved in apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BNIP3 binding to OPA1 promotes mitochondrial fragmentation and apoptosis. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. The IBA node (PTN001032684, Bilateria) for this term is seeded only by human BNIP3, so its deep placement rests on mammalian data. Supporting Evidence: PMID:20436456 We show that Bnip3 interacts with Opa1, leading to mitochondrial fragmentation and apoptosis. PMID:20436456 Fission is due to inhibition of Opa1-mediated fusion and is counteracted by Opa1 in an Mfn1-dependent manner. |
| GO:0043653 mitochondrial fragmentation involved in apoptotic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: BNIP3 binding to OPA1 promotes mitochondrial fragmentation and apoptosis. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. The IBA node (PTN001032684, Bilateria) for this term is seeded only by human BNIP3, so its deep placement rests on mammalian data. Supporting Evidence: PMID:20436456 We show that Bnip3 interacts with Opa1, leading to mitochondrial fragmentation and apoptosis. PMID:20436456 Fission is due to inhibition of Opa1-mediated fusion and is counteracted by Opa1 in an Mfn1-dependent manner. |
| GO:0045837 negative regulation of membrane potential | IEA GO_REF:0000107 | MODIFY | Summary: BNIP3 overexpression dissipates the mitochondrial membrane potential. Reason: The effect is specifically on the mitochondrial membrane potential, so the mitochondrial term is more precise. It is a secondary, death-associated effect. Proposed replacements: negative regulation of mitochondrial membrane potential Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0045837 negative regulation of membrane potential | ISO GO_REF:0000119 | MODIFY | Summary: BNIP3 overexpression dissipates the mitochondrial membrane potential. Reason: The effect is specifically on the mitochondrial membrane potential, so the mitochondrial term is more precise. It is a secondary, death-associated effect. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q12983 · BNIP3 SUPPORTS TRANSFER Human BNIP3 IDA (PMID:10891486) shows loss of mitochondrial membrane potential; the mitochondrial child term GO:0010917 is more precise. Proposed replacements: negative regulation of mitochondrial membrane potential Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0045837 negative regulation of membrane potential | ISS GO_REF:0000024 | MODIFY | Summary: BNIP3 overexpression dissipates the mitochondrial membrane potential. Reason: The effect is specifically on the mitochondrial membrane potential, so the mitochondrial term is more precise. It is a secondary, death-associated effect. Proposed replacements: negative regulation of mitochondrial membrane potential Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0046902 regulation of mitochondrial membrane permeability | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BNIP3 promotes PT pore opening. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0046902 regulation of mitochondrial membrane permeability | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: BNIP3 promotes PT pore opening. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0046902 regulation of mitochondrial membrane permeability | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: BNIP3 promotes PT pore opening. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0048102 autophagic cell death | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ortholog transfer of a contested process concept. Reason: The evidence supports Bnip3 promoting autophagy and, separately, necrosis-like death. It does not show that autophagy is the means by which cells die. Supporting Evidence: PMID:10891486 We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction. PMID:19273585 Herein, we propose a model in which the atypical BH3 domains of hypoxia-induced BNIP3/BNIP3L have been designed to induce autophagy by disrupting the Bcl-2-Beclin1 complex without inducing cell death. |
| GO:0048102 autophagic cell death | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: Ortholog transfer of a contested process concept. Reason: The evidence supports Bnip3 promoting autophagy and, separately, necrosis-like death. It does not show that autophagy is the means by which cells die. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: RGD:620800 · Bnip3 SOURCE WEAK OR INFERRED Rat source treats Bnip3-associated autophagy and death as autophagic cell death; evidence separates the two activities. Supporting Evidence: PMID:10891486 We propose that BNIP3 is a gene that mediates a necrosis-like cell death through PT pore opening and mitochondrial dysfunction. PMID:19273585 Herein, we propose a model in which the atypical BH3 domains of hypoxia-induced BNIP3/BNIP3L have been designed to induce autophagy by disrupting the Bcl-2-Beclin1 complex without inducing cell death. |
| GO:0048678 response to axon injury | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Rat-sourced annotation to response to axon injury. Reason: This is an ortholog transfer of a rat annotation that most likely rests on altered Bnip3 expression or a phenotype seen under this stimulus. Bnip3 is a HIF-responsive stress gene, and a stress-induced change in its level does not show that it carries out part of a dedicated response to this stimulus. |
| GO:0048709 oligodendrocyte differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Rat-sourced developmental annotation. Reason: Ortholog-transferred developmental process. Bnip3 has no established direct role in this developmental program. Any phenotype is most plausibly secondary to its effects on mitochondrial turnover and cell death. |
| GO:0050873 brown fat cell differentiation | IDA PMID:18492766 Wdnm1-like, a new adipokine with a role in MMP-2 activation. | MARK AS OVER ANNOTATED | Summary: Bnip3 is one of many transcripts upregulated during in vitro brown adipogenesis. Reason: I checked the full text (PMC2493586). Bnip3 appears only in Table 1, the PCR validation of genes upregulated during in vitro brown adipogenesis; the paper is about the adipokine Wdnm1-like. This is expression evidence with no functional test, so it does not show that Bnip3 acts in brown fat cell differentiation. Supporting Evidence: PMID:18492766 DNA microarray analysis led us to identify Wdnm1-like |
| GO:0051020 GTPase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BNIP3 binds the dynamin-related GTPase OPA1. Reason: An experimentally supported interaction with a GTPase. It informs the fragmentation/apoptosis mechanism but is secondary to the receptor function. Supporting Evidence: PMID:20436456 We show that Bnip3 interacts with Opa1, leading to mitochondrial fragmentation and apoptosis. |
| GO:0051020 GTPase binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: BNIP3 binds the dynamin-related GTPase OPA1. Reason: An experimentally supported interaction with a GTPase. It informs the fragmentation/apoptosis mechanism but is secondary to the receptor function. Supporting Evidence: PMID:20436456 We show that Bnip3 interacts with Opa1, leading to mitochondrial fragmentation and apoptosis. |
| GO:0051402 neuron apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat Bnip3 is implicated in neuronal death after hypoxic/ischaemic stress. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. |
| GO:0051402 neuron apoptotic process | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Rat Bnip3 is implicated in neuronal death after hypoxic/ischaemic stress. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. |
| GO:0051402 neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Rat Bnip3 is implicated in neuronal death after hypoxic/ischaemic stress. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. |
| GO:0051561 positive regulation of mitochondrial calcium ion concentration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Rat-sourced annotation; BNIP3 may repartition Ca2+ between ER and mitochondria. Reason: A plausible secondary role, not core. |
| GO:0051561 positive regulation of mitochondrial calcium ion concentration | ISO GO_REF:0000096 | KEEP AS NON CORE | Summary: Rat-sourced annotation; BNIP3 may repartition Ca2+ between ER and mitochondria. Reason: A plausible secondary role, not core. |
| GO:0051607 defense response to virus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from a human IDA (PMID:9973195) that reports BNIP3 binding to viral anti-apoptotic proteins. Reason: Binding by viral anti-apoptotic proteins makes BNIP3 a target of viral immune evasion, not an antiviral effector. The human source annotation itself could not be verified (marked UNDECIDED in the human review), and there is no mouse evidence of antiviral activity. |
| GO:0051607 defense response to virus | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Transferred from a human IDA (PMID:9973195) that reports BNIP3 binding to viral anti-apoptotic proteins. Reason: Binding by viral anti-apoptotic proteins makes BNIP3 a target of viral immune evasion, not an antiviral effector. The human source annotation itself could not be verified (marked UNDECIDED in the human review), and there is no mouse evidence of antiviral activity. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q12983 · BNIP3 SOURCE BAD Human IDA (PMID:9973195) reports binding by viral anti-apoptotic proteins, which makes BNIP3 a viral target, not an antiviral effector; UNDECIDED in the human review. |
| GO:0051607 defense response to virus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from a human IDA (PMID:9973195) that reports BNIP3 binding to viral anti-apoptotic proteins. Reason: Binding by viral anti-apoptotic proteins makes BNIP3 a target of viral immune evasion, not an antiviral effector. The human source annotation itself could not be verified (marked UNDECIDED in the human review), and there is no mouse evidence of antiviral activity. |
| GO:0055093 response to hyperoxia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Rat-sourced annotation to response to hyperoxia. Reason: This is an ortholog transfer of a rat annotation that most likely rests on altered Bnip3 expression or a phenotype seen under this stimulus. Bnip3 is a HIF-responsive stress gene, and a stress-induced change in its level does not show that it carries out part of a dedicated response to this stimulus. |
| GO:0061709 reticulophagy | IBA GO_REF:0000033 | ACCEPT | Summary: Bnip3 induces LIR-dependent removal of ER via autophagy. Reason: Directly supported by PMID:22505714 and the IBA (PTN002689498). Supporting Evidence: PMID:22505714 We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. |
| GO:0061709 reticulophagy | IEA GO_REF:0000107 | ACCEPT | Summary: Bnip3 induces LIR-dependent removal of ER via autophagy. Reason: Directly supported by PMID:22505714 and the IBA (PTN002689498). Supporting Evidence: PMID:22505714 We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. |
| GO:0061709 reticulophagy | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 induces LIR-dependent removal of ER via autophagy. Reason: Directly supported by PMID:22505714 and the IBA (PTN002689498). Supporting Evidence: PMID:22505714 We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. |
| GO:0061753 obsolete substrate localization to autophagosome | IEA GO_REF:0000120 | REMOVE | Summary: GOA labels this term obsolete (substrate localization to autophagosome). Reason: The term is obsolete. The underlying biology, Bnip3 delivering mitochondria and ER to autophagosomes, is captured by GO:0140580, GO:0140506, GO:0000423 and GO:0061709. |
| GO:0070301 cellular response to hydrogen peroxide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Rat-sourced annotation to cellular response to hydrogen peroxide. Reason: This is an ortholog transfer of a rat annotation that most likely rests on altered Bnip3 expression or a phenotype seen under this stimulus. Bnip3 is a HIF-responsive stress gene, and a stress-induced change in its level does not show that it carries out part of a dedicated response to this stimulus. |
| GO:0070301 cellular response to hydrogen peroxide | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: Rat-sourced annotation to cellular response to hydrogen peroxide. Reason: This is an ortholog transfer of a rat annotation that most likely rests on altered Bnip3 expression or a phenotype seen under this stimulus. Bnip3 is a HIF-responsive stress gene, and a stress-induced change in its level does not show that it carries out part of a dedicated response to this stimulus. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH ROLE CONFLATION Sources checked: RGD:620800 · Bnip3 SUPPORTS SOURCE BUT NOT TARGET Rat annotation reflects stress-induced Bnip3 expression or death in a specific cell model; not a dedicated H2O2 response role. |
| GO:0071260 cellular response to mechanical stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: Electronic transfer of a human IEP annotation (PMID:19593445) to cellular response to mechanical stimulus. Reason: The human source evidence could not be located in the cached text and is UNDECIDED in the human review. There is no mouse evidence either way. |
| GO:0071279 cellular response to cobalt ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cobalt is used as a hypoxia mimetic that stabilizes HIF. Reason: BNIP3 has no cobalt-specific role. The relevant biology is captured by cellular response to hypoxia. |
| GO:0071279 cellular response to cobalt ion | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Cobalt is used as a hypoxia mimetic that stabilizes HIF. Reason: BNIP3 has no cobalt-specific role. The relevant biology is captured by cellular response to hypoxia. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q12983 · BNIP3 SOURCE WEAK OR INFERRED Human IMP (PMID:20436456) used cobalt as a hypoxia mimetic; the biology is captured by cellular response to hypoxia. |
| GO:0071456 cellular response to hypoxia | IEA GO_REF:0000120 | ACCEPT | Summary: Bnip3 is a HIF-1 target and an effector of the cellular response to hypoxia, needed with NIX for hypoxic autophagy. Reason: Well supported. Supporting Evidence: PMID:19273585 the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy PMID:19273585 In addition, the ablation of BNIP3 and/or BNIP3L triggers cell death, and BNIP3 and BNIP3L are crucial for hypoxia-induced autophagy. PMID:16954213 Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction |
| GO:0071456 cellular response to hypoxia | ISO GO_REF:0000008 | ACCEPT | Summary: Bnip3 is a HIF-1 target and an effector of the cellular response to hypoxia, needed with NIX for hypoxic autophagy. Reason: Well supported. Supporting Evidence: PMID:19273585 the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy PMID:19273585 In addition, the ablation of BNIP3 and/or BNIP3L triggers cell death, and BNIP3 and BNIP3L are crucial for hypoxia-induced autophagy. PMID:16954213 Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction |
| GO:0071456 cellular response to hypoxia | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 is a HIF-1 target and an effector of the cellular response to hypoxia, needed with NIX for hypoxic autophagy. Reason: Well supported. Supporting Evidence: PMID:19273585 the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy PMID:19273585 In addition, the ablation of BNIP3 and/or BNIP3L triggers cell death, and BNIP3 and BNIP3L are crucial for hypoxia-induced autophagy. PMID:16954213 Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction |
| GO:0072593 reactive oxygen species metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: BNIP3-induced mitochondrial damage increases ROS. Reason: Increased ROS is a downstream consequence of mitochondrial damage, not participation in ROS metabolism. Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0072593 reactive oxygen species metabolic process | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: BNIP3-induced mitochondrial damage increases ROS. Reason: Increased ROS is a downstream consequence of mitochondrial damage, not participation in ROS metabolism. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q12983 · BNIP3 SOURCE WEAK OR INFERRED Human IDA (PMID:10891486) observes increased ROS as a consequence of BNIP3-induced mitochondrial damage, not ROS metabolism by BNIP3. Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0072593 reactive oxygen species metabolic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: BNIP3-induced mitochondrial damage increases ROS. Reason: Increased ROS is a downstream consequence of mitochondrial damage, not participation in ROS metabolism. Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:0090141 positive regulation of mitochondrial fission | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: BNIP3 causes mitochondrial fragmentation. Reason: The reported mechanism is inhibition of fusion (captured by GO:0010637), so a positive-regulation-of-fission annotation misdescribes it. Supporting Evidence: PMID:20436456 Fission is due to inhibition of Opa1-mediated fusion and is counteracted by Opa1 in an Mfn1-dependent manner. |
| GO:0090141 positive regulation of mitochondrial fission | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: BNIP3 causes mitochondrial fragmentation. Reason: The reported mechanism is inhibition of fusion (captured by GO:0010637), so a positive-regulation-of-fission annotation misdescribes it. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q12983 · BNIP3 SOURCE WEAK OR INFERRED Human IDA (PMID:20436456) shows fragmentation via inhibition of OPA1-mediated fusion, captured by GO:0010637. Supporting Evidence: PMID:20436456 Fission is due to inhibition of Opa1-mediated fusion and is counteracted by Opa1 in an Mfn1-dependent manner. |
| GO:0090200 positive regulation of release of cytochrome c from mitochondria | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: BNIP3-OPA1 interaction can lead to Bax/Bak-dependent apoptosis. Reason: Context-dependent. Other studies find BNIP3-induced death independent of cytochrome c release. Supporting Evidence: PMID:20436456 Bnip3-Opa1 interaction is necessary to trigger Opa1 complex disruption in a Bax- and/or Bak-dependent manner, ultimately leading to apoptosis. PMID:10891486 Surprisingly, BNIP3-mediated cell death is independent of Apaf-1, caspase activation, cytochrome c release, and nuclear translocation of apoptosis-inducing factor. |
| GO:0090200 positive regulation of release of cytochrome c from mitochondria | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: BNIP3-OPA1 interaction can lead to Bax/Bak-dependent apoptosis. Reason: Context-dependent. Other studies find BNIP3-induced death independent of cytochrome c release. Supporting Evidence: PMID:20436456 Bnip3-Opa1 interaction is necessary to trigger Opa1 complex disruption in a Bax- and/or Bak-dependent manner, ultimately leading to apoptosis. PMID:10891486 Surprisingly, BNIP3-mediated cell death is independent of Apaf-1, caspase activation, cytochrome c release, and nuclear translocation of apoptosis-inducing factor. |
| GO:0090649 response to oxygen-glucose deprivation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Rat-sourced annotation to response to oxygen-glucose deprivation. Reason: This is an ortholog transfer of a rat annotation that most likely rests on altered Bnip3 expression or a phenotype seen under this stimulus. Bnip3 is a HIF-responsive stress gene, and a stress-induced change in its level does not show that it carries out part of a dedicated response to this stimulus. |
| GO:0097193 intrinsic apoptotic signaling pathway | IGI PMID:16954213 Activation of Ras up-regulates pro-apoptotic BNIP3 in nitric... | KEEP AS NON CORE | Summary: NO-induced, Ras/MEK/ERK/HIF-1-driven Bnip3 expression mediates macrophage death. Reason: Supported by mouse macrophage knockdown and promoter genetics (PMID:16954213; the IGI row is with MGI:96224). Cell death roles are context-dependent and secondary to the receptor function. Supporting Evidence: PMID:16954213 These results suggest that NO-induced death of macrophages is mediated, at least in part, by BNIP3 induction. PMID:16954213 Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction |
| GO:0097193 intrinsic apoptotic signaling pathway | IMP PMID:16954213 Activation of Ras up-regulates pro-apoptotic BNIP3 in nitric... | KEEP AS NON CORE | Summary: NO-induced, Ras/MEK/ERK/HIF-1-driven Bnip3 expression mediates macrophage death. Reason: Supported by mouse macrophage knockdown and promoter genetics (PMID:16954213; the IGI row is with MGI:96224). Cell death roles are context-dependent and secondary to the receptor function. Supporting Evidence: PMID:16954213 These results suggest that NO-induced death of macrophages is mediated, at least in part, by BNIP3 induction. PMID:16954213 Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction |
| GO:0097345 mitochondrial outer membrane permeabilization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Overexpressed BNIP3 can permeabilize mitochondria. Reason: Experimental in the human source, but cell-death roles are secondary and context-dependent. Other studies find death independent of cytochrome c release. Supporting Evidence: PMID:10891486 Surprisingly, BNIP3-mediated cell death is independent of Apaf-1, caspase activation, cytochrome c release, and nuclear translocation of apoptosis-inducing factor. |
| GO:0097345 mitochondrial outer membrane permeabilization | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Overexpressed BNIP3 can permeabilize mitochondria. Reason: Experimental in the human source, but cell-death roles are secondary and context-dependent. Other studies find death independent of cytochrome c release. Supporting Evidence: PMID:10891486 Surprisingly, BNIP3-mediated cell death is independent of Apaf-1, caspase activation, cytochrome c release, and nuclear translocation of apoptosis-inducing factor. |
| GO:0097345 mitochondrial outer membrane permeabilization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Overexpressed BNIP3 can permeabilize mitochondria. Reason: Experimental in the human source, but cell-death roles are secondary and context-dependent. Other studies find death independent of cytochrome c release. Supporting Evidence: PMID:10891486 Surprisingly, BNIP3-mediated cell death is independent of Apaf-1, caspase activation, cytochrome c release, and nuclear translocation of apoptosis-inducing factor. |
| GO:0140506 endoplasmic reticulum-autophagosome adaptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Bnip3 acts as an ER-phagy receptor, linking ER to LC3 on autophagosomes. Reason: A specific receptor activity, supported directly by PMID:22505714. Supporting Evidence: PMID:22505714 We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. PMID:22505714 The clearance of these organelles was mediated in part via binding of Bnip3 to LC3 on the autophagosome. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. |
| GO:0140506 endoplasmic reticulum-autophagosome adaptor activity | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 acts as an ER-phagy receptor, linking ER to LC3 on autophagosomes. Reason: A specific receptor activity, supported directly by PMID:22505714. Supporting Evidence: PMID:22505714 We also discovered that Bnip3 induced removal of both ER (ERphagy) and mitochondria (mitophagy) via autophagy. PMID:22505714 The clearance of these organelles was mediated in part via binding of Bnip3 to LC3 on the autophagosome. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. |
| GO:0140507 granzyme-mediated programmed cell death signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Overexpressed NIP3 sensitizes cells to granzyme B. Reason: A sensitization effect of overexpression does not show that Bnip3 is a component of the granzyme signalling pathway. Supporting Evidence: PMID:9396766 Nip3 overexpression increases the sensitivity to apoptosis induced by granzyme B and topoisomerase I and II inhibitors. |
| GO:0140580 mitochondrion autophagosome adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Bnip3 binds LC3/GABARAP through its N-terminal LIR, tethering mitochondria to autophagosomes. Reason: Core molecular function. Consistent with the IBA and directly supported, including LIR-phosphorylation studies in the mouse HL-1 cardiomyocyte line. Supporting Evidence: PMID:22505714 The clearance of these organelles was mediated in part via binding of Bnip3 to LC3 on the autophagosome. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. PMID:23209295 The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. PMID:23209295 phosphorylation of serine residues 17 and 24 flanking the Bnip3 LIR promotes binding to specific Atg8 members LC3B and GATE-16 file:mouse/Bnip3/Bnip3-deep-research-falcon.md BNIP3 is a stress-responsive **mitochondrial-autophagy receptor** |
| GO:0140580 mitochondrion autophagosome adaptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: Bnip3 binds LC3/GABARAP through its N-terminal LIR, tethering mitochondria to autophagosomes. Reason: Core molecular function. Consistent with the IBA and directly supported, including LIR-phosphorylation studies in the mouse HL-1 cardiomyocyte line. Supporting Evidence: PMID:22505714 The clearance of these organelles was mediated in part via binding of Bnip3 to LC3 on the autophagosome. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. PMID:23209295 The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. PMID:23209295 phosphorylation of serine residues 17 and 24 flanking the Bnip3 LIR promotes binding to specific Atg8 members LC3B and GATE-16 file:mouse/Bnip3/Bnip3-deep-research-falcon.md BNIP3 is a stress-responsive **mitochondrial-autophagy receptor** |
| GO:0140580 mitochondrion autophagosome adaptor activity | ISO GO_REF:0000119 | ACCEPT | Summary: Bnip3 binds LC3/GABARAP through its N-terminal LIR, tethering mitochondria to autophagosomes. Reason: Core molecular function. Consistent with the IBA and directly supported, including LIR-phosphorylation studies in the mouse HL-1 cardiomyocyte line. Supporting Evidence: PMID:22505714 The clearance of these organelles was mediated in part via binding of Bnip3 to LC3 on the autophagosome. PMID:22505714 Although ablation of the Bnip3-LC3 interaction by mutating the LC3 binding site did not impair the prodeath activity of Bnip3, it significantly reduced both mitophagy and ERphagy. PMID:23209295 The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. PMID:23209295 phosphorylation of serine residues 17 and 24 flanking the Bnip3 LIR promotes binding to specific Atg8 members LC3B and GATE-16 file:mouse/Bnip3/Bnip3-deep-research-falcon.md BNIP3 is a stress-responsive **mitochondrial-autophagy receptor** |
| GO:1902109 negative regulation of mitochondrial membrane permeability involved in apoptotic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Rat-sourced annotation stating that Bnip3 negatively regulates mitochondrial permeability during apoptosis. Reason: The direction conflicts with direct evidence that BNIP3 promotes PT-pore opening and loss of membrane potential. The rat source may reflect a context-specific finding, but it is not representative of Bnip3 function. Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:1902109 negative regulation of mitochondrial membrane permeability involved in apoptotic process | ISO GO_REF:0000096 | MARK AS OVER ANNOTATED | Summary: Rat-sourced annotation stating that Bnip3 negatively regulates mitochondrial permeability during apoptosis. Reason: The direction conflicts with direct evidence that BNIP3 promotes PT-pore opening and loss of membrane potential. The rat source may reflect a context-specific finding, but it is not representative of Bnip3 function. Propagation Review Root cause: SOURCE BAD Failure modes: REGULATORY SIGN INVERSION Sources checked: RGD:620800 · Bnip3 SOURCE BAD Direction conflicts with direct evidence that BNIP3 promotes PT-pore opening and depolarization (PMID:10891486). Supporting Evidence: PMID:10891486 These changes were accompanied by rapid and profound mitochondrial dysfunction characterized by opening of the mitochondrial PT pore, proton electrochemical gradient (Deltapsim) suppression, and increased reactive oxygen species production. |
| GO:1903599 positive regulation of autophagy of mitochondrion | IEA GO_REF:0000107 | ACCEPT | Summary: Bnip3 promotes mitophagy. Reason: Consistent with the core function. Supporting Evidence: PMID:23209295 The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. PMID:22547685 These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver |
| GO:1903599 positive regulation of autophagy of mitochondrion | ISO GO_REF:0000096 | ACCEPT | Summary: Bnip3 promotes mitophagy. Reason: Consistent with the core function. Supporting Evidence: PMID:23209295 The BH3-only protein Bnip3 is an autophagy receptor that signals autophagic degradation of mitochondria (mitophagy) via interaction of its LC3-interacting region (LIR) with Atg8 proteins. PMID:22547685 These results identify a role for BNip3 in limiting mitochondrial mass and maintaining mitochondrial integrity in the liver |
| GO:1990144 intrinsic apoptotic signaling pathway in response to hypoxia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Hypoxia-induced BNIP3 can promote intrinsic apoptosis. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:20436456 Bnip3-Opa1 interaction is necessary to trigger Opa1 complex disruption in a Bax- and/or Bak-dependent manner, ultimately leading to apoptosis. PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium |
| GO:1990144 intrinsic apoptotic signaling pathway in response to hypoxia | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Hypoxia-induced BNIP3 can promote intrinsic apoptosis. Reason: Bnip3 regulates cell death in a context-dependent way. Overexpression drives mitochondrial, often necrosis-like death through permeability transition pore opening, and in mouse heart Bnip3 contributes to post-ischaemic cardiomyocyte apoptosis. Under hypoxia, however, BNIP3-driven autophagy is frequently pro-survival. This is a genuine but secondary aspect of Bnip3 biology, relative to its conserved Atg8-binding organelle-receptor function. Supporting Evidence: PMID:20436456 Bnip3-Opa1 interaction is necessary to trigger Opa1 complex disruption in a Bax- and/or Bak-dependent manner, ultimately leading to apoptosis. PMID:17909626 at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium |
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Download this section (compressed HTML)Q: Is the deep (Bilateria) PAINT placement of nucleus (PTN001032684) and the root placement of nuclear envelope/ER (PTN000795991) justified, given that the nuclear-envelope signal largely reflects E1B-19K co-expression and nuclear BNIP3 is cell-type-restricted?
Q: Should GO:0140580 mitochondrion autophagosome adaptor activity be placed at the Bilateria node (with mitophagy), given LIR-dependent receptor activity of worm DCT-1 and fly BNIP3, instead of at Euteleostomi?
Q: Does endogenous mouse Bnip3 act as an ER-phagy receptor? Reticulophagy and ER-autophagosome adaptor activity rest on HeLa-cell overexpression of BNIP3 and on propagated annotations, with no mouse experimental evidence.
Q: Which signals decide whether Bnip3 drives protective mitophagy/ER-phagy or cell death in vivo, for example in post-infarct myocardium compared with fasting liver?
Experiment: Generate Bnip3 LIR-mutant (core LIR residue, or the flanking phosphoserines) knock-in mice and compare them with Bnip3-null mice for liver mitochondrial mass (mt-Keima), steatosis, rescue of Fbxl4-/- lethality and post-infarct cardiomyocyte death.
Hypothesis: In vivo, Bnip3's role in limiting mitochondrial mass needs its LIR but not its BH3 or pro-death activity.
Type: knock-in mouse structure-function analysis
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