Bnip3l (NIX) is a tail-anchored member of the BNIP3/NIP3 family that is inserted into the mitochondrial outer membrane through its C-terminal transmembrane helix, with a largely disordered N-terminal region facing the cytosol and an atypical BH3-like motif. Its principal physiological function is as a selective mitophagy receptor: an LC3-interacting region binds Atg8-family proteins (LC3 and GABARAP subfamilies) and a nearby minimal essential region engages further autophagy machinery, so that NIX tethers mitochondria to forming autophagosomes. Transmembrane-mediated homodimerization strengthens this activity. In mouse, NIX is required for programmed elimination of mitochondria during reticulocyte maturation; Nix-null mice retain mitochondria in red cells and develop anaemia with reticulocytosis and compensatory erythropoiesis. NIX-dependent programmed mitophagy also accompanies retinal ganglion cell differentiation and pro-inflammatory macrophage polarization, and NIX is induced by hypoxia. When overexpressed or targeted to the endoplasmic reticulum, NIX can promote apoptotic or permeability-transition-dependent cell death (for example in cardiomyocytes), but these death-promoting activities are context-dependent and separable from its role in physiological mitochondrial clearance.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:17095503 Proapoptotic Nix activates the JNK pathway by interacting wi... | REMOVE | Summary: Nix binds the scaffold POSH (SH3RF1) in yeast two-hybrid, co-IP and in vitro binding assays; the interaction is linked to JNK/c-Jun activation and death in overexpression models. Reason: GO:0005515 protein binding is uninformative. The POSH interaction was characterised in overexpression/cell-line death assays and is tied to the context-dependent pro-death role of Nix rather than its core mitophagy-receptor function; the abstract does not identify the binding domains, so no more specific MF (e.g. SH3 domain binding) can be asserted. Removal does not mean the interaction is false. Supporting Evidence: PMID:17095503 These results indicate that Nix promotes cell death via interaction with POSH and activation of the JNK/c-Jun pathway |
| GO:0005515 protein binding | IPI PMID:20010802 Nix is a selective autophagy receptor for mitochondrial clea... | MODIFY | Summary: Nix binds the Atg8-family protein GABARAP via its N-terminal LIR; Novak et al. identified Nix as a selective autophagy receptor binding LC3/GABARAP proteins. Reason: Generic protein binding is uninformative. The cited paper establishes the functional meaning of the LC3/GABARAP interaction: Nix tethers mitochondria to Atg8-family proteins on the forming autophagosome, and loss of the interaction retards mitochondrial clearance in murine reticulocytes. This is precisely GO:0140580 mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins PMID:20010802 In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. PMID:20010802 Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. |
| GO:0005515 protein binding | IPI PMID:20010802 Nix is a selective autophagy receptor for mitochondrial clea... | MODIFY | Summary: Nix binds the Atg8-family protein GABARAPL2 via its N-terminal LIR; Novak et al. identified Nix as a selective autophagy receptor binding LC3/GABARAP proteins. Reason: Generic protein binding is uninformative. The cited paper establishes the functional meaning of the LC3/GABARAP interaction: Nix tethers mitochondria to Atg8-family proteins on the forming autophagosome, and loss of the interaction retards mitochondrial clearance in murine reticulocytes. This is precisely GO:0140580 mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins PMID:20010802 In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. PMID:20010802 Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. |
| GO:0005515 protein binding | IPI PMID:20010802 Nix is a selective autophagy receptor for mitochondrial clea... | MODIFY | Summary: Nix binds the Atg8-family protein MAP1LC3B via its N-terminal LIR; Novak et al. identified Nix as a selective autophagy receptor binding LC3/GABARAP proteins. Reason: Generic protein binding is uninformative. The cited paper establishes the functional meaning of the LC3/GABARAP interaction: Nix tethers mitochondria to Atg8-family proteins on the forming autophagosome, and loss of the interaction retards mitochondrial clearance in murine reticulocytes. This is precisely GO:0140580 mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins PMID:20010802 In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. PMID:20010802 Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. |
| GO:0005515 protein binding | IPI PMID:20010802 Nix is a selective autophagy receptor for mitochondrial clea... | MODIFY | Summary: Nix binds the Atg8-family protein GABARAPL1 via its N-terminal LIR; Novak et al. identified Nix as a selective autophagy receptor binding LC3/GABARAP proteins. Reason: Generic protein binding is uninformative. The cited paper establishes the functional meaning of the LC3/GABARAP interaction: Nix tethers mitochondria to Atg8-family proteins on the forming autophagosome, and loss of the interaction retards mitochondrial clearance in murine reticulocytes. This is precisely GO:0140580 mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins PMID:20010802 In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. PMID:20010802 Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. |
| GO:0005515 protein binding | IPI PMID:20010802 Nix is a selective autophagy receptor for mitochondrial clea... | MODIFY | Summary: Nix binds the Atg8-family protein MAP1LC3A via its N-terminal LIR; Novak et al. identified Nix as a selective autophagy receptor binding LC3/GABARAP proteins. Reason: Generic protein binding is uninformative. The cited paper establishes the functional meaning of the LC3/GABARAP interaction: Nix tethers mitochondria to Atg8-family proteins on the forming autophagosome, and loss of the interaction retards mitochondrial clearance in murine reticulocytes. This is precisely GO:0140580 mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins PMID:20010802 In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. PMID:20010802 Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. |
| GO:0005515 protein binding | IPI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | REMOVE | Summary: Reported interaction of Nix with ATG13 (curated from the Kanki 2010 commentary). Reason: GO:0005515 protein binding conveys no functional information. The cached source is an abstract-only commentary that does not describe the ATG13 interaction, and no more informative molecular function can be justified from this interaction alone. Removal of the generic term does not imply that the interaction is false; the functional consequence of Nix engaging the autophagy machinery is captured by GO:0140580. Supporting Evidence: PMID:20200478 Recently, it was reported that Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. |
| GO:0005515 protein binding | IPI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | MODIFY | Summary: Interaction of Nix with the Atg8-family protein GABARAP, attributed to the Kanki 2010 commentary, which summarises Nix as a mitochondrial receptor directly binding LC3 and GABARAP. Reason: Generic protein binding is uninformative. The cited article (an abstract-only commentary in our cache, summarising the primary data of Novak et al. 2010) describes the LC3/GABARAP interaction as the basis of the Nix mitophagy-receptor function; the informative MF is GO:0140580 mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20200478 Recently, it was reported that Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins |
| GO:0005515 protein binding | IPI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | MODIFY | Summary: Interaction of Nix with the Atg8-family protein GABARAPL2, attributed to the Kanki 2010 commentary, which summarises Nix as a mitochondrial receptor directly binding LC3 and GABARAP. Reason: Generic protein binding is uninformative. The cited article (an abstract-only commentary in our cache, summarising the primary data of Novak et al. 2010) describes the LC3/GABARAP interaction as the basis of the Nix mitophagy-receptor function; the informative MF is GO:0140580 mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20200478 Recently, it was reported that Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins |
| GO:0005515 protein binding | IPI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | MODIFY | Summary: Interaction of Nix with the Atg8-family protein MAP1LC3B, attributed to the Kanki 2010 commentary, which summarises Nix as a mitochondrial receptor directly binding LC3 and GABARAP. Reason: Generic protein binding is uninformative. The cited article (an abstract-only commentary in our cache, summarising the primary data of Novak et al. 2010) describes the LC3/GABARAP interaction as the basis of the Nix mitophagy-receptor function; the informative MF is GO:0140580 mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20200478 Recently, it was reported that Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins |
| GO:0005515 protein binding | IPI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | MODIFY | Summary: Interaction of Nix with the Atg8-family protein GABARAPL1, attributed to the Kanki 2010 commentary, which summarises Nix as a mitochondrial receptor directly binding LC3 and GABARAP. Reason: Generic protein binding is uninformative. The cited article (an abstract-only commentary in our cache, summarising the primary data of Novak et al. 2010) describes the LC3/GABARAP interaction as the basis of the Nix mitophagy-receptor function; the informative MF is GO:0140580 mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20200478 Recently, it was reported that Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins |
| GO:0005521 lamin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Lamin binding transferred from the human orthologue (B5/BNIP3L), which was reported at the nuclear envelope. Reason: Transferred from the human B5 study, where the protein was found in the nuclear envelope, ER and mitochondria. Not tested in mouse and unrelated to the core mitophagy-receptor function; retained as non-core, consistent with the human review. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005521 lamin binding | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Lamin binding transferred from the human orthologue (B5/BNIP3L), which was reported at the nuclear envelope. Reason: Transferred from the human B5 study, where the protein was found in the nuclear envelope, ER and mitochondria. Not tested in mouse and unrelated to the core mitophagy-receptor function; retained as non-core, consistent with the human review. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005634 nucleus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Nucleus IBA from PANTHER node PTN001032684. Reason: Nix is a tail-anchored mitochondrial outer membrane protein. In the original mouse/human Nix characterisation, diffuse cytoplasmic and nuclear signal appeared only after deletion of the transmembrane domain, so nucleoplasmic localization is an artefact of the truncated protein rather than a site of action. Nuclear-envelope localization (reported for human B5) is captured separately. The broad nucleus IBA is an over-annotation for NIX. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH GRANULARITY MISMATCH Sources checked: PANTHER:PTN001032684 SUPPORTS SOURCE BUT NOT TARGET Bilateria node; nuclear signal for NIX is seen only for TM-deleted protein (PMID:9867803); the defensible location is nuclear envelope, annotated separately. Supporting Evidence: PMID:9867803 Nix colocalizes with the mitochondrial matrix protein HSP60, and removal of the putative transmembrane domain (TM) results in general cytoplasmic and nuclear expression. PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005635 nuclear envelope | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear envelope localization, from the PTN000795991 root IBA and from transfer of the human orthologue observation. Reason: The human orthologue (B5) was observed in the nuclear envelope and ER as well as mitochondria; the nuclear envelope is continuous with the ER, where a pool of Nix acts in some contexts. This is a minor, non-core location relative to the mitochondrial outer membrane. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005635 nuclear envelope | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Nuclear envelope localization, from the PTN000795991 root IBA and from transfer of the human orthologue observation. Reason: The human orthologue (B5) was observed in the nuclear envelope and ER as well as mitochondria; the nuclear envelope is continuous with the ER, where a pool of Nix acts in some contexts. This is a minor, non-core location relative to the mitochondrial outer membrane. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005635 nuclear envelope | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Nuclear envelope localization, from the PTN000795991 root IBA and from transfer of the human orthologue observation. Reason: The human orthologue (B5) was observed in the nuclear envelope and ER as well as mitochondria; the nuclear envelope is continuous with the ER, where a pool of Nix acts in some contexts. This is a minor, non-core location relative to the mitochondrial outer membrane. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005739 mitochondrion | HDA PMID:14651853 Integrated analysis of protein composition, tissue diversity... | ACCEPT | Summary: Mouse mitochondrial proteomics (brain, heart, kidney, liver) detected Bnip3l in purified mitochondria. Reason: High-throughput proteomic detection in purified mouse mitochondria is consistent with the well-established mitochondrial outer membrane localization of Nix. Mitochondrial outer membrane is the more precise term, but mitochondrion is correct. Supporting Evidence: PMID:14651853 we performed a proteomic survey of mitochondria from mouse brain, heart, kidney, and liver PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. |
| GO:0005739 mitochondrion | IDA PMID:23028046 Cellular adaptation to anthrax lethal toxin-induced mitochon... | ACCEPT | Summary: Mitochondrial localization in macrophages from a study of anthrax lethal toxin adaptation (full text not cached). Reason: The cached abstract does not mention Nix, but the curator read the full text and the localization agrees with all other evidence; deferring to the curator. Nix is a mitochondrial outer membrane protein. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. |
| GO:0005739 mitochondrion | IDA PMID:9867803 Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial... | ACCEPT | Summary: Nix colocalizes with mitochondrial HSP60 and requires its TM domain for this localization. Reason: Direct imaging evidence of mitochondrial localization of Nix, consistent with its tail-anchored insertion in the mitochondrial outer membrane. Supporting Evidence: PMID:9867803 Nix colocalizes with the mitochondrial matrix protein HSP60, and removal of the putative transmembrane domain (TM) results in general cytoplasmic and nuclear expression. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial localization transferred from the human orthologue / automated pipelines. Reason: Correct; Nix resides in the mitochondrial outer membrane (more precise term GO:0005741 is also annotated). Supporting Evidence: PMID:9867803 Nix colocalizes with the mitochondrial matrix protein HSP60, and removal of the putative transmembrane domain (TM) results in general cytoplasmic and nuclear expression. PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. |
| GO:0005739 mitochondrion | ISO GO_REF:0000119 | ACCEPT | Summary: Mitochondrial localization transferred from the human orthologue / automated pipelines. Reason: Correct; Nix resides in the mitochondrial outer membrane (more precise term GO:0005741 is also annotated). Supporting Evidence: PMID:9867803 Nix colocalizes with the mitochondrial matrix protein HSP60, and removal of the putative transmembrane domain (TM) results in general cytoplasmic and nuclear expression. PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial localization transferred from the human orthologue / automated pipelines. Reason: Correct; Nix resides in the mitochondrial outer membrane (more precise term GO:0005741 is also annotated). Supporting Evidence: PMID:9867803 Nix colocalizes with the mitochondrial matrix protein HSP60, and removal of the putative transmembrane domain (TM) results in general cytoplasmic and nuclear expression. PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. |
| GO:0005740 mitochondrial envelope | IEA GO_REF:0000002 | MODIFY | Summary: Mitochondrial envelope from InterPro IPR010548 (BNIP3 family) mapping. Reason: Correct but less precise than the known location. Nix is tail-anchored in the mitochondrial outer membrane via its C-terminal TM helix with the N-terminus in the cytosol; GO:0005741 mitochondrial outer membrane is the appropriate term. Proposed replacements: mitochondrial outer membrane Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. PMID:22906961 BNIP3L is a mitochondrial outer membrane protein that is required for clearance. |
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Mitochondrial outer membrane IBA from PTN001032684 (Bilateria), seeded by human BNIP3/BNIP3L, fly BNIP3 and worm DCT-1. Reason: Well supported and phylogenetically sound: the mitochondrial outer membrane is the site of the conserved mitophagy-receptor function of the family. For mouse Nix it is directly supported by mouse reticulocyte studies. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. PMID:22906961 BNIP3L is a mitochondrial outer membrane protein that is required for clearance. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Mitochondrial outer membrane localization of Nix. Reason: Nix is a tail-anchored mitochondrial outer membrane protein, the site of its mitophagy-receptor activity. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. PMID:22906961 BNIP3L is a mitochondrial outer membrane protein that is required for clearance. file:mouse/Bnip3l/Bnip3l-uniprot.txt TRANSMEM 187..207 |
| GO:0005741 mitochondrial outer membrane | ISO GO_REF:0000119 | ACCEPT | Summary: Mitochondrial outer membrane localization of Nix. Reason: Nix is a tail-anchored mitochondrial outer membrane protein, the site of its mitophagy-receptor activity. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. PMID:22906961 BNIP3L is a mitochondrial outer membrane protein that is required for clearance. file:mouse/Bnip3l/Bnip3l-uniprot.txt TRANSMEM 187..207 |
| GO:0005741 mitochondrial outer membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial outer membrane localization of Nix. Reason: Nix is a tail-anchored mitochondrial outer membrane protein, the site of its mitophagy-receptor activity. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. PMID:22906961 BNIP3L is a mitochondrial outer membrane protein that is required for clearance. file:mouse/Bnip3l/Bnip3l-uniprot.txt TRANSMEM 187..207 |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Endoplasmic reticulum localization (PTN000795991 root IBA; transfer from human). Reason: A pool of Nix localizes to the ER (human B5 imaging; reticular Nix in mouse cardiomyocyte/fibroblast studies where ER-targeted Nix triggers MPTP-dependent death). Real but secondary to the mitochondrial outer membrane location of the core mitophagy function. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria PMID:20418503 Localization of these factors to mitochondria and endoplasmic reticulum (ER) provides additional complexity. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Endoplasmic reticulum localization (PTN000795991 root IBA; transfer from human). Reason: A pool of Nix localizes to the ER (human B5 imaging; reticular Nix in mouse cardiomyocyte/fibroblast studies where ER-targeted Nix triggers MPTP-dependent death). Real but secondary to the mitochondrial outer membrane location of the core mitophagy function. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria PMID:20418503 Localization of these factors to mitochondria and endoplasmic reticulum (ER) provides additional complexity. |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Endoplasmic reticulum localization (PTN000795991 root IBA; transfer from human). Reason: A pool of Nix localizes to the ER (human B5 imaging; reticular Nix in mouse cardiomyocyte/fibroblast studies where ER-targeted Nix triggers MPTP-dependent death). Real but secondary to the mitochondrial outer membrane location of the core mitophagy function. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria PMID:20418503 Localization of these factors to mitochondria and endoplasmic reticulum (ER) provides additional complexity. |
| GO:0010917 negative regulation of mitochondrial membrane potential | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of mitochondrial membrane potential, transferred from rat. Reason: In mouse erythroid cells, Nix deficiency prevents the loss of mitochondrial membrane potential that precedes mitochondrial sequestration, and ER-targeted Nix dissipates potential via the MPTP. These are consequences that accompany mitophagy/death rather than a defined activity of Nix; retained as non-core. Supporting Evidence: PMID:18454133 Deficiency in Nix inhibited the loss of mitochondrial membrane potential (DeltaPsi(m)) PMID:20418503 ER-Nix cells, but not mitochondrial-Nix cells, showed dissipation of mitochondrial inner membrane potential, Deltapsi(m), and were protected from cell death by cyclosporine A or ppif ablation, implicating the mitochondrial permeability transition pore (MPTP). |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: Generic membrane localization from InterPro/SubCell mapping. Reason: Correct but uninformative; Nix is a single-pass tail-anchored protein of the mitochondrial outer membrane. Proposed replacements: mitochondrial outer membrane Supporting Evidence: file:mouse/Bnip3l/Bnip3l-uniprot.txt TRANSMEM 187..207 PMID:22906961 BNIP3L is a mitochondrial outer membrane protein that is required for clearance. |
| GO:0016239 positive regulation of macroautophagy | ISO GO_REF:0000008 | KEEP AS NON CORE | Summary: Positive regulation of macroautophagy, transferred from the human hypoxia study (Bellot 2009) in which BNIP3/BNIP3L BH3 domains induce autophagy. Reason: In human cells under hypoxia, combined BNIP3/BNIP3L loss suppresses autophagy and ectopic expression activates it. However, in the best-characterised physiological setting (mouse reticulocytes) NIX is not required for autophagy induction but for selective incorporation of mitochondria into autophagosomes. Bulk autophagy induction is therefore a context-dependent, non-core role. Supporting Evidence: PMID:19273585 the ectopic expression of both BNIP3 and BNIP3L in normoxia activates autophagy PMID:18048346 Similarly, NIX is not required for the induction of autophagy during terminal erythroid differentiation. |
| GO:0016607 nuclear speck | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Nuclear speck, transferred from human antibody-based (HPA) imaging. Reason: No mechanistic or orthogonal evidence places Nix in nuclear speckles; Nix is a tail-anchored outer mitochondrial membrane protein and nuclear signal has been seen only for TM-deleted protein. Likely an antibody-staining artefact transferred by orthology. Supporting Evidence: PMID:9867803 Nix colocalizes with the mitochondrial matrix protein HSP60, and removal of the putative transmembrane domain (TM) results in general cytoplasmic and nuclear expression. |
| GO:0016607 nuclear speck | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Nuclear speck, transferred from human antibody-based (HPA) imaging. Reason: No mechanistic or orthogonal evidence places Nix in nuclear speckles; Nix is a tail-anchored outer mitochondrial membrane protein and nuclear signal has been seen only for TM-deleted protein. Likely an antibody-staining artefact transferred by orthology. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:O60238 · BNIP3L SOURCE WEAK OR INFERRED Human source is antibody-based HPA imaging (GO_REF:0000052) without orthogonal support; inconsistent with tail-anchored mitochondrial outer membrane topology. Supporting Evidence: PMID:9867803 Nix colocalizes with the mitochondrial matrix protein HSP60, and removal of the putative transmembrane domain (TM) results in general cytoplasmic and nuclear expression. |
| GO:0035694 mitochondrial protein catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mitochondrial protein catabolic process (MIEAP-induced MALM), transferred from human. Reason: In human cancer cells, NIX interacts with MIEAP via its BH3 domain and is required for MALM, an intramitochondrial lysosome-like degradation of oxidized proteins. This has not been tested in mouse and is a non-canonical quality-control role distinct from the core mitophagy-receptor function; retained as non-core. Supporting Evidence: PMID:21264228 A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. PMID:21264228 Deficiency of NIX also completely impaired MALM. |
| GO:0035694 mitochondrial protein catabolic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Mitochondrial protein catabolic process (MIEAP-induced MALM), transferred from human. Reason: In human cancer cells, NIX interacts with MIEAP via its BH3 domain and is required for MALM, an intramitochondrial lysosome-like degradation of oxidized proteins. This has not been tested in mouse and is a non-canonical quality-control role distinct from the core mitophagy-receptor function; retained as non-core. Supporting Evidence: PMID:21264228 A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. PMID:21264228 Deficiency of NIX also completely impaired MALM. |
| GO:0035694 mitochondrial protein catabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mitochondrial protein catabolic process (MIEAP-induced MALM), transferred from human. Reason: In human cancer cells, NIX interacts with MIEAP via its BH3 domain and is required for MALM, an intramitochondrial lysosome-like degradation of oxidized proteins. This has not been tested in mouse and is a non-canonical quality-control role distinct from the core mitophagy-receptor function; retained as non-core. Supporting Evidence: PMID:21264228 A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. PMID:21264228 Deficiency of NIX also completely impaired MALM. |
| GO:0035794 positive regulation of mitochondrial membrane permeability | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of mitochondrial membrane permeability, transferred from rat. Reason: Mouse studies show ER-localized Nix triggers mitochondrial permeability transition (cyclosporine A/ppif-sensitive) and mitochondrial Nix triggers Bax/Bak-dependent death. These overexpression-driven death pathways are context-dependent and not the core physiological function. Supporting Evidence: PMID:20418503 ER-Nix cells, but not mitochondrial-Nix cells, showed dissipation of mitochondrial inner membrane potential, Deltapsi(m), and were protected from cell death by cyclosporine A or ppif ablation, implicating the mitochondrial permeability transition pore (MPTP). PMID:20418503 Thus, Nix stimulates dual autonomous death pathways, determined by its subcellular localization. |
| GO:0042802 identical protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: Nix self-associates (homodimer). Reason: Nix runs as an SDS-resistant dimer, and TM-mediated homodimerization is required for efficient LC3 recruitment and mitophagy, making self-association functionally relevant to the receptor role. Supporting Evidence: PMID:9867803 Nix encodes a 23. 8-kDa protein but it is expressed as a 48-kDa protein, suggesting that it homodimerizes similarly to Nip3. PMID:32286918 Forming stable homodimers, BNIP3L recruits autophagosomes more robustly than its monomeric form. |
| GO:0042802 identical protein binding | IPI PMID:9867803 Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial... | ACCEPT | Summary: Nix self-associates (homodimer). Reason: Nix runs as an SDS-resistant dimer, and TM-mediated homodimerization is required for efficient LC3 recruitment and mitophagy, making self-association functionally relevant to the receptor role. Supporting Evidence: PMID:9867803 Nix encodes a 23. 8-kDa protein but it is expressed as a 48-kDa protein, suggesting that it homodimerizes similarly to Nip3. PMID:32286918 Forming stable homodimers, BNIP3L recruits autophagosomes more robustly than its monomeric form. |
| GO:0042802 identical protein binding | ISO GO_REF:0000119 | ACCEPT | Summary: Nix self-associates (homodimer). Reason: Nix runs as an SDS-resistant dimer, and TM-mediated homodimerization is required for efficient LC3 recruitment and mitophagy, making self-association functionally relevant to the receptor role. Supporting Evidence: PMID:9867803 Nix encodes a 23. 8-kDa protein but it is expressed as a 48-kDa protein, suggesting that it homodimerizes similarly to Nip3. PMID:32286918 Forming stable homodimers, BNIP3L recruits autophagosomes more robustly than its monomeric form. |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: Protein homodimerization activity via the transmembrane domain. Reason: Homodimerization of NIX (through TM-domain GxxxG residues and Ser212) is required for robust recruitment of autophagic machinery; a supporting activity of the mitophagy receptor. Supporting Evidence: PMID:32286918 Forming stable homodimers, BNIP3L recruits autophagosomes more robustly than its monomeric form. PMID:9867803 Nix encodes a 23. 8-kDa protein but it is expressed as a 48-kDa protein, suggesting that it homodimerizes similarly to Nip3. |
| GO:0042803 protein homodimerization activity | ISO GO_REF:0000119 | ACCEPT | Summary: Protein homodimerization activity via the transmembrane domain. Reason: Homodimerization of NIX (through TM-domain GxxxG residues and Ser212) is required for robust recruitment of autophagic machinery; a supporting activity of the mitophagy receptor. Supporting Evidence: PMID:32286918 Forming stable homodimers, BNIP3L recruits autophagosomes more robustly than its monomeric form. PMID:9867803 Nix encodes a 23. 8-kDa protein but it is expressed as a 48-kDa protein, suggesting that it homodimerizes similarly to Nip3. |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Positive regulation of apoptotic process IBA from PTN001032684, seeded by mouse Bnip3l, rat, human BNIP3/BNIP3L and zebrafish. Reason: Overexpressed Nix kills cells, and Nix-null erythroblasts show reduced apoptosis, so the term is supported. However, physiological mitochondrial clearance by Nix is independent of BAX/BAK/BIM/PUMA, and the apoptosis-promoting effects are context- and dose-dependent. Retained as non-core, consistent with the family node. Supporting Evidence: PMID:9867803 When transiently expressed, Nix and Nip3 but not TM deletion mutants rapidly activate apoptosis. PMID:17420462 Nix null mice exhibited massive splenomegaly, with splenic and bone marrow erythroblastosis and reduced apoptosis in vivo during erythrocyte maturation. PMID:18048346 Mitochondrial clearance does not require BAX, BAK, BCL-X(L), BIM, or PUMA, indicating that NIX does not function through established proapoptotic pathways. |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:9867803 Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial... | KEEP AS NON CORE | Summary: Transient overexpression of Nix rapidly activates apoptosis, dependent on the TM domain. Reason: Supported by the cited overexpression data; physiologically, Nix-dependent mitophagy does not use canonical apoptotic machinery, so pro-apoptotic activity is non-core. Supporting Evidence: PMID:9867803 When transiently expressed, Nix and Nip3 but not TM deletion mutants rapidly activate apoptosis. PMID:18048346 Mitochondrial clearance does not require BAX, BAK, BCL-X(L), BIM, or PUMA, indicating that NIX does not function through established proapoptotic pathways. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Positive regulation of apoptotic process transferred from orthologues / InterPro. Reason: Consistent with Nix overexpression and erythroblast data, but non-core relative to the mitophagy receptor function. Supporting Evidence: PMID:9867803 When transiently expressed, Nix and Nip3 but not TM deletion mutants rapidly activate apoptosis. PMID:17420462 Nix null mice exhibited massive splenomegaly, with splenic and bone marrow erythroblastosis and reduced apoptosis in vivo during erythrocyte maturation. |
| GO:0043065 positive regulation of apoptotic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Positive regulation of apoptotic process transferred from orthologues / InterPro. Reason: Consistent with Nix overexpression and erythroblast data, but non-core relative to the mitophagy receptor function. Supporting Evidence: PMID:9867803 When transiently expressed, Nix and Nip3 but not TM deletion mutants rapidly activate apoptosis. PMID:17420462 Nix null mice exhibited massive splenomegaly, with splenic and bone marrow erythroblastosis and reduced apoptosis in vivo during erythrocyte maturation. |
| GO:0043065 positive regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of apoptotic process transferred from orthologues / InterPro. Reason: Consistent with Nix overexpression and erythroblast data, but non-core relative to the mitophagy receptor function. Supporting Evidence: PMID:9867803 When transiently expressed, Nix and Nip3 but not TM deletion mutants rapidly activate apoptosis. PMID:17420462 Nix null mice exhibited massive splenomegaly, with splenic and bone marrow erythroblastosis and reduced apoptosis in vivo during erythrocyte maturation. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of apoptotic process, transferred from the human B5 study showing inhibition of Nip3-induced apoptosis. Reason: The human orthologue inhibited Nip3-induced apoptosis in overexpression assays, and NIX-dependent mitophagy can be pro-survival (e.g. retained mitochondria in Nix-null RBCs drive caspase activation). The direction of Nix effects on death is context-dependent; non-core. Supporting Evidence: PMID:10381623 B5 does not induce apoptosis, but inhibits apoptosis induced by Nip3. PMID:18454133 Nix(-/-) mice developed anaemia with reduced mature erythrocytes and compensatory expansion of erythroid precursors. |
| GO:0043066 negative regulation of apoptotic process | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Negative regulation of apoptotic process, transferred from the human B5 study showing inhibition of Nip3-induced apoptosis. Reason: The human orthologue inhibited Nip3-induced apoptosis in overexpression assays, and NIX-dependent mitophagy can be pro-survival (e.g. retained mitochondria in Nix-null RBCs drive caspase activation). The direction of Nix effects on death is context-dependent; non-core. Supporting Evidence: PMID:10381623 B5 does not induce apoptosis, but inhibits apoptosis induced by Nip3. PMID:18454133 Nix(-/-) mice developed anaemia with reduced mature erythrocytes and compensatory expansion of erythroid precursors. |
| GO:0043069 negative regulation of programmed cell death | ISO GO_REF:0000008 | KEEP AS NON CORE | Summary: Negative regulation of programmed cell death, transferred from the human hypoxia study. Reason: In human tumor cells, ablation of BNIP3 and/or BNIP3L triggers cell death under hypoxia and their induced autophagy is pro-survival. A context-dependent effect; non-core. 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. PMID:19273585 Hypoxia-induced autophagy via BNIP3 and BNIP3L is clearly a survival mechanism that promotes tumor progression. |
| GO:0043653 mitochondrial fragmentation involved in apoptotic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Mitochondrial fragmentation involved in apoptotic process IBA from PTN001032684, seeded only by human BNIP3. Reason: The only experimental seed for this node assertion is BNIP3. There is no experimental evidence that Nix drives apoptotic mitochondrial fragmentation; Nix-dependent mitochondrial clearance in reticulocytes proceeds independently of the apoptotic machinery. The term overstates what is known for the NIX clade. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG Sources checked: PANTHER:PTN001032684 SUPPORTS SOURCE BUT NOT TARGET Node assertion is seeded only by the paralog BNIP3 (Q12983); no experimental evidence for apoptotic mitochondrial fragmentation by NIX, whose physiological mitophagy is independent of the apoptotic machinery. Supporting Evidence: PMID:18048346 Mitochondrial clearance does not require BAX, BAK, BCL-X(L), BIM, or PUMA, indicating that NIX does not function through established proapoptotic pathways. |
| GO:0051607 defense response to virus | IEA GO_REF:0000107 | REMOVE | Summary: Defense response to virus, transferred from the human BNIP3alpha (BNIP3L) study. Reason: The source study showed only that BNIP3alpha binds the viral anti-apoptotic protein E1B-19K (and cellular BCL-2/BCL-xL) and promotes apoptosis when overexpressed. Binding a viral anti-apoptotic protein is not a host antiviral defense response; the human source annotation was also judged incorrect in the human BNIP3L review. Later reports of viruses exploiting NIX-mediated mitophagy do not establish a host defense role. Supporting Evidence: PMID:9973195 BNIP3alpha interacts with viral antiapoptosis protein E1B-19K and cellular antiapoptosis proteins BCL-2 and BCL-xL. |
| GO:0051607 defense response to virus | ISO GO_REF:0000119 | REMOVE | Summary: Defense response to virus, transferred from the human BNIP3alpha (BNIP3L) study. Reason: The source study showed only that BNIP3alpha binds the viral anti-apoptotic protein E1B-19K (and cellular BCL-2/BCL-xL) and promotes apoptosis when overexpressed. Binding a viral anti-apoptotic protein is not a host antiviral defense response; the human source annotation was also judged incorrect in the human BNIP3L review. Later reports of viruses exploiting NIX-mediated mitophagy do not establish a host defense role. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:O60238 · BNIP3L SOURCE BAD Human IDA from PMID:9973195 reports only binding to viral anti-apoptotic E1B-19K and pro-apoptotic activity; this is not a host antiviral defense response (also REMOVE in the human BNIP3L review). Supporting Evidence: PMID:9973195 BNIP3alpha interacts with viral antiapoptosis protein E1B-19K and cellular antiapoptosis proteins BCL-2 and BCL-xL. |
| GO:0051607 defense response to virus | ISS GO_REF:0000024 | REMOVE | Summary: Defense response to virus, transferred from the human BNIP3alpha (BNIP3L) study. Reason: The source study showed only that BNIP3alpha binds the viral anti-apoptotic protein E1B-19K (and cellular BCL-2/BCL-xL) and promotes apoptosis when overexpressed. Binding a viral anti-apoptotic protein is not a host antiviral defense response; the human source annotation was also judged incorrect in the human BNIP3L review. Later reports of viruses exploiting NIX-mediated mitophagy do not establish a host defense role. Supporting Evidence: PMID:9973195 BNIP3alpha interacts with viral antiapoptosis protein E1B-19K and cellular antiapoptosis proteins BCL-2 and BCL-xL. |
| GO:0071456 cellular response to hypoxia | ISO GO_REF:0000008 | KEEP AS NON CORE | Summary: Cellular response to hypoxia, transferred from human (Nix/BNIP3L is a HIF target). Reason: Human BNIP3/BNIP3L mediate hypoxia-induced autophagy, and in mouse retina local hypoxia induces NIX at peak retinal ganglion cell differentiation. NIX is induced by hypoxia and executes mitophagy in that context; the response itself is upstream regulation of the gene, so non-core. Supporting Evidence: PMID:19273585 the ectopic expression of both BNIP3 and BNIP3L in normoxia activates autophagy PMID:28465321 Local hypoxia triggered expression of the mitophagy regulator BCL2/adenovirus E1B 19-kDa-interacting protein 3-like (BNIP3L, best known as NIX) at peak RGC differentiation. |
| GO:1901524 regulation of mitophagy | IGI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | ACCEPT | Summary: Regulation of mitophagy (IGI; curated by ParkinsonsUK-UCL to the Kanki 2010 commentary). Reason: Nix is the mitophagy receptor whose abundance and activity determine mitochondrial clearance in reticulocytes and other programmed settings. Although NIX more precisely participates in mitophagy as a receptor (proposed as NEW GO:0000423 mitophagy), control of mitophagy flux by NIX levels is well established and the regulation term is acceptable. The cached commentary is abstract-only; deferring to the curator for the genetic-interaction detail. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. PMID:20200478 Recently, it was reported that Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. |
| GO:1903747 obsolete regulation of protein localization to mitochondrion | IGI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | MODIFY | Summary: Regulation of protein localization to mitochondrion (IGI; Kanki 2010). The GO term is now obsolete. Reason: QuickGO lists GO:1903747 as obsolete because it represents a phenotype, recommending annotation to the specific process regulated, e.g. regulation of mitophagy. The underlying observation (Nix recruits LC3/GABARAP to mitochondria) is captured by mitophagy and the mitochondrion autophagosome adaptor activity. Proposed replacements: regulation of mitophagy Supporting Evidence: PMID:20200478 Recently, it was reported that Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. PMID:20010802 In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. |
| GO:0140580 mitochondrion autophagosome adaptor activity | IMP PMID:20010802 Nix is a selective autophagy receptor for mitochondrial clea... | NEW | Summary: Nix uses its N-terminal LIR to bind LC3/GABARAP and recruit them to mitochondria, tethering mitochondria to autophagosomal membranes; LIR ablation retards mitochondrial clearance in Nix-/- murine reticulocytes rescued by retroviral Nix. Reason: This is the core molecular function of Nix and is absent from mouse GOA. It is also absent from the PAINT propagation because the GO:0140580 IBD sits on PTN002689498, the vertebrate BNIP3 clade, which does not include NIX. The MER motif (binding WIPI2) contributes further to adaptor function in mouse reticulocytes. Supporting Evidence: PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins PMID:20010802 In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. PMID:20010802 Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. PMID:22906961 These findings support an adaptor model of BNIP3L, centered on the MER. file:mouse/Bnip3l/Bnip3l-deep-research-falcon.md The best-supported primary function of NIX is as a **membrane-anchored selective-autophagy receptor** |
| GO:0000423 mitophagy | IMP PMID:18048346 NIX is required for programmed mitochondrial clearance durin... | NEW | Summary: Nix-/- mice fail to clear mitochondria from maturing reticulocytes; mitochondria are not incorporated into autophagosomes. Reason: Participation test: Nix performs a step of mitophagy, selecting mitochondrial cargo and tethering it to the phagophore via its LIR/MER motifs (the step at which Nix-null cells arrest), rather than merely being required for or acted on by the process. Comparator check: the paralog BNIP3 and FUNDC1 carry GO:0000423 (QuickGO), as does Ulk1 in mouse. The PAINT IBD for mitophagy at PTN001032684 is blocked from NIX by an IRD at PTN002689506 (the NIX clade node), which is contrary to the mouse genetics. Supporting Evidence: PMID:18048346 Here, we show that mitochondrial clearance in reticulocytes requires the BCL2-related protein NIX (BNIP3L). PMID:18048346 NIX is required for the selective elimination of mitochondria PMID:18454133 Although the clearance of ribosomes proceeded normally in the absence of Nix, the entry of mitochondria into autophagosomes for clearance was defective. PMID:28465321 Retinas from NIX-deficient mice displayed increased mitochondrial mass, reduced expression of glycolytic enzymes and decreased neuronal differentiation. |
| GO:0043249 erythrocyte maturation | IMP PMID:18454133 Essential role for Nix in autophagic maturation of erythroid... | NEW | Summary: Nix-/- mice have anaemia, reticulocytosis and erythrocytes that retain mitochondria, owing to failed autophagic mitochondrial clearance during reticulocyte maturation. Reason: Mitochondrial elimination is an intrinsic step of reticulocyte-to-erythrocyte maturation and Nix executes that step as the mitophagy receptor, so this passes the participation test as a process Nix does part of the work of (not merely a downstream phenotype). Comparator check: GO:0043249 is widely annotated by MGI from knockout phenotypes, though Ulk1 lacks it, so this is proposed conservatively and treated as non-core context for the core mitophagy function. Erythroblast-level effects (Diwan 2007) are not used here. Supporting Evidence: PMID:18454133 Here we report a role for a Bcl-2 family member, Nix (also called Bnip3L), in the regulation of erythroid maturation through mitochondrial autophagy. PMID:18454133 Nix(-/-) mice developed anaemia with reduced mature erythrocytes and compensatory expansion of erythroid precursors. PMID:18454133 Although the clearance of ribosomes proceeded normally in the absence of Nix, the entry of mitochondria into autophagosomes for clearance was defective. PMID:18048346 Here, we show that mitochondrial clearance in reticulocytes requires the BCL2-related protein NIX (BNIP3L). |
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Download this section (compressed HTML)Q: Is the erythroid phenotype of Nix-null mice (reticulocytosis, erythroblast expansion) primarily a consequence of failed mitophagy (Sandoval/Schweers model) or of loss of Nix-dependent erythroblast apoptosis (Diwan model), and can these be separated with LIR/MER mutants that preserve BH3 function?
Q: Should the PAINT IRD that blocks GO:0000423 mitophagy at the vertebrate BNIP3L clade node (PTN002689506) be removed, and should GO:0140580 mitochondrion autophagosome adaptor activity be placed at the BNIP3/BNIP3L duplication ancestor rather than only on the BNIP3 clade (PTN002689498)?
Q: Does mouse NIX have a physiological role at the ER (reticulophagy, calcium handling) comparable to the GO:0061709 reticulophagy assertion for BNIP3, or is ER-localized NIX relevant only to pathological death in cardiomyocytes?
Experiment: Generate knock-in mice carrying LIR (W35A), MER (central leucine) or BH3 mutations in endogenous Bnip3l and quantify mitochondrial retention in reticulocytes (MitoTracker/mt-Keima flow cytometry), red-cell lifespan and erythroblast apoptosis.
Hypothesis: Both the LIR and MER of NIX are required in vivo for programmed mitochondrial clearance, independently of its BH3 motif.
Type: knock-in mouse genetics and flow cytometry
Experiment: Compare single and double Bnip3/Bnip3l knockouts in retinal ganglion cell differentiation and M1 macrophage polarization using mito-QC reporters and metabolic (glycolytic switch) readouts.
Hypothesis: NIX and BNIP3 are partially redundant mitophagy receptors in non-erythroid programmed mitophagy.
Type: genetic redundancy analysis with mitophagy reporters
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