FUNDC1 (FUN14 domain-containing protein 1) is a small multi-pass integral protein of the mitochondrial outer membrane and belongs to the FUN14 family. Its N-terminal cytosolic region carries a Y18xxL21 LC3-interacting region (LIR) that binds Atg8-family proteins (MAP1LC3A, MAP1LC3B, GABARAP). Through this binding FUNDC1 acts as a ubiquitin-independent receptor for hypoxia-induced mitophagy, tethering mitochondria to forming autophagosomes. Phosphorylation controls the receptor. Under normoxia, SRC (Tyr18) and CK2 (Ser13) phosphorylation inhibits LC3 binding. Under hypoxia, the phosphatase PGAM5 removes these phosphates, and ULK1, which translocates to mitochondria, phosphorylates Ser17; both changes enhance LC3 binding. FUNDC1 also gathers at ER-mitochondria contact sites (MAMs), where it binds calnexin and recruits DRP1 (DNM1L), promoting DRP1 oligomerization and mitochondrial fission before mitophagy. FUNDC1 is ubiquitinated, and USP19 stabilizes it at MAMs. Other reported roles in MAM formation, Ca2+ signalling, angiogenesis and GPX4 import/ferroptosis are less well established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000422 autophagy of mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: FUNDC1 is a mitochondrial outer-membrane receptor for hypoxia-induced mitophagy; knockdown blocks hypoxia-induced mitophagy and only LIR-competent FUNDC1 rescues. Reason: Core function, directly established in human cells (PMID:22267086) and consistent with the PANTHER (FUN14 family) IBA. The IDA/IMP/IGI rows from the same paper and the IBA are all appropriate. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. PMID:22267086 Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. |
| GO:0000422 autophagy of mitochondrion | IDA PMID:22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia... | ACCEPT | Summary: FUNDC1 is a mitochondrial outer-membrane receptor for hypoxia-induced mitophagy; knockdown blocks hypoxia-induced mitophagy and only LIR-competent FUNDC1 rescues. Reason: Core function, directly established in human cells (PMID:22267086) and consistent with the PANTHER (FUN14 family) IBA. The IDA/IMP/IGI rows from the same paper and the IBA are all appropriate. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. PMID:22267086 Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. |
| GO:0000422 autophagy of mitochondrion | IGI PMID:22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia... | ACCEPT | Summary: FUNDC1 is a mitochondrial outer-membrane receptor for hypoxia-induced mitophagy; knockdown blocks hypoxia-induced mitophagy and only LIR-competent FUNDC1 rescues. Reason: Core function, directly established in human cells (PMID:22267086) and consistent with the PANTHER (FUN14 family) IBA. The IDA/IMP/IGI rows from the same paper and the IBA are all appropriate. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. PMID:22267086 Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. |
| GO:0000422 autophagy of mitochondrion | IMP PMID:22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia... | ACCEPT | Summary: FUNDC1 is a mitochondrial outer-membrane receptor for hypoxia-induced mitophagy; knockdown blocks hypoxia-induced mitophagy and only LIR-competent FUNDC1 rescues. Reason: Core function, directly established in human cells (PMID:22267086) and consistent with the PANTHER (FUN14 family) IBA. The IDA/IMP/IGI rows from the same paper and the IBA are all appropriate. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. PMID:22267086 Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. |
| GO:0000423 mitophagy | IGI PMID:34244144 Loss of UCHL1 rescues the defects related to Parkinson's dis... | ACCEPT | Summary: Mitophagy (GO:0000423, the selective autophagy of mitochondria) is the core process in which FUNDC1 acts as an Atg8-binding receptor. Reason: Consistent with the receptor function established in PMID:22267086. The IGI row comes from a study in which FUNDC1 was the only conserved LIR mitochondrial protein whose knockdown worsened PINK1/UCH-L1 double-null fly phenotypes; this genetic evidence agrees with the core role. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. PMID:34244144 FUNDC1 knockdown generated swollen mitochondria morphologies in the double null flies |
| GO:0001666 response to hypoxia | IDA PMID:22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia... | ACCEPT | Summary: FUNDC1-mediated mitophagy is induced by hypoxia: hypoxia causes dephosphorylation of FUNDC1 (Tyr18/Ser13), which strengthens LC3 binding and triggers mitophagy. Reason: FUNDC1 is the hypoxia-responsive mitophagy receptor; its response to hypoxia is part of the regulated receptor mechanism rather than an indirect phenotype, so the IDA/IMP rows from PMID:22267086 are acceptable. Supporting Evidence: PMID:22267086 hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy PMID:22267086 Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. |
| GO:0001666 response to hypoxia | IMP PMID:22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia... | ACCEPT | Summary: FUNDC1-mediated mitophagy is induced by hypoxia: hypoxia causes dephosphorylation of FUNDC1 (Tyr18/Ser13), which strengthens LC3 binding and triggers mitophagy. Reason: FUNDC1 is the hypoxia-responsive mitophagy receptor; its response to hypoxia is part of the regulated receptor mechanism rather than an indirect phenotype, so the IDA/IMP rows from PMID:22267086 are acceptable. Supporting Evidence: PMID:22267086 hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy PMID:22267086 Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:20562859 Network organization of the human autophagy system. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia... | MODIFY | Summary: FUNDC1 binds LC3 (MAP1LC3A/B) and GABARAP via its N-terminal Y18xxL21 LIR motif; this binding is the receptor activity that links mitochondria to autophagosomes. Reason: Generic protein binding is uninformative. The paper shows LIR-dependent binding to Atg8-family proteins is required for FUNDC1-mediated mitophagy, which is captured precisely by mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:22267086 FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. PMID:22267086 Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. |
| GO:0005515 protein binding | IPI PMID:22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia... | MODIFY | Summary: FUNDC1 binds LC3 (MAP1LC3A/B) and GABARAP via its N-terminal Y18xxL21 LIR motif; this binding is the receptor activity that links mitochondria to autophagosomes. Reason: Generic protein binding is uninformative. The paper shows LIR-dependent binding to Atg8-family proteins is required for FUNDC1-mediated mitophagy, which is captured precisely by mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:22267086 FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. PMID:22267086 Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. |
| GO:0005515 protein binding | IPI PMID:22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia... | MODIFY | Summary: FUNDC1 binds LC3 (MAP1LC3A/B) and GABARAP via its N-terminal Y18xxL21 LIR motif; this binding is the receptor activity that links mitochondria to autophagosomes. Reason: Generic protein binding is uninformative. The paper shows LIR-dependent binding to Atg8-family proteins is required for FUNDC1-mediated mitophagy, which is captured precisely by mitochondrion autophagosome adaptor activity. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:22267086 FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. PMID:22267086 Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. |
| GO:0005515 protein binding | IPI PMID:24671035 ULK1 translocates to mitochondria and phosphorylates FUNDC1 ... | REMOVE | Summary: Interaction with ULK1 (and LC3B) in a study showing ULK1 translocates to mitochondria and phosphorylates FUNDC1 at Ser17, enhancing LC3 binding. Reason: Generic protein binding is uninformative. FUNDC1 is the substrate of ULK1 here; its receptor activity is captured by GO:0140580. Removal does not dispute the interaction. Supporting Evidence: PMID:24671035 The translocated ULK1 interacts with its substrate FUNDC1 and phosphorylates FUNDC1 at Ser-17. |
| GO:0005515 protein binding | IPI PMID:24671035 ULK1 translocates to mitochondria and phosphorylates FUNDC1 ... | REMOVE | Summary: Interaction with ULK1 (and LC3B) in a study showing ULK1 translocates to mitochondria and phosphorylates FUNDC1 at Ser17, enhancing LC3 binding. Reason: Generic protein binding is uninformative. FUNDC1 is the substrate of ULK1 here; its receptor activity is captured by GO:0140580. Removal does not dispute the interaction. Supporting Evidence: PMID:24671035 The translocated ULK1 interacts with its substrate FUNDC1 and phosphorylates FUNDC1 at Ser-17. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Protein-protein interaction detected in a high-throughput interactome (yeast two-hybrid or AP-MS) screen. Reason: Generic protein binding is uninformative. The informative Atg8-family binding is captured by GO:0140580 (mitochondrion autophagosome adaptor activity). Removal does not imply the interactions are false. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Detected in the high-confidence human mitochondrial proteome; correct but less specific than mitochondrial outer membrane. Reason: Correct broader localization from a high-throughput proteomic study; the more informative location is GO:0005741. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:27145933 FUNDC1 regulates mitochondrial dynamics at the ER-mitochondr... | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | EXP PMID:33978709 USP19 promotes hypoxia-induced mitochondrial division via FU... | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | IDA PMID:22267086 Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia... | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-8948039 | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-8948139 | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-8948143 | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-8948146 | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-8959571 | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-8959573 | ACCEPT | Summary: FUNDC1 is an integral, multi-pass protein of the mitochondrial outer membrane with its N-terminal LIR facing the cytosol. Reason: Directly shown (PMID:22267086, PMID:27145933, PMID:33978709) and the location where its receptor function operates. The Reactome TAS and UniProt-mapped IEA rows agree. Supporting Evidence: PMID:22267086 Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. |
| GO:0008053 mitochondrial fusion | IGI PMID:37931419 FUNDC1 collaborates with PINK1 in regulating mitochondrial F... | UNDECIDED | Summary: The cited study (Drosophila genetics) reports that FUNDC1 suppresses PINK1-mutant phenotypes through Drp1 and mitochondrial fission, independent of its LIR. The abstract does not describe a role in mitochondrial fusion. Reason: Only the abstract is cached, and it presents the FUNDC1-PINK1 genetic interaction as acting through Drp1-dependent fission, not fusion. Fusion may be assayed in the full text (e.g. via Marf/Opa1 genetics), so without the full text I cannot confirm or refute the fusion annotation and do not overrule the curator. Supporting Evidence: PMID:37931419 Moreover, the absence of Drp1 affects the phenotypic restoration of PINK1 mediated by FUNDC1 in flies. PMID:37931419 The restoration of PINK1-deficient phenotypes through FUNDC1 is not reliant on its LC3-binding motif Y (18)L (21) or autophagy-related pathway. |
| GO:0090141 positive regulation of mitochondrial fission | IMP PMID:27145933 FUNDC1 regulates mitochondrial dynamics at the ER-mitochondr... | NEW | Summary: Under hypoxia, FUNDC1 at ER-mitochondria contact sites recruits DRP1 and promotes its oligomerization and activation to drive mitochondrial fission ahead of mitophagy; FUNDC1 knockdown prevents hypoxic fission. Reason: FUNDC1 does some of the work of this process: it is the outer-membrane adaptor that recruits DRP1 (comparable to the DRP1 receptors MFF and FIS1, which carry mitochondrial fission terms). Two independent human-cell studies support this (PMID:27145933, PMID:33978709). Supporting Evidence: PMID:27145933 Further, we found that FUNDC1 is specifically required for mitochondrial fragmentation: It recruits DRP1 to drive mitochondrial fission in response to hypoxic stress. PMID:33978709 In response to hypoxia, USP19 tends to interact with FUNDC1, removing the ubiquitin chains from FUNDC1 at MAM and stabilizing FUNDC1 at ER-mitochondria contact sites, thereby facilitating the oligomerization of Drp1 at the ER-mitochondria contact sites to complete the fission events. |
| GO:0044233 mitochondria-associated endoplasmic reticulum membrane contact site | IDA PMID:27145933 FUNDC1 regulates mitochondrial dynamics at the ER-mitochondr... | NEW | Summary: FUNDC1 accumulates at ER-mitochondria contact sites (MAMs) under hypoxia, where it binds calnexin and then DRP1. Reason: Directly shown by imaging and fractionation in PMID:27145933 and supported by PMID:33978709. This is the site of its fission-adaptor activity and is not captured by any existing annotation. Supporting Evidence: PMID:27145933 Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells. PMID:33978709 In response to hypoxia, USP19 tends to interact with FUNDC1, removing the ubiquitin chains from FUNDC1 at MAM and stabilizing FUNDC1 at ER-mitochondria contact sites, thereby facilitating the oligomerization of Drp1 at the ER-mitochondria contact sites to complete the fission events. |
| GO:0043495 protein-membrane adaptor activity | IMP PMID:27145933 FUNDC1 regulates mitochondrial dynamics at the ER-mitochondr... | NEW | Summary: FUNDC1 acts as an outer-membrane adaptor that recruits cytosolic DRP1 to mitochondria at ER contact sites under hypoxia; silencing FUNDC1 sharply reduces DRP1 translocation to mitochondria. Reason: The authors describe FUNDC1 as a MAM adaptor for DRP1, and loss of FUNDC1 reduced DRP1 recruitment more than loss of MFF, FIS1 or MiD49/51. A specific adaptor MF is more informative than protein binding. Supporting Evidence: PMID:27145933 Taken together, these findings reveal that FUNDC1 is not only a novel MAM protein that acts as an adaptor for DRP1 during the mitochondrial fission process, but also involved in hypoxia‐induced mitophagy. PMID:27145933 Further, we found that FUNDC1 is specifically required for mitochondrial fragmentation: It recruits DRP1 to drive mitochondrial fission in response to hypoxic stress. |
Loading supporting content…
Download this section (compressed HTML)Q: How do FUNDC1-mediated (receptor, ubiquitin-independent) and PINK1/Parkin-mediated (ubiquitin-dependent) mitophagy divide labour in vivo, and in which tissues is FUNDC1 required rather than redundant with BNIP3/NIX?
Q: Does FUNDC1 rescue of PINK1-deficient phenotypes act only through DRP1-dependent fission, or does it also affect mitochondrial fusion?
Experiment: Reconstitute FUNDC1-knockout cells with LIR mutant (Y18A/L21A) versus DRP1-binding-deficient FUNDC1 and measure hypoxic mitochondrial fission (live imaging) and mitophagy flux (mt-Keima) separately.
Hypothesis: FUNDC1 LIR binding and DRP1 recruitment are separable activities that contribute independently to hypoxic mitochondrial clearance.
Type: structure-function rescue
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)