PINK-1 is the C. elegans ortholog of mammalian PINK1 (PTEN-induced kinase 1), a mitochondrial serine/threonine kinase that functions as a key sensor of mitochondrial damage and initiator of mitophagy. The protein contains an N-terminal mitochondrial targeting sequence (residues 1-74), a transmembrane domain, and a cytosol-facing protein kinase catalytic domain (residues 137-483). By analogy with mammalian PINK1, PINK-1 is expected to be imported into healthy mitochondria and cleaved by proteases, and to accumulate on the outer membrane of depolarized or damaged mitochondria, where it autophosphorylates and becomes active. Mammalian PINK1 then phosphorylates ubiquitin and the Ubl domain of Parkin at Ser65, starting a feed-forward ubiquitination cascade that labels damaged mitochondria for autophagic clearance (mitophagy); the equivalent phosphorylation of ubiquitin and of PDR-1, the C. elegans Parkin homolog, by worm PINK-1 is inferred from this conservation rather than shown directly. In C. elegans, PINK-1 and PDR-1 are required for stress-induced mitophagy, for example after frataxin depletion, and they shape the tissue distribution of a deleterious mitochondrial genome. PINK-1 is also required for mitochondrial quality control during aging, and stress responses including oxidative stress. pink-1 mutants show reduced mitochondrial cristae length, increased paraquat sensitivity, and defects in axon guidance. PINK-1 acts antagonistically to LRK-1 (LRRK2 homolog) in stress response and neurite outgrowth.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000422 autophagy of mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation based on phylogenetic inference from orthologs. This annotation accurately reflects the core function of PINK-1 in initiating mitophagy. The PINK-1/PDR-1 pathway is the canonical mitophagy pathway in C. elegans, and multiple studies demonstrate PINK-1's essential role in this process [PMID:25896323, file:worm/pink-1/pink-1-deep-research-falcon.md]. Reason: PINK-1 is a central regulator of mitophagy. Upon mitochondrial depolarization, PINK-1 stabilizes on the outer mitochondrial membrane where it phosphorylates ubiquitin and PDR-1/Parkin to initiate the mitophagic cascade. This is well-established across species and supported by direct experimental evidence in C. elegans. The IBA annotation is phylogenetically sound and consistent with experimental data. Supporting Evidence: PMID:25896323 DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans file:worm/pink-1/pink-1-deep-research-falcon.md The PINK-1/PDR-1 (Parkin homolog) pathway mediates mitophagy and mitochondrial quality control in worms |
| GO:0004674 protein serine/threonine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for the core molecular function of PINK-1 as a serine/threonine kinase. PINK-1 contains a conserved protein kinase domain (residues 137-483) and is classified in the Ser/Thr protein kinase family. The kinase catalyzes phosphorylation of serine residues on ubiquitin (Ser65) and Parkin/PDR-1 (Ser65 in the Ubl domain). Reason: This is the fundamental molecular function of PINK-1. The protein contains a conserved kinase domain with canonical N- and C-lobes and PINK1-specific insert regions. UniProt records the catalytic activity (EC 2.7.11.1) and the active site at position 338. The annotation is appropriately specific and reflects the core enzymatic activity. Supporting Evidence: UniProt:Q09298 Serine/threonine-protein kinase pink-1, mitochondrial |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for mitochondrial localization. PINK-1 contains an N-terminal mitochondrial targeting sequence (residues 1-74) and localizes to mitochondria. This localization is described in the deep research file based on PMID:19251702 and other sources. Reason: Mitochondrial localization is central to PINK-1 function. The N-terminal transit peptide directs PINK-1 to mitochondria. Under normal conditions PINK-1 is imported and cleaved; upon mitochondrial damage, full-length PINK-1 accumulates on the outer mitochondrial membrane where it functions. Supporting Evidence: file:worm/pink-1/pink-1-deep-research-falcon.md A rescuing Ppink-1::pink-1::gfp transgene shows broad expression in neurons and other tissues with partial mitochondrial co-localization |
| GO:0042981 regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA annotation suggesting PINK-1 involvement in regulation of apoptosis. While mammalian PINK1 has been implicated in apoptosis regulation, direct experimental evidence for this role in C. elegans is limited. The primary role of PINK-1 in worms appears to be in mitophagy and mitochondrial quality control rather than direct apoptosis regulation. Reason: PINK1 involvement in apoptosis regulation is primarily characterized in mammalian systems. While mitochondrial dysfunction (which PINK-1 regulates) can influence apoptotic pathways, direct evidence for PINK-1 regulation of apoptosis in C. elegans is not well established. The annotation may be valid based on phylogenetic inference but represents a secondary rather than core function in worms. Supporting Evidence: GO_REF:0000033 |
| GO:0090141 positive regulation of mitochondrial fission | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for positive regulation of mitochondrial fission. PINK-1 and Parkin are known to impact mitochondrial dynamics including fission/fusion. In C. elegans, pink-1 loss leads to altered mitochondrial morphology as described in the deep research file. Reason: PINK-1/Parkin impacts mitochondrial dynamics as part of the mitophagy quality control process. Damaged mitochondria undergo fission before mitophagic clearance. The IBA annotation reflects conserved roles in mitochondrial dynamics. Supporting Evidence: file:worm/pink-1/pink-1-deep-research-falcon.md PINK1-Parkin impacts fission/fusion components and mitochondrial motility; in worms, pink-1 loss alters cristae and stress responses |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProtKB keyword mapping. PINK-1 is a kinase that requires ATP for catalysis. The annotation is correct but overly general - ATP binding (GO:0005524) is a more specific and informative term. Reason: This is a correct but broad annotation. PINK-1 binds ATP as a kinase substrate. The annotation is technically accurate but less informative than GO:0005524 (ATP binding), which is also annotated. Acceptable as a parent term capture. Supporting Evidence: UniProt:Q09298 Nucleotide-binding; Reference proteome; Serine/threonine-protein kinase |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro domain IPR000719 (protein kinase domain). PINK-1 has a well-characterized protein kinase domain. This annotation is correct but less specific than GO:0004674 (protein serine/threonine kinase activity). Reason: Correct annotation based on the presence of the protein kinase domain. While GO:0004674 (protein serine/threonine kinase activity) is more specific and also annotated, this parent term is acceptable as a complementary IEA annotation. Supporting Evidence: UniProt:Q09298 InterPro; IPR000719; Prot_kinase_dom |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from combined automated methods including InterPro and EC number. Duplicates the IBA annotation for the same term. PINK-1 is a serine/threonine kinase (EC 2.7.11.1) that phosphorylates ubiquitin Ser65 and Parkin Ser65. Reason: Duplicate of the IBA annotation but via different evidence. The annotation is correct - PINK-1 is a serine/threonine kinase with defined catalytic activity. Having both IBA and IEA evidence provides independent support. Supporting Evidence: UniProt:Q09298 Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for ATP binding. PINK-1 binds ATP as a substrate for its kinase activity. The ATP binding site is located at residues 143-151 and 199, as defined in the UniProt feature annotations. Reason: ATP binding is essential for PINK-1 kinase activity. The annotation is well-supported by the presence of canonical ATP-binding motifs in the kinase domain and explicit binding site annotations in UniProt. This is more specific and informative than the general nucleotide binding annotation. Supporting Evidence: UniProt:Q09298 ATP-binding; Kinase; Magnesium; Metal-binding; Mitochondrion |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for mitochondrial localization. Duplicates the IBA annotation. PINK-1 contains an N-terminal mitochondrial transit peptide (residues 1-74) that targets it to mitochondria. Reason: Correct annotation supported by the presence of a mitochondrial targeting sequence and UniProt subcellular location annotation. The IEA provides computational support for the IBA and IDA annotations for this localization. Supporting Evidence: UniProt:Q09298 SUBCELLULAR LOCATION: Mitochondrion |
| GO:0006950 response to stress | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation from ARBA machine learning models. PINK-1 is involved in stress responses, particularly mitochondrial stress and oxidative stress. However, this term is very broad and more specific annotations exist (e.g., GO:0034599 cellular response to oxidative stress). Reason: PINK-1 is indeed involved in stress responses, functioning as a mitochondrial stress sensor. While the term is broad, it is not incorrect. More specific stress-related annotations (oxidative stress, ER stress) provide additional detail. The broad term captures the general stress-responsive role of PINK-1. Supporting Evidence: PMID:19251702 increased vulnerability to oxidative and endoplasmic reticulum stress |
| GO:0016301 kinase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on keyword mapping. Very broad parent term of the more specific protein serine/threonine kinase activity annotation. PINK-1 is a kinase. Reason: This is a correct but very general annotation. It is a parent term of GO:0004674 (protein serine/threonine kinase activity) which is also annotated. Acceptable as broad IEA capture but provides less information than the specific kinase type. Supporting Evidence: UniProt:Q09298 Kinase; Magnesium; Metal-binding; Mitochondrion |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on keyword mapping. Very broad parent term - kinases are transferases that transfer phosphate groups. This is the highest-level function class for PINK-1. Reason: Correct but extremely general annotation. Kinases are a subclass of transferases (they transfer phosphate groups from ATP to substrates). The annotation is technically accurate but provides minimal functional insight. Acceptable as broad IEA capture. Supporting Evidence: UniProt:Q09298 Transferase; Transit peptide |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for metal ion binding. PINK-1 requires Mg2+ as a cofactor for kinase activity, which is typical for protein kinases. Reason: Protein kinases require divalent metal ions (typically Mg2+) for catalytic activity. UniProt records Mg2+ as a cofactor for PINK-1. This is a correct annotation reflecting the metal ion requirement for phosphotransfer reactions. Supporting Evidence: UniProt:Q09298 Name=Mg(2+); Xref=ChEBI:CHEBI:18420 |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: IEA annotation from Rhea reaction mapping. PINK-1 phosphorylates serine residues, specifically Ser65 of ubiquitin and Ser65 of Parkin. The Rhea database links the catalytic reaction (RHEA:17989) to this GO term. Reason: The best-characterized substrates of PINK1 are phosphorylated on serine residues (ubiquitin Ser65, Parkin Ser65). This annotation is appropriately specific and supported by the known substrate specificity. Complements the broader serine/threonine kinase activity annotation. Supporting Evidence: file:worm/pink-1/pink-1-deep-research-falcon.md The best-established substrates are ubiquitin (Ser65) and Parkin's Ubl domain (Ser65) |
| GO:0000423 mitophagy | IMP PMID:26469957 A bacterial metabolite induces glutathione-tractable proteos... | ACCEPT | Summary: IMP annotation based on mutant phenotype analysis in C. elegans. The study showed that a bacterial metabolite induces PINK-1-dependent autophagy, and pink-1 loss eliminates the autophagic response to mitochondrial stress. Reason: Direct experimental evidence in C. elegans demonstrating PINK-1's role in mitophagy. The study showed that metabolite-induced autophagy was PINK-1 dependent, and pink-1 loss-of-function epistatically regulated the effects of the metabolite on proteostasis and mitochondrial morphology. Supporting Evidence: file:worm/pink-1/pink-1-deep-research-falcon.md The PINK-1/PDR-1 (Parkin homolog) pathway mediates mitophagy and mitochondrial quality control in worms PMID:26469957 A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. |
| GO:0000423 mitophagy | IMP PMID:25896323 Coordination of mitophagy and mitochondrial biogenesis durin... | ACCEPT | Summary: IMP annotation from a key Nature paper demonstrating PINK-1 role in mitophagy during aging in C. elegans. The study established that mitophagy coordinates with mitochondrial biogenesis and that PINK-1/PDR-1 pathway is essential for this process. Reason: High-quality evidence from a Nature publication establishing PINK-1's central role in mitophagy in C. elegans. The study showed that impairment of mitophagy compromises stress resistance and that the PINK-1/PDR-1 pathway is critical for mitochondrial quality control during aging. This is a core function. Supporting Evidence: PMID:25896323 Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling UniProt:Q09298 Plays a role in mitophagy (PubMed:25896323) |
| GO:0031398 positive regulation of protein ubiquitination | IMP PMID:25896323 Coordination of mitophagy and mitochondrial biogenesis durin... | ACCEPT | Summary: IMP annotation for PINK-1's role in promoting protein ubiquitination. PINK-1 phosphorylates ubiquitin and Parkin to activate the ubiquitin ligase activity of Parkin/PDR-1, leading to ubiquitination of outer mitochondrial membrane proteins. Reason: This accurately reflects PINK-1's mechanism of action. Activated PINK-1 phosphorylates ubiquitin at Ser65 and Parkin at Ser65, which promotes Parkin's E3 ligase activity and creates a feed-forward loop of ubiquitination. This leads to ubiquitin chain deposition on mitochondrial proteins and recruitment of autophagy machinery. Supporting Evidence: file:worm/pink-1/pink-1-deep-research-falcon.md Activated PINK1 phosphorylates ubiquitin at Ser65 and also phosphorylates Parkin (PRKN) on Ser65 in its Ubl domain, promoting Parkin activation PMID:25896323 Coordination of mitophagy and mitochondrial biogenesis during ageing in C. |
| GO:0034976 response to endoplasmic reticulum stress | IGI PMID:19251702 Caenorhabditits elegans LRK-1 and PINK-1 act antagonisticall... | KEEP AS NON CORE | Summary: IGI annotation based on genetic interaction with lrk-1. The study showed that lrk-1 mutants are hypersensitive to ER stress (tunicamycin), and this was reduced in a pink-1 mutant background, demonstrating antagonistic interaction. Reason: The annotation is based on genetic interaction showing that pink-1 mutation suppresses the ER stress sensitivity of lrk-1 mutants. This indicates PINK-1 is involved in ER stress response, but the mechanism is indirect - through antagonistic interaction with LRK-1 rather than direct ER stress sensing. This is a secondary function related to the stress response network involving PINK-1 and LRK-1. Supporting Evidence: PMID:19251702 the hypersensitivity of lrk-1 mutant animals to the endoplasmic reticulum stressor tunicamycin was reduced in a pink-1 mutant background |
| GO:0007005 mitochondrion organization | IMP PMID:19251702 Caenorhabditits elegans LRK-1 and PINK-1 act antagonisticall... | ACCEPT | Summary: IMP annotation based on mutant phenotype. pink-1 mutants show reduced mitochondrial cristae length in body-wall muscle (approximately 12% reduction) and neurons (>30% reduction), demonstrating PINK-1's role in mitochondrial organization/morphology. Reason: Direct experimental evidence in C. elegans showing that pink-1 loss affects mitochondrial ultrastructure. The reduced cristae length indicates PINK-1 is required for proper mitochondrial organization. This is consistent with PINK-1's role in mitochondrial quality control. Supporting Evidence: PMID:19251702 a mutation in the Caenorhabditits elegans homologue of the PTEN-induced kinase pink-1 gene resulted in reduced mitochondrial cristae length |
| GO:0007411 axon guidance | IMP PMID:19251702 Caenorhabditits elegans LRK-1 and PINK-1 act antagonisticall... | KEEP AS NON CORE | Summary: IMP annotation based on mutant phenotype. pink-1 mutants display defects in axonal outgrowth of canal-associated neurons (CAN neurons). These defects are suppressed by lrk-1 loss, indicating antagonistic function. Reason: Direct experimental evidence shows pink-1 mutants have axon guidance defects. However, this appears to be a secondary consequence of mitochondrial dysfunction rather than a direct role in axon guidance signaling. The phenotype is suppressed by lrk-1 loss, suggesting it reflects the stress response network. Not a core function of PINK-1. Supporting Evidence: PMID:19251702 the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons |
| GO:0034599 cellular response to oxidative stress | IMP PMID:19251702 Caenorhabditits elegans LRK-1 and PINK-1 act antagonisticall... | ACCEPT | Summary: IMP annotation based on mutant phenotype. pink-1 mutants show increased sensitivity to paraquat, a known inducer of oxidative stress. This demonstrates PINK-1's role in protection against oxidative stress. Reason: Direct experimental evidence showing pink-1 mutants are hypersensitive to oxidative stress (paraquat). This is consistent with PINK-1's role in mitochondrial quality control - damaged mitochondria are major sources of ROS, and failure to clear them leads to increased oxidative damage. The annotation reflects a core protective function. Supporting Evidence: PMID:19251702 reduced mitochondrial cristae length and increased paraquat sensitivity of the nematode |
| GO:0048846 axon extension involved in axon guidance | IMP PMID:19251702 Caenorhabditits elegans LRK-1 and PINK-1 act antagonisticall... | KEEP AS NON CORE | Summary: IMP annotation for more specific aspect of axon guidance. pink-1 mutants show defects in axonal extension of CAN neurons. Reason: This is a more specific child term of axon guidance (GO:0007411). The experimental evidence is the same - pink-1 mutants have CAN neuron axonal outgrowth defects. As with the parent term, this likely represents a secondary consequence of mitochondrial dysfunction rather than a direct axon extension function. Supporting Evidence: PMID:19251702 the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons |
| GO:0048846 axon extension involved in axon guidance | IGI PMID:19251702 Caenorhabditits elegans LRK-1 and PINK-1 act antagonisticall... | KEEP AS NON CORE | Summary: IGI annotation based on genetic interaction with lrk-1. Loss of lrk-1 suppresses the axon extension defects of pink-1 mutants, demonstrating antagonistic interaction. Reason: Duplicate term with different evidence code. The genetic interaction evidence supports the antagonistic relationship between PINK-1 and LRK-1 in neuronal development. This reflects the stress response/neuronal function network rather than a core function of PINK-1. Supporting Evidence: PMID:19251702 in the absence of lrk-1, the C. elegans homologue of human LRRK2, all phenotypic aspects of pink-1 loss-of-function mutants were suppressed |
| GO:0005737 cytoplasm | IDA PMID:19251702 Caenorhabditits elegans LRK-1 and PINK-1 act antagonisticall... | ACCEPT | Summary: IDA annotation for cytoplasmic localization based on GFP-tagged PINK-1 imaging. The study showed PINK-1::GFP localizes to both mitochondria and cytoplasm. Reason: Direct experimental evidence from imaging of PINK-1::GFP transgene. PINK-1 is found in both mitochondria and cytoplasm. Under normal conditions, PINK-1 is imported into mitochondria, cleaved, and retrotranslocated to cytoplasm for degradation. The cytoplasmic pool reflects this processing pathway. Supporting Evidence: file:worm/pink-1/pink-1-deep-research-falcon.md A rescuing Ppink-1::pink-1::gfp transgene shows broad expression in neurons and other tissues with partial mitochondrial co-localization PMID:19251702 Epub 2009 Feb 27. Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. |
| GO:0005739 mitochondrion | IDA PMID:19251702 Caenorhabditits elegans LRK-1 and PINK-1 act antagonisticall... | ACCEPT | Summary: IDA annotation for mitochondrial localization based on direct imaging of PINK-1::GFP in C. elegans. Shows co-localization with mitochondrial markers. Reason: High-quality direct experimental evidence. PINK-1::GFP shows mitochondrial co-localization, confirming that PINK-1 targets to mitochondria as expected from its N-terminal mitochondrial targeting sequence. This is the primary site of PINK-1 function in mitophagy initiation. Supporting Evidence: file:worm/pink-1/pink-1-deep-research-falcon.md A rescuing Ppink-1::pink-1::gfp transgene shows broad expression in neurons and other tissues with partial mitochondrial co-localization PMID:19251702 Epub 2009 Feb 27. Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. |
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Download this section (compressed HTML)Q: What are the direct phosphorylation substrates of C. elegans PINK-1 beyond the conserved ubiquitin Ser65?
Q: Does C. elegans PINK-1 have kinase-independent functions as observed in some mammalian studies?
Q: What is the precise mechanism of PINK-1/LRK-1 antagonism in stress response?
Experiment: In vitro kinase assays with purified C. elegans PINK-1 to identify substrates
Hypothesis: C. elegans PINK-1 phosphorylates ubiquitin and PDR-1 at conserved Ser65 positions
Experiment: Phosphoproteomics in pink-1 mutants to identify PINK-1-dependent phosphorylation events
Hypothesis: PINK-1 has additional substrates beyond ubiquitin and Parkin
Experiment: Tissue-specific rescue experiments to determine cell-autonomous vs non-autonomous functions
Hypothesis: PINK-1 function in neurons is cell-autonomous for mitophagy and stress response
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