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). Under normal conditions with healthy mitochondria, PINK-1 is imported into mitochondria and cleaved by proteases. Upon mitochondrial depolarization or damage, full-length PINK-1 accumulates on the outer mitochondrial membrane where it autophosphorylates and becomes active. Activated PINK-1 phosphorylates ubiquitin at Ser65 and also phosphorylates PDR-1 (the C. elegans Parkin homolog) at Ser65, promoting PDR-1 activation and recruitment. This initiates a feed-forward ubiquitination cascade that labels damaged mitochondria for autophagic clearance (mitophagy). In C. elegans, PINK-1 is required for mitophagy, 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 [IBA annotation inferred from phylogenetic trees] |
| 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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