id: Q09298 gene_symbol: pink-1 product_type: PROTEIN status: IN_PROGRESS taxon: id: NCBITaxon:6239 label: Caenorhabditis elegans description: 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. existing_annotations: - term: id: GO:0000422 label: autophagy of mitochondrion evidence_type: IBA original_reference_id: GO_REF:0000033 review: 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]. action: ACCEPT 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. supported_by: - reference_id: PMID:25896323 supporting_text: DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: The PINK-1/PDR-1 (Parkin homolog) pathway mediates mitophagy and mitochondrial quality control in worms - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IBA original_reference_id: GO_REF:0000033 review: 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). action: ACCEPT 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. supported_by: - reference_id: UniProt:Q09298 supporting_text: Serine/threonine-protein kinase pink-1, mitochondrial - term: id: GO:0005739 label: mitochondrion evidence_type: IBA original_reference_id: GO_REF:0000033 review: 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. action: ACCEPT 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. supported_by: - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: A rescuing Ppink-1::pink-1::gfp transgene shows broad expression in neurons and other tissues with partial mitochondrial co-localization - term: id: GO:0042981 label: regulation of apoptotic process evidence_type: IBA original_reference_id: GO_REF:0000033 review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: GO_REF:0000033 supporting_text: '[IBA annotation inferred from phylogenetic trees]' - term: id: GO:0090141 label: positive regulation of mitochondrial fission evidence_type: IBA original_reference_id: GO_REF:0000033 review: 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. action: ACCEPT 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. supported_by: - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: PINK1-Parkin impacts fission/fusion components and mitochondrial motility; in worms, pink-1 loss alters cristae and stress responses - term: id: GO:0000166 label: nucleotide binding evidence_type: IEA original_reference_id: GO_REF:0000043 review: 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. action: ACCEPT 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. supported_by: - reference_id: UniProt:Q09298 supporting_text: Nucleotide-binding; Reference proteome; Serine/threonine-protein kinase - term: id: GO:0004672 label: protein kinase activity evidence_type: IEA original_reference_id: GO_REF:0000002 review: 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). action: ACCEPT 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. supported_by: - reference_id: UniProt:Q09298 supporting_text: InterPro; IPR000719; Prot_kinase_dom - term: id: GO:0004674 label: protein serine/threonine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000120 review: 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. action: ACCEPT 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. supported_by: - reference_id: UniProt:Q09298 supporting_text: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000120 review: 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. action: ACCEPT 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. supported_by: - reference_id: UniProt:Q09298 supporting_text: ATP-binding; Kinase; Magnesium; Metal-binding; Mitochondrion - term: id: GO:0005739 label: mitochondrion evidence_type: IEA original_reference_id: GO_REF:0000120 review: 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. action: ACCEPT 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. supported_by: - reference_id: UniProt:Q09298 supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion' - term: id: GO:0006950 label: response to stress evidence_type: IEA original_reference_id: GO_REF:0000117 review: 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). action: ACCEPT 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. supported_by: - reference_id: PMID:19251702 supporting_text: increased vulnerability to oxidative and endoplasmic reticulum stress - term: id: GO:0016301 label: kinase activity evidence_type: IEA original_reference_id: GO_REF:0000043 review: 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. action: ACCEPT 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. supported_by: - reference_id: UniProt:Q09298 supporting_text: Kinase; Magnesium; Metal-binding; Mitochondrion - term: id: GO:0016740 label: transferase activity evidence_type: IEA original_reference_id: GO_REF:0000043 review: 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. action: ACCEPT 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. supported_by: - reference_id: UniProt:Q09298 supporting_text: Transferase; Transit peptide - term: id: GO:0046872 label: metal ion binding evidence_type: IEA original_reference_id: GO_REF:0000043 review: summary: IEA annotation for metal ion binding. PINK-1 requires Mg2+ as a cofactor for kinase activity, which is typical for protein kinases. action: ACCEPT 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. supported_by: - reference_id: UniProt:Q09298 supporting_text: Name=Mg(2+); Xref=ChEBI:CHEBI:18420 - term: id: GO:0106310 label: protein serine kinase activity evidence_type: IEA original_reference_id: GO_REF:0000116 review: 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. action: ACCEPT 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. supported_by: - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: The best-established substrates are ubiquitin (Ser65) and Parkin's Ubl domain (Ser65) - term: id: GO:0000423 label: mitophagy evidence_type: IMP original_reference_id: PMID:26469957 review: 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. action: ACCEPT 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. supported_by: - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: The PINK-1/PDR-1 (Parkin homolog) pathway mediates mitophagy and mitochondrial quality control in worms - reference_id: PMID:26469957 supporting_text: A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. - term: id: GO:0000423 label: mitophagy evidence_type: IMP original_reference_id: PMID:25896323 review: 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. action: ACCEPT 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. supported_by: - reference_id: PMID:25896323 supporting_text: Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling - reference_id: UniProt:Q09298 supporting_text: Plays a role in mitophagy (PubMed:25896323) - term: id: GO:0031398 label: positive regulation of protein ubiquitination evidence_type: IMP original_reference_id: PMID:25896323 review: 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. action: ACCEPT 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. supported_by: - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: Activated PINK1 phosphorylates ubiquitin at Ser65 and also phosphorylates Parkin (PRKN) on Ser65 in its Ubl domain, promoting Parkin activation - reference_id: PMID:25896323 supporting_text: Coordination of mitophagy and mitochondrial biogenesis during ageing in C. - term: id: GO:0034976 label: response to endoplasmic reticulum stress evidence_type: IGI original_reference_id: PMID:19251702 review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: PMID:19251702 supporting_text: the hypersensitivity of lrk-1 mutant animals to the endoplasmic reticulum stressor tunicamycin was reduced in a pink-1 mutant background - term: id: GO:0007005 label: mitochondrion organization evidence_type: IMP original_reference_id: PMID:19251702 review: 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. action: ACCEPT 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. supported_by: - reference_id: PMID:19251702 supporting_text: a mutation in the Caenorhabditits elegans homologue of the PTEN-induced kinase pink-1 gene resulted in reduced mitochondrial cristae length - term: id: GO:0007411 label: axon guidance evidence_type: IMP original_reference_id: PMID:19251702 review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: PMID:19251702 supporting_text: the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons - term: id: GO:0034599 label: cellular response to oxidative stress evidence_type: IMP original_reference_id: PMID:19251702 review: 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. action: ACCEPT 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. supported_by: - reference_id: PMID:19251702 supporting_text: reduced mitochondrial cristae length and increased paraquat sensitivity of the nematode - term: id: GO:0048846 label: axon extension involved in axon guidance evidence_type: IMP original_reference_id: PMID:19251702 review: summary: IMP annotation for more specific aspect of axon guidance. pink-1 mutants show defects in axonal extension of CAN neurons. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: PMID:19251702 supporting_text: the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons - term: id: GO:0048846 label: axon extension involved in axon guidance evidence_type: IGI original_reference_id: PMID:19251702 review: 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. action: KEEP_AS_NON_CORE 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. supported_by: - reference_id: PMID:19251702 supporting_text: 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 - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:19251702 review: 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. action: ACCEPT 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. supported_by: - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: A rescuing Ppink-1::pink-1::gfp transgene shows broad expression in neurons and other tissues with partial mitochondrial co-localization - reference_id: PMID:19251702 supporting_text: Epub 2009 Feb 27. Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. - term: id: GO:0005739 label: mitochondrion evidence_type: IDA original_reference_id: PMID:19251702 review: summary: IDA annotation for mitochondrial localization based on direct imaging of PINK-1::GFP in C. elegans. Shows co-localization with mitochondrial markers. action: ACCEPT 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. supported_by: - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: A rescuing Ppink-1::pink-1::gfp transgene shows broad expression in neurons and other tissues with partial mitochondrial co-localization - reference_id: PMID:19251702 supporting_text: Epub 2009 Feb 27. Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: - statement: PAINT/IBA annotations provide phylogenetically consistent annotations based on well-characterized orthologs - id: GO_REF:0000043 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping findings: [] - id: GO_REF:0000116 title: Automatic Gene Ontology annotation based on Rhea mapping findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:19251702 title: Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. findings: - statement: pink-1 mutants have reduced mitochondrial cristae length and increased paraquat sensitivity supporting_text: a mutation in the Caenorhabditits elegans homologue of the PTEN-induced kinase pink-1 gene resulted in reduced mitochondrial cristae length and increased paraquat sensitivity of the nematode - statement: pink-1 mutants display axon guidance defects in CAN neurons supporting_text: the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons - statement: lrk-1 loss suppresses all pink-1 phenotypes supporting_text: 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 - statement: pink-1 loss reduces lrk-1 ER stress sensitivity (tunicamycin) supporting_text: the hypersensitivity of lrk-1 mutant animals to the endoplasmic reticulum stressor tunicamycin was reduced in a pink-1 mutant background - id: PMID:25896323 title: Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. findings: - statement: PINK-1/PDR-1 pathway is essential for mitophagy in C. elegans supporting_text: DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans - statement: Mitophagy coordinates with mitochondrial biogenesis during aging supporting_text: mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity - statement: Impairment of mitophagy compromises stress resistance supporting_text: Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling - id: PMID:26469957 title: A bacterial metabolite induces glutathione-tractable proteostatic damage, proteasomal disturbances, and PINK1-dependent autophagy in C. elegans. findings: - statement: Metabolite-induced autophagy is PINK-1 dependent supporting_text: the induced autophagy observed in metabolite-treated animals is PINK-1 dependent - statement: PINK-1 is required for stress-induced autophagic response supporting_text: animals with reduced pink-1 no longer have increased mCherry::LGG-1 accumulation in the presence of the metabolite - id: file:worm/pink-1/pink-1-deep-research-falcon.md title: Deep research on C. elegans pink-1 findings: - statement: PINK-1 is a mitochondrial stress-activated serine/threonine kinase supporting_text: PINK-1 is a mitochondrial stress-activated serine/threonine kinase whose substrates include ubiquitin (Ser65) and Parkin/PRKN (Ser65) - statement: PINK-1 localizes to mitochondria with a cytoplasmic pool supporting_text: A rescuing Ppink-1::pink-1::gfp transgene shows broad expression in neurons and other tissues with partial mitochondrial co-localization - statement: pink-1 loss reduces mitochondrial cristae length supporting_text: pink-1 loss reduces mitochondrial cristae length (approximately 12% reduction in body-wall muscle; >30% in neurons) core_functions: - molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity directly_involved_in: - id: GO:0000423 label: mitophagy locations: - id: GO:0005739 label: mitochondrion description: PINK-1 is a serine/threonine kinase that phosphorylates ubiquitin (Ser65) and Parkin/PDR-1 (Ser65) to activate the mitophagic cascade at the outer mitochondrial membrane. Loss of pink-1 eliminates stress-induced autophagic responses and prevents clearance of damaged mitochondria. supported_by: - reference_id: PMID:25896323 supporting_text: Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: The PINK-1/PDR-1 (Parkin homolog) pathway mediates mitophagy and mitochondrial quality control in worms - molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity directly_involved_in: - id: GO:0031398 label: positive regulation of protein ubiquitination locations: - id: GO:0005739 label: mitochondrion description: PINK-1 phosphorylates ubiquitin and Parkin to activate Parkin's E3 ligase activity, promoting ubiquitination of outer mitochondrial membrane proteins as part of the mitophagy initiation cascade. supported_by: - reference_id: file:worm/pink-1/pink-1-deep-research-falcon.md supporting_text: Activated PINK1 phosphorylates ubiquitin at Ser65 and also phosphorylates Parkin (PRKN) on Ser65 in its Ubl domain, promoting Parkin activation - molecular_function: id: GO:0004674 label: protein serine/threonine kinase activity directly_involved_in: - id: GO:0034599 label: cellular response to oxidative stress locations: - id: GO:0005739 label: mitochondrion description: pink-1 mutants are hypersensitive to paraquat-induced oxidative stress. PINK-1-dependent clearance of damaged mitochondria (which produce ROS) is protective against oxidative damage. supported_by: - reference_id: PMID:19251702 supporting_text: reduced mitochondrial cristae length and increased paraquat sensitivity of the nematode proposed_new_terms: [] suggested_questions: - question: What are the direct phosphorylation substrates of C. elegans PINK-1 beyond the conserved ubiquitin Ser65? - question: Does C. elegans PINK-1 have kinase-independent functions as observed in some mammalian studies? - question: What is the precise mechanism of PINK-1/LRK-1 antagonism in stress response? suggested_experiments: - description: 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 - description: Phosphoproteomics in pink-1 mutants to identify PINK-1-dependent phosphorylation events hypothesis: PINK-1 has additional substrates beyond ubiquitin and Parkin - description: 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 tags: - caeel-mitophagy