Affinage

PINK1

Serine/threonine-protein kinase PINK1, mitochondrial · UniProt Q9BXM7

Length
581 aa
Mass
62.8 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PINK1 is a mitochondrial serine/threonine kinase that functions as a sentinel for mitochondrial damage, coupling organelle quality surveillance to selective autophagy and inflammatory suppression. On healthy mitochondria, PINK1 is constitutively imported through TOM-TIM23 translocase complexes and degraded by PARL and Lon proteases, keeping its levels low; upon loss of membrane potential, PINK1 accumulates as a dimer on the outer mitochondrial membrane at a TOM-VDAC supercomplex, undergoes trans-autophosphorylation, and phosphorylates ubiquitin at Ser65, which allosterically activates the E3 ligase Parkin and directly recruits the autophagy receptors NDP52 and optineurin to initiate mitophagy (PMID:20126261, PMID:24784582, PMID:26266977, PMID:40080546, PMID:34933320). Beyond mitophagy, PINK1 phosphorylates mitofusin 2 to regulate mitochondrial dynamics, phosphorylates HDAC3 to modulate p53-dependent apoptosis, and directs Keap1/Cullin3-dependent ER-phagy independently of Parkin (PMID:23620051, PMID:25305081, PMID:37633267). Loss of PINK1-mediated mitophagy causes mitochondrial DNA release that activates cGAS-STING innate immune inflammation, and concurrent STING deletion rescues dopaminergic neurodegeneration in Pink1-knockout mice, establishing a mechanistic link between PINK1 loss-of-function and Parkinson's disease pathogenesis (PMID:30135585).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 Medium

    Establishing where PINK1 resides resolved the question of which organelle compartment the kinase surveys: PINK1 localizes to mitochondrial membranes in human brain tissue, placing it at the site where it could sense mitochondrial damage.

    Evidence Subcellular fractionation and immunohistochemistry in human and rat brain

    PMID:16702191

    Open questions at the time
    • No functional consequence of mitochondrial localization demonstrated
    • Precise sub-mitochondrial topology not resolved
  2. 2008 High

    Genetic epistasis in Drosophila established that PINK1 and Parkin operate in a common pathway controlling mitochondrial fission-fusion balance, providing the first in vivo functional framework for their cooperation.

    Evidence Drosophila double mutants and dosage suppression with fission/fusion factors (drp1, OPA1, Mfn2)

    PMID:18230723

    Open questions at the time
    • Biochemical mechanism linking PINK1-Parkin to fission machinery unknown
    • Whether this pathway is conserved in mammalian neurons not tested
  3. 2010 High

    The discovery that PINK1 accumulates selectively on depolarized mitochondria and is both necessary and sufficient for Parkin recruitment established the voltage-gated damage-sensing mechanism and placed PINK1 unambiguously upstream of Parkin in mitophagy.

    Evidence Biochemical fractionation, live-cell imaging, and genetic epistasis in mammalian cells

    PMID:20126261

    Open questions at the time
    • Identity of the PINK1 substrate that activates Parkin unknown
    • Mechanism of voltage-dependent PINK1 proteolysis not molecularly defined
  4. 2013 High

    Identification of mitofusin 2 as a PINK1 substrate that serves as a mitochondrial receptor for Parkin revealed a phosphorylation-dependent docking mechanism for Parkin recruitment.

    Evidence In vitro kinase assay, cardiac myocyte-specific Mfn2 knockout mouse, co-immunoprecipitation

    PMID:23620051

    Open questions at the time
    • Whether Mfn2 is the sole or primary Parkin receptor debated (later superseded by phospho-ubiquitin model)
    • Cardiac-specific phenotype not confirmed in neurons
  5. 2014 High

    The breakthrough identification of ubiquitin Ser65 as the direct PINK1 substrate that allosterically unlocks Parkin's catalytic cysteine resolved how PINK1 kinase activity is transduced into E3 ligase activation, establishing the phospho-ubiquitin feedforward amplification model.

    Evidence Mass spectrometry, in vitro kinase assays with recombinant TcPINK1, phosphomimetic rescue, thioester discharge assay — independently replicated by two groups

    PMID:24751536 PMID:24784582

    Open questions at the time
    • Structural basis for PINK1-ubiquitin recognition unknown
    • In vivo stoichiometry of phospho-ubiquitin not measured
  6. 2014 Medium

    Characterization of PINK1 autophosphorylation sites (Ser228, Ser402) showed that self-activation is required for substrate phosphorylation and mitophagy, explaining how PINK1 transitions from an inactive imported form to an active kinase, and the Lon protease was identified as a degradation pathway keeping processed PINK1 low in healthy mitochondria.

    Evidence Site-directed mutagenesis with in vitro kinase and cell-based mitophagy assays; Drosophila Lon RNAi knockdown with mitochondrial fractionation

    PMID:24874806 PMID:25527497

    Open questions at the time
    • Structural basis for autophosphorylation-dependent activation not visualized
    • Whether Lon or PARL is the primary protease in mammalian cells debated
  7. 2015 High

    Demonstrating that phospho-ubiquitin directly recruits NDP52 and optineurin independently of Parkin to initiate mitophagy established that PINK1 alone can trigger selective autophagy, broadening the pathway beyond a simple PINK1→Parkin linear model.

    Evidence Genome-edited HeLa cells with five autophagy receptors knocked out, individual receptor reconstitution

    PMID:26266977

    Open questions at the time
    • Relative contribution of Parkin-dependent versus Parkin-independent arms in vivo unknown
    • Mechanism of NDP52/optineurin preference over p62 not explained
  8. 2017 High

    The first crystal structure of PINK1 bound to ubiquitin revealed how unique N-lobe insertions grip the Ser65 loop in a C-terminally retracted conformation, explaining substrate recognition and rationalizing disease mutations.

    Evidence X-ray crystallography of PhPINK1-ubiquitin complex stabilized by nanobody, mutagenesis of AR-JP mutations

    PMID:29160309

    Open questions at the time
    • Structure solved with insect ortholog; human PINK1-ubiquitin complex structure lacking
    • Dynamics of substrate binding and release not captured
  9. 2018 High

    Structural determination of phosphorylated Parkin at 1.8 Å showed how phospho-Ubl rebinding to UPD and the ACT linker drive RING2 release, completing the mechanistic picture of how PINK1 phosphorylation propagates through Parkin to expose its catalytic center.

    Evidence X-ray crystallography of phosphorylated human Parkin, HDX-MS

    PMID:29995846

    Open questions at the time
    • Full-length activated Parkin on membrane not structurally resolved
    • Kinetics of domain rearrangement in vivo unknown
  10. 2018 High

    Connecting PINK1/Parkin loss to cGAS-STING-mediated inflammation and dopaminergic neurodegeneration in vivo revealed that the physiological role of PINK1-dependent mitophagy extends beyond organelle quality to suppression of innate immune activation by mitochondrial DNA.

    Evidence Pink1−/− and Pink1−/−;Sting−/− double-knockout mice with exhaustive exercise and mtDNA mutator backgrounds, cytokine measurements

    PMID:30135585

    Open questions at the time
    • Whether STING activation is the primary driver of neurodegeneration in human PD not established
    • Cell-type specificity of the inflammatory response in brain not dissected
  11. 2021 High

    Cryo-EM structures capturing unphosphorylated, dimeric trans-autophosphorylating, and phosphorylated active states of PINK1 resolved the multi-step activation cascade, showing that dimerization on the membrane enables trans-autophosphorylation before substrate engagement.

    Evidence X-ray crystallography and cryo-EM of multiple PhPINK1 states with in vitro phosphorylation assays

    PMID:34933320

    Open questions at the time
    • Structures based on insect ortholog; human PINK1 activation intermediates not visualized
    • How membrane context constrains dimerization geometry unclear
  12. 2022 High

    Discovery that Pink1 mRNA is co-transported with mitochondria to distal axons via SYNJ2BP/SYNJ2 tethering established a local translation mechanism ensuring PINK1 protein availability at distant neuronal sites, explaining how neurons achieve spatial mitophagy control.

    Evidence Live mRNA imaging, RNA immunoprecipitation, SYNJ2BP/SYNJ2 knockdown, local translation assays in primary neurons

    PMID:35216662

    Open questions at the time
    • Whether local translation is rate-limiting for distal mitophagy in vivo not tested
    • Regulation of mRNA release from mitochondria incompletely understood
  13. 2023 Medium

    Identification of TIM23 as a PINK1 complex component that protects PINK1 from OMA1-mediated degradation, and the finding that PINK1 can direct ER-phagy through Keap1/Cullin3 independently of Parkin, expanded PINK1's mechanistic repertoire beyond mitochondrial quality control.

    Evidence Mass spectrometry of PINK1 co-immunoprecipitates with TIM23 knockdown/OMA1 rescue; Drosophila genetics for ER-phagy with Keap1/Cullin3 mutants

    PMID:37160114 PMID:37633267

    Open questions at the time
    • Structural basis for PINK1-TIM23 interaction not resolved
    • Whether PINK1-directed ER-phagy occurs in mammalian systems unknown
  14. 2025 High

    The 3.1 Å cryo-EM structure of endogenous human dimeric PINK1 at a TOM-VDAC supercomplex revealed the precise architecture of PINK1 stabilization on damaged mitochondria: PINK1 enters through the proximal TOM40 barrel guided by TOM7/TOM22, with TOM5/TOM20 binding the kinase C-lobes and VDAC2 bridging two TOM complexes.

    Evidence Cryo-EM of endogenous human PINK1-TOM-VDAC complex at 3.1 Å

    PMID:40080546

    Open questions at the time
    • How this supercomplex disassembles after mitophagy initiation is unknown
    • Whether VDAC2 bridging is functionally required or structural has not been tested by mutagenesis

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how PINK1 activity is spatiotemporally integrated with its newly identified non-mitophagy functions (ER-phagy, innate immunity, cell cycle regulation), the structural basis for human PINK1-ubiquitin recognition, and whether pharmacological PINK1 activation can rescue neurodegeneration.
  • No human PINK1-ubiquitin co-structure available
  • In vivo tissue-specific quantification of phospho-ubiquitin dynamics lacking
  • Therapeutic activation of endogenous PINK1 not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0098772 molecular function regulator activity 5
Localization
GO:0005739 mitochondrion 4 GO:0005886 plasma membrane 2
Pathway
R-HSA-9612973 Autophagy 6 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 1
Partners
BNIP3MFN2PRKNSYNJ2BPTIMM23TOM20TOM7VDAC2
Complex memberships
PINK1-TOM-TIM23 supercomplexPINK1-TOM-VDAC supercomplex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 PINK1 accumulates selectively on damaged/depolarized mitochondria via voltage-dependent proteolysis that keeps PINK1 levels low on healthy mitochondria; PINK1 accumulation is both necessary and sufficient for Parkin recruitment to mitochondria, placing PINK1 upstream of Parkin in the mitophagy pathway. Biochemical fractionation, live-cell imaging, genetic epistasis (disease mutations in PINK1 and Parkin block Parkin recruitment at distinct steps), dominant-negative and overexpression experiments PLoS Biology High 20126261
2014 PINK1 directly phosphorylates ubiquitin at Ser65 both in vitro and in cells upon mitochondrial depolarization; phospho-ubiquitin allosterically activates Parkin E3 ligase activity by unlocking autoinhibition of its catalytic cysteine, and phosphomimetic ubiquitin bypasses PINK1 requirement for Parkin activation. Mass spectrometry (phosphopeptide identification), in vitro kinase assay with recombinant TcPINK1 and ubiquitin, cell-based phosphomimetic rescue experiments, thioester discharge assay Nature High 24751536 24784582
2014 Endogenous PINK1 phosphorylates ubiquitin at Ser65 (detected by mass spectrometry); recombinant TcPINK1 directly phosphorylates ubiquitin in vitro; phospho-ubiquitin activates Parkin E3 ligase activity in cell-free assays; a ubiquitin S65A mutant inhibits Parkin translocation to damaged mitochondria. Mass spectrometry, in vitro kinase assay, cell-free ubiquitin ligase assay, dominant-negative ubiquitin S65A expression Journal of Cell Biology High 24751536
2015 PINK1-generated phospho-ubiquitin recruits autophagy receptors NDP52 and optineurin (but not p62) directly to mitochondria to initiate mitophagy independently of Parkin; once recruited, NDP52 and optineurin activate ULK1, DFCP1, and WIPI1 upstream of LC3, establishing that PINK1 can directly initiate mitophagy. Genome-edited HeLa cells with five autophagy receptors knocked out, reconstitution of individual receptors, epistasis experiments Nature High 26266977
2013 PINK1 phosphorylates mitofusin 2 (Mfn2), promoting its Parkin-mediated ubiquitination; Mfn2 functions as a mitochondrial receptor for Parkin recruitment to damaged mitochondria; ablation of Mfn2 prevents depolarization-induced Parkin translocation and suppresses mitophagy. Co-immunoprecipitation, in vitro phosphorylation assay, cardiac myocyte-specific Mfn2 knockout mouse, mitophagy assays Science High 23620051
2018 PINK1 and Parkin mitigate STING-mediated innate immune inflammation; loss of PINK1 leads to release of mitochondrial DNA that activates the cGAS-STING pathway; concurrent STING loss rescues inflammatory phenotypes and dopaminergic neuron loss in Pink1-/- mutator mice. Pink1-/- mouse genetics, double knockout (Pink1-/-;Sting-/-), exhaustive exercise and mtDNA mutator models, cytokine measurements Nature High 30135585
2018 Parkin activation by PINK1 involves large-scale domain rearrangement: phospho-Ubl rebinds to the parkin core (unique parkin domain, UPD), releasing the catalytic RING2 domain; a crystal structure of phosphorylated human parkin at 1.8 Å reveals the phospho-Ubl binding site on UPD and an activating element (ACT linker) that mimics RING2 interactions to drive RING2 release. Hydrogen-deuterium exchange mass spectrometry, 1.8 Å crystal structure of phosphorylated human parkin, AR-JP mutation mapping Nature High 29995846
2017 Crystal structure of PhPINK1 bound to ubiquitin in the C-terminally retracted (Ub-CR) conformation reveals that the N lobe of PINK1 binds ubiquitin via a unique insertion, that the flexible Ser65 loop contacts the activation segment placing Ser65 in a phosphate-accepting position, and that autophosphorylation in the N lobe stabilizes important structural insertions. X-ray crystallography (nanobody-stabilized complex), mutagenesis of AR-JP mutations Nature High 29160309
2021 PINK1 activation proceeds through: (1) an unphosphorylated but active state oriented on mitochondria (crystal structure of unphosphorylated PhPINK1); (2) a symmetric dimeric intermediate undergoing trans-autophosphorylation (cryo-EM); (3) a phosphorylated active ubiquitin kinase conformation (cryo-EM); additionally, regulatory PINK1 oxidation modulates its activity. X-ray crystallography, cryo-EM structures of multiple PINK1 states, in vitro phosphorylation assays Nature High 34933320
2025 Cryo-EM structure of dimeric human PINK1 at 3.1 Å stabilized at an endogenous TOM-VDAC array reveals that PINK1 enters mitochondria through the proximal TOM40 barrel guided by TOM7 and TOM22, while TOM5 and TOM20 bind PINK1 kinase C-lobes; a central VDAC2 dimer bridges two TOM core complexes; this supercomplex architecture explains PINK1 stabilization and regulation. Cryo-EM structure determination of endogenous human PINK1-TOM-VDAC complex at 3.1 Å resolution Science High 40080546
2008 In Drosophila, PINK1 acts upstream of Parkin in a pathway that promotes mitochondrial fission; heterozygous loss of drp1 (fission factor) is lethal in PINK1 or parkin mutants, while increased drp1 or reduced OPA1/Mfn2 (fusion factors) suppress PINK1/parkin mutant phenotypes, establishing genetic epistasis between PINK1-Parkin and the fission/fusion machinery. Drosophila genetic epistasis: double mutants, dosage suppression/enhancement with drp1, OPA1, Mfn2 PNAS High 18230723
2014 PINK1 autophosphorylation at Ser228 and Ser402 regulates its kinase activity toward substrates Parkin and ubiquitin; Ser402 phosphorylation is specifically required for Parkin recruitment and mitophagy induction; the N-terminus of full-length PINK1 exerts an inhibitory effect on these autophosphorylation sites. Site-directed mutagenesis of phosphorylation sites, in vitro kinase assays, mitophagy assays in cells Journal of Biological Chemistry Medium 25527497
2014 The matrix-localized protease Lon (Lon protease) promotes constitutive degradation of processed PINK1 in healthy mitochondria in Drosophila, thereby regulating PINK1 pathway activity; Lon knockdown causes dramatic accumulation of processed PINK1 in multiple mitochondrial compartments without depolarization. Drosophila genetic screen of mitochondrial proteases, Lon RNAi knockdown, mitochondrial fractionation, membrane potential measurements PLoS Genetics Medium 24874806
2016 BNIP3 interacts with PINK1 to promote accumulation of full-length PINK1 on the outer mitochondrial membrane, suppressing PINK1 proteolytic processing and facilitating Parkin recruitment and mitophagy; loss of BNIP3 promotes PINK1 cleavage and suppresses mitophagy. Co-immunoprecipitation, knockdown/overexpression in mammalian cells, Drosophila rescue experiments, mitophagy assays Journal of Biological Chemistry Medium 27528605
2013 SARM1 and TRAF6 form a complex with PINK1 on depolarized mitochondria; TRAF6 mediates K63-chain ubiquitination of PINK1 at Lys433, which stabilizes PINK1 and promotes Parkin recruitment; pathogenic PINK1 mutations reduce complex formation and ubiquitination. Co-immunoprecipitation, knockdown of SARM1/TRAF6, ubiquitin linkage-specific analysis Molecular Biology of the Cell Medium 23885119
2017 S-nitrosylation of PINK1 (SNO-PINK1) inhibits PINK1 kinase activity, decreases Parkin translocation to mitochondria, and disrupts mitophagy in iPSC-derived human neurons and cell lines; elevated SNO-PINK1 is found in α-synuclein transgenic PD mouse brains. Biotin-switch assay for S-nitrosylation, kinase activity assays, Parkin translocation assays, iPSC-derived neurons, mouse model Cell Reports Medium 29166608
2013 Cytosolic PINK1 (ΔN111-PINK1) promotes dendritic outgrowth and increases anterograde transport of dendritic mitochondria via protein kinase A signaling; this function requires kinase activity but is distinct from the mitochondria-localized pool's role in mitophagy. Compartment-targeted PINK1 constructs (OMM-PINK1 vs. ΔN111-PINK1), neurite outgrowth assays in SH-SY5Y cells and primary neurons, PKA activity measurements Journal of Neurochemistry Medium 24151868
2010 PINK1 interacts with Beclin1 via both its N- and C-terminal regions (requiring full-length PINK1); PINK1 enhances basal and starvation-induced autophagy through this interaction; a disease mutant (W437X) with impaired Beclin1 binding lacks this autophagy-promoting activity. Co-immunoprecipitation, Beclin1 knockdown, Vps34 inhibition, autophagy flux assays Cell Death and Differentiation Medium 20057503
2019 PHB2 depletion destabilizes PINK1 on mitochondria, blocking Parkin/ubiquitin/OPTN recruitment and mitophagy; PHB2 interacts with the inner membrane protease PARL and PGAM5 (processed by PARL) participates in PHB2-mediated PINK1 stabilization, establishing a PHB2-PARL-PGAM5-PINK1 axis. Co-immunoprecipitation, knockdown/overexpression, mitophagy assays, chemical inhibitor (FL3) Autophagy Medium 31177901
2024 Mitochondrial stress induces formation of a PINK1-TOM-TIM23 supercomplex; PINK1 stably tethers TOM to TIM23 complexes via its N-terminal/C-terminal extension module interacting with the cytosolic domain of Tom20; disruption of this interaction by PD-associated mutations inhibits downstream mitophagy. Co-immunoprecipitation, blue native PAGE, designer and PD-associated mutation analysis, dopamine neuron and midbrain organoid models PNAS Medium 38416681
2023 TIM23 is a component of the PINK1 complex (identified by mass spectrometry of PINK1 co-immunoprecipitates); TIM23 downregulation decreases PINK1 levels and delays autophosphorylation; TIM23 protects PINK1 from degradation by the mitochondrial protease OMA1. Mass spectrometry of co-immunoprecipitates, TIM23 knockdown, OMA1 inactivation rescue, PINK1 autophosphorylation assays Cell Reports Medium 37160114
2021 AMBRA1 is recruited to the outer mitochondrial membrane upon depolarization, interacts with PINK1 and ATAD3A, and promotes PINK1 stability by counteracting ATAD3A-mediated LONP1 degradation of PINK1; AMBRA1 loss reduces PINK1-dependent ubiquitin phosphorylation and Parkin recruitment. Co-immunoprecipitation, AMBRA1/ATAD3A knockdown, PINK1 ubiquitin phosphorylation assay, LONP1 inhibition rescue Autophagy Medium 34798798
2022 Pink1 mRNA is co-transported with neuronal mitochondria to distal axons via the mitochondrial outer membrane proteins SYNJ2BP and SYNJ2; SYNJ2 tethers Pink1 mRNA to mitochondria through an RNA-binding domain, enabling local PINK1 translation to support distal mitophagy. Live imaging of mRNA transport, SYNJ2BP/SYNJ2 knockdown, RNA immunoprecipitation, local translation assays in neurons Neuron High 35216662
2024 AMPK phosphorylates SYNJ2BP within its PDZ domain to enable its interaction with SYNJ2 and tether Pink1 mRNA to mitochondria; insulin signaling inhibits AMPK, releasing Pink1 mRNA from mitochondria, which is required for proper PINK1 protein activation as a ubiquitin kinase; ApoE4 induces insulin resistance and retains Pink1 mRNA at mitochondria, impairing PINK1 activity. AMPK inhibition/activation, phospho-site mutagenesis of SYNJ2BP, insulin treatment, RNA-mitochondria association assays, PINK1 ubiquitin kinase activity assays in neurons Nature Metabolism Medium 38504131
2014 PINK1 phosphorylates HDAC3 at Ser424 to enhance its deacetylase activity; this phosphorylation prevents H2O2-induced C-terminal cleavage of HDAC3, promotes HDAC3-p53 association and p53 hypoacetylation, thereby suppressing p53-dependent apoptosis in dopaminergic neurons; protein phosphatase 4c reverses this phosphorylation. In vitro HDAC3 kinase assay, phosphomimetic HDAC3 S424E rescue, PINK1 knockout cells, p53 acetylation assays Human Molecular Genetics Medium 25305081
2012 PINK1 undergoes NEDD8 conjugation (neddylation); neddylation of PINK1 selectively stabilizes the 55 kDa PINK1 fragment; dAPP-BP1 (NEDD8 activation enzyme subunit) overexpression in Drosophila suppresses dPINK1 RNAi phenotypes; PD neurotoxin MPP+ inhibits neddylation of PINK1. Co-immunoprecipitation for NEDD8 conjugation, Drosophila genetic rescue, MPP+ treatment Human Molecular Genetics Low 22388932
2016 PINK1 phosphorylates TUFm at Ser222; phospho-Ser222-TUFm localizes predominantly to the cytosol where it inhibits mitophagy by impeding Atg5-Atg12 complex formation; this creates a self-antagonizing feedback loop in which PINK1 both activates (via p-S65-ubiquitin) and suppresses (via p-S222-TUFm) mitophagy. Co-immunoprecipitation, phosphosite mutagenesis, Atg5-Atg12 complex assays, mitophagy flux assays Molecular Cell Medium 33113344
2016 PINK1 phosphorylation of Parkin at Ser65 of its ubiquitin-like domain disrupts hydrophobic core packing and alters surface electrostatics, reducing autoinhibitory UBL-core association; phospho-UBL and phospho-ubiquitin together are required to activate Parkin by releasing the UBL domain for E2-ubiquitin binding. NMR structure of phospho-UBL, ITC binding measurements, ubiquitin vinyl sulfone activity assays PNAS High 28007983
2019 PINK1 and Parkin sequester TBK1 at damaged mitochondria during mitophagy, blocking its role at centrosomes and causing a mitosis arrest; loss of PINK1 or Parkin accelerates cell growth; genetic interaction screen links PINK1/Parkin to cell cycle regulators. PINK1/Parkin knockout HeLa cells, TBK1 localization by immunofluorescence, cell cycle assays, Drosophila genetic interaction screen Cell Reports Medium 31577952
2019 PINK1 positively regulates innate antiviral immunity: PINK1 associates with TRAF3 via its kinase domain and inhibits Parkin-mediated K48-linked proteasomal degradation of TRAF3, sustaining RLR signaling; PINK1 also interacts with YAP1 upon viral infection, disrupting the YAP1-IRF3 inhibitory complex. Co-immunoprecipitation, PINK1 knockdown, viral infection assays, IRF3/NF-κB activation measurements Frontiers in Immunology Medium 31139191
2019 Phospho-ubiquitin (pS65-Ub) can bind to two distinct sites on Parkin: a high-affinity RING1 site controlling Parkin localization and a low-affinity RING0 site releasing autoinhibition; tetra-phospho-ubiquitin chains can activate Parkin in a feedforward mechanism; a chimeric parkin with Ubl replaced by ubiquitin is readily activated by PINK1. ITC, NMR titrations, ubiquitin vinyl sulfone activity assay, chimeric Parkin construction, PINK1 phosphorylation assays EMBO Journal High 35491809
2019 PPEF2 phosphatase dephosphorylates p-S65-ubiquitin in vitro and in cells, counteracting PINK1; PPEF2 knockdown amplifies p-S65-ubiquitin and enhances baseline mitophagy; overexpression of active PPEF2 reduces p-S65-ubiquitin signal, establishing PPEF2 as an eraser of the PINK1 phospho-ubiquitin signal. In vitro dephosphorylation assay with partially purified PPEF2 and recombinant p-S65-ubiquitin chains, mass spectrometry, knockdown/overexpression in neurons Cell Reports Medium 31801089
2023 In Drosophila development, PINK1 regulates selective ER clearance (ER-phagy) through Keap1/Cullin3-dependent ubiquitylation of the ER-phagy receptor Rtnl1, while Parkin is dispensable for ER clearance; PINK1 regulates a change in Keap1 localization, establishing PINK1 at a branch point that differentially directs ER versus mitochondria clearance. Drosophila genetics (PINK1, Parkin, Keap1, Cullin3 mutants), ubiquitylation assays, localization studies of Keap1 Cell Medium 37633267
2006 PINK1 protein localizes to mitochondrial membranes in human brain; fractionation studies confirm mitochondrial membrane localization in human and rat brain; PINK1 shows punctate cytoplasmic staining consistent with mitochondria in all brain cell types; PINK1 is detected in a proportion of Lewy bodies in Parkinson's disease. Subcellular fractionation of human and rat brain, immunohistochemistry, western blot with validated antibodies Brain Medium 16702191
2016 PINK1 autophosphorylation (Ser346 in Drosophila) is required for its ability to recruit Parkin to mitochondria; Parkin phosphorylation by PINK1 is required for Parkin activation but not translocation; substitution with autophosphorylation-deficient PINK1 fails to rescue pink1 null phenotypes in vivo. LC-MS/MS phosphosite mapping in Drosophila, phosphomimetic and phospho-null PINK1 mutants, in vivo rescue assays Cell Death & Disease Medium 27906179
2013 PINK1 interacts with synphilin-1, which is recruited to mitochondria and promotes PINK1-dependent mitophagy independently of Parkin by recruiting SIAH-1 E3 ligase to mitochondria to drive ubiquitination and mitophagy. Co-immunoprecipitation, synphilin-1/SIAH-1 knockdown, LC3/LAMP1 recruitment assays, Atg5 knockdown epistasis Human Molecular Genetics Low 27334109
2023 ATAD3A disrupts PINK1 proteostasis by restraining PINK1-dependent mitophagy; PINK1 recruits PD-L1 to mitochondria for degradation via mitophagy; paclitaxel increases ATAD3A expression to prevent PD-L1 mitochondrial distribution by blocking PINK1-dependent mitophagy. Co-immunoprecipitation of ATAD3A-PINK1, knockdown/overexpression, subcellular fractionation, mitophagy flux assays, patient tumor samples Cell Research Medium 36627348

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS biology 2377 20126261
2015 The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 2248 26266977
2014 Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 1199 24784582
2013 PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science (New York, N.Y.) 1075 23620051
2018 Parkin and PINK1 mitigate STING-induced inflammation. Nature 1057 30135585
2014 PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. The Journal of cell biology 1034 24751536
2009 Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. The Journal of biological chemistry 808 19279012
2008 The PINK1/Parkin pathway regulates mitochondrial morphology. Proceedings of the National Academy of Sciences of the United States of America 710 18230723
2016 Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. Trends in cell biology 581 27291334
2014 PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. The Journal of clinical investigation 512 25562319
2015 PINK1/Parkin-mediated mitophagy in mammalian cells. Current opinion in cell biology 484 25697963
2019 Intestinal infection triggers Parkinson's disease-like symptoms in Pink1-/- mice. Nature 374 31316206
2020 PINK1/PARKIN signalling in neurodegeneration and neuroinflammation. Acta neuropathologica communications 368 33168089
2019 PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 334 31177901
2011 PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Proceedings of the National Academy of Sciences of the United States of America 329 21606348
2014 Parkin and PINK1: much more than mitophagy. Trends in neurosciences 312 24735649
2018 Mechanism of parkin activation by PINK1. Nature 306 29995846
2011 Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxidants & redox signaling 294 21194381
2022 PINK1/Parkin-mediated mitophagy in neurodegenerative diseases. Ageing research reviews 269 36503124
2006 PINK1 protein in normal human brain and Parkinson's disease. Brain : a journal of neurology 266 16702191
2016 Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond. Free radical biology & medicine 261 27094585
2024 The role of PINK1-Parkin in mitochondrial quality control. Nature cell biology 244 39358449
2016 BNIP3 Protein Suppresses PINK1 Kinase Proteolytic Cleavage to Promote Mitophagy. The Journal of biological chemistry 229 27528605
2015 Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy. Journal of neurochemistry 227 26509433
2010 The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell death and differentiation 217 20057503
2018 Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila. eLife 172 29809156
2002 Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study. Annals of neurology 162 12447943
2006 Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiology of disease 158 17141510
2011 Regulation of PINK1-Parkin-mediated mitophagy. Autophagy 153 21187721
2015 (Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation. EMBO reports 150 26162776
2015 NRF2 Regulates PINK1 Expression under Oxidative Stress Conditions. PloS one 149 26555609
2021 Activation mechanism of PINK1. Nature 147 34933320
2016 The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway. Human molecular genetics 144 27334109
2020 Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism. Brain : a journal of neurology 139 33029617
2009 FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation. Proceedings of the National Academy of Sciences of the United States of America 138 19276113
2017 Structure of PINK1 in complex with its substrate ubiquitin. Nature 132 29160309
2016 Parkin and PINK1 functions in oxidative stress and neurodegeneration. Brain research bulletin 122 28017782
2022 Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy. Neuron 115 35216662
2009 PINK1 function in health and disease. EMBO molecular medicine 115 20049715
2009 The PINK1/Parkin pathway: a mitochondrial quality control system? Journal of bioenergetics and biomembranes 114 19967438
2017 S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson's Disease Models. Cell reports 111 29166608
2013 Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through protein kinase A. Journal of neurochemistry 110 24151868
2016 Mitochondrial quality control by the Pink1/Parkin system. Cell and tissue research 107 27586587
2014 PINK1 kinase catalytic activity is regulated by phosphorylation on serines 228 and 402. The Journal of biological chemistry 100 25527497
2011 PARK6 PINK1 mutants are defective in maintaining mitochondrial membrane potential and inhibiting ROS formation of substantia nigra dopaminergic neurons. Biochimica et biophysica acta 100 21421046
2014 PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix. PLoS genetics 99 24874806
2023 Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria. Cell research 96 36627348
2018 PINK1-PARK2-mediated mitophagy in COPD and IPF pathogeneses. Inflammation and regeneration 93 30386443
2023 Unconventional initiation of PINK1/Parkin mitophagy by Optineurin. Molecular cell 90 37207627
2020 PINK1: The guard of mitochondria. Life sciences 87 32805222
2019 Mechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond. Cellular and molecular life sciences : CMLS 87 31254044
2016 A novel PINK1- and PARK2-dependent protective neuroimmune pathway in lethal sepsis. Autophagy 85 27754761
2016 The mitochondrial kinase PINK1: functions beyond mitophagy. Journal of neurochemistry 79 27251035
2013 TRAP1 rescues PINK1 loss-of-function phenotypes. Human molecular genetics 79 23525905
2008 Biochemical aspects of the neuroprotective mechanism of PTEN-induced kinase-1 (PINK1). Journal of neurochemistry 77 18221368
2019 PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis. Cell reports 74 31577952
2016 Structure of phosphorylated UBL domain and insights into PINK1-orchestrated parkin activation. Proceedings of the National Academy of Sciences of the United States of America 72 28007983
2011 Genetic mutations and functions of PINK1. Trends in pharmacological sciences 70 21784538
2016 PINK1-dependent phosphorylation of PINK1 and Parkin is essential for mitochondrial quality control. Cell death & disease 67 27906179
2021 AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability. Autophagy 66 34798798
2016 PINK1 in the limelight: multiple functions of an eclectic protein in human health and disease. The Journal of pathology 66 27701735
2012 Regulation of parkin and PINK1 by neddylation. Human molecular genetics 65 22388932
2010 Dopaminergic cell damage and vulnerability to MPTP in Pink1 knockdown zebrafish. Neurobiology of disease 64 20600915
2013 SARM1 and TRAF6 bind to and stabilize PINK1 on depolarized mitochondria. Molecular biology of the cell 61 23885119
2024 Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress. Proceedings of the National Academy of Sciences of the United States of America 54 38416681
2020 Paradoxical Mitophagy Regulation by PINK1 and TUFm. Molecular cell 53 33113344
2020 PINK1 import regulation at a crossroad of mitochondrial fate: the molecular mechanisms of PINK1 import. Journal of biochemistry 47 31504668
2017 Hexokinases link DJ-1 to the PINK1/parkin pathway. Molecular neurodegeneration 46 28962651
2023 PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development. Cell 43 37633267
2002 Autosomal recessive early onset parkinsonism is linked to three loci: PARK2, PARK6, and PARK7. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 43 12548343
2023 Structural Mechanisms of Mitochondrial Quality Control Mediated by PINK1 and Parkin. Journal of molecular biology 42 37054910
2014 PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death. Human molecular genetics 42 25305081
2017 Mitochondrial quality control pathways: PINK1 acts as a gatekeeper. Biochemical and biophysical research communications 41 28647367
2009 Tickled PINK1: mitochondrial homeostasis and autophagy in recessive Parkinsonism. Biochimica et biophysica acta 41 19595762
2021 PINK1: A Bridge between Mitochondria and Parkinson's Disease. Life (Basel, Switzerland) 40 33919398
2020 Comprehensive assessment of PINK1 variants in Parkinson's disease. Neurobiology of aging 40 32249012
2015 DJ1 represses glycolysis and cell proliferation by transcriptionally up-regulating Pink1. The Biochemical journal 40 25670069
2017 High expression of PINK1 promotes proliferation and chemoresistance of NSCLC. Oncology reports 38 28259921
2015 Functions and characteristics of PINK1 and Parkin in cancer. Frontiers in bioscience (Landmark edition) 38 25553463
2014 Loss of PINK1 impairs stress-induced autophagy and cell survival. PloS one 38 24751806
2023 TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria. Cell reports 36 37160114
2018 Induction of PINK1/Parkin-Mediated Mitophagy. Methods in molecular biology (Clifton, N.J.) 35 28361482
2015 Molecular mechanisms underlying PINK1 and Parkin catalyzed ubiquitylation of substrates on damaged mitochondria. Biochimica et biophysica acta 35 25700839
2010 Enhanced vulnerability of PARK6 patient skin fibroblasts to apoptosis induced by proteasomal stress. Neuroscience 34 20045449
2025 Structure of human PINK1 at a mitochondrial TOM-VDAC array. Science (New York, N.Y.) 33 40080546
2015 Pyruvate stimulates mitophagy via PINK1 stabilization. Cellular signalling 33 26071202
2022 The emerging multifaceted role of PINK1 in cancer biology. Cancer science 32 36071695
2012 Analysis of the regulatory and catalytic domains of PTEN-induced kinase-1 (PINK1). Human mutation 32 22644621
2007 PINK1 mutation heterozygosity and the risk of Parkinson's disease. Journal of neurology, neurosurgery, and psychiatry 32 17172567
2004 The gene responsible for PARK6 Parkinson's disease, PINK1, does not influence common forms of parkinsonism. Annals of neurology 32 15349859
2020 N-degron-mediated degradation and regulation of mitochondrial PINK1 kinase. Current genetics 31 32157382
2016 PINK1 signaling in mitochondrial homeostasis and in aging (Review). International journal of molecular medicine 31 27959386
2006 Parkin blushed by PINK1. Neuron 31 16701203
2019 Mitochondrial Protein PINK1 Positively Regulates RLR Signaling. Frontiers in immunology 30 31139191
2014 Short mitochondrial ARF triggers Parkin/PINK1-dependent mitophagy. The Journal of biological chemistry 29 25217637
2024 Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons. Nature metabolism 28 38504131
2022 Structural basis for feedforward control in the PINK1/Parkin pathway. The EMBO journal 28 35491809
2025 Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1. Nature 27 39972141
2019 PPEF2 Opposes PINK1-Mediated Mitochondrial Quality Control by Dephosphorylating Ubiquitin. Cell reports 27 31801089
2015 Beyond mitophagy: cytosolic PINK1 as a messenger of mitochondrial health. Antioxidants & redox signaling 27 25557302