Affinage

PINK1

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

Length
581 aa
Mass
62.8 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PINK1 is a mitochondrial Ser/Thr protein kinase that functions as the damage-sensing, initiating kinase of the PINK1–Parkin mitophagy pathway, controlling the selective autophagic clearance of dysfunctional mitochondria (PMID:20126261, PMID:24751536). On healthy, polarized mitochondria PINK1 is held at low levels by voltage-dependent proteolysis, but mitochondrial depolarization triggers rapid accumulation of full-length PINK1 on the outer membrane, an event that is necessary and sufficient to recruit Parkin and that places PINK1 genetically upstream of Parkin (PMID:20126261). Upon stress, PINK1 stabilizes at a TOM–TIM23 supercomplex through an interaction between its N-terminal–C-terminal extension module and the cytosolic domain of Tom20, with the dimeric kinase entering through the TOM40 barrel around a central VDAC2 dimer (PMID:40080546, PMID:38416681). PINK1 dimerizes and trans-autophosphorylates, undergoing a conformational change to an active ubiquitin-kinase state in which autophosphorylated PINK1 binds substrates with high affinity through a Ub/UBL-binding groove wider than that of conventional kinases (PMID:34933320, PMID:29475881, PMID:29991771). Active PINK1 phosphorylates ubiquitin and the Parkin ubiquitin-like domain at Ser65; phospho-ubiquitin allosterically activates Parkin via a feedforward mechanism in which phospho-Ubl and phospho-ubiquitin engage distinct sites that release the autoinhibited RING2/RING0 catalytic core (PMID:24751536, PMID:29995846, PMID:35491809). The resulting ubiquitin signal on damaged mitochondria recruits the autophagy receptors NDP52 and optineurin independently of Parkin, which in turn engage distinct autophagy-initiation machineries—NDP52 via ULK1/FIP200 and optineurin via TBK1–PI3KC3-C1—to nucleate autophagosomes (PMID:26266977, PMID:37207627). PINK1 stability and activation are governed by an upstream regulatory network including PHB2–PARL–PGAM5, AMBRA1–ATAD3A, TIM23–OMA1, and BNIP3 (PMID:31177901, PMID:34798798, PMID:37160114, PMID:27528605). Beyond mitophagy, PINK1 restrains mtDNA-driven STING-dependent type I interferon inflammation, whose loss in mice drives dopaminergic neuron loss and motor deficits (PMID:30135585), and neuronal Pink1 mRNA is tethered to mitochondria and locally translated via SYNJ2BP/SYNJ2 under insulin–AMPK metabolic control (PMID:35216662, PMID:38504131). Pathogenic PINK1 mutations that disrupt mitochondrial accumulation, kinase activity, or ubiquitin phosphorylation are linked to Parkinson's disease and fail to rescue mitochondrial defects in dopaminergic neurons (PMID:21421046, PMID:28438176).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 Medium

    Establishing PINK1's basic enzymatic identity was the necessary starting point: it answered whether the gene product is catalytically active at all.

    Evidence recombinant protein in vitro autophosphorylation assay

    PMID:14607334

    Open questions at the time
    • No substrate beyond autophosphorylation identified
    • No subcellular context or pathway placement
  2. 2006 Medium

    Localizing PINK1 to mitochondrial membranes in human brain anchored the kinase to the organelle whose quality control it would later be shown to govern.

    Evidence immunohistochemistry, western blotting and subcellular fractionation of human and rat brain

    PMID:16702191

    Open questions at the time
    • Membrane sub-topology not resolved
    • Functional consequence of mitochondrial localization not addressed
  3. 2010 High

    Defining voltage-dependent PINK1 accumulation as necessary and sufficient for Parkin recruitment established PINK1 as the upstream damage sensor of mitophagy.

    Evidence genetic epistasis with disease mutations, fractionation and live-cell imaging in uncoupler-treated mammalian cells

    PMID:20126261

    Open questions at the time
    • Molecular signal linking depolarization to PINK1 stabilization not defined
    • Direct PINK1 substrate not yet known
  4. 2014 High

    Identifying ubiquitin Ser65 as a direct PINK1 substrate solved the central question of how PINK1 activates Parkin, revealing a phospho-ubiquitin feedforward loop.

    Evidence mass spectrometry, in vitro kinase assay with recombinant TcPINK1, cell-free Parkin activation, and phosphomimetic ubiquitin mutants

    PMID:24751536

    Open questions at the time
    • Structural basis of phospho-ubiquitin recognition by Parkin not yet resolved
    • How autophosphorylation gates substrate phosphorylation unknown
  5. 2015 High

    Showing PINK1 recruits NDP52 and optineurin independently of Parkin established phospho-ubiquitin as the primary autophagy signal feeding into core autophagy initiation.

    Evidence CRISPR knockout of five autophagy receptors in HeLa cells with imaging and flux assays

    PMID:26266977

    Open questions at the time
    • Distinct initiation machineries used by each receptor not yet defined
    • In vivo relevance in neurons not tested here
  6. 2018 High

    Structural and biochemical dissection of PINK1 autophosphorylation and Parkin domain rearrangement defined the molecular logic of substrate recognition and feedforward activation.

    Evidence TcPINK1 crystal structures with ATP analogue, NMR/SAXS/HDX of PINK1–Parkin Ubl, and 1.8 Å crystal structure of phosphorylated parkin with mutagenesis

    PMID:29475881 PMID:29991771 PMID:29995846

    Open questions at the time
    • Structures used insect/protozoan orthologs rather than human PINK1
    • Membrane-embedded activation state not captured
  7. 2021 High

    Capturing the PINK1 dimer mid-trans-autophosphorylation explained how an inactive kinase converts to an active ubiquitin kinase and how it orients on the membrane.

    Evidence crystal and cryo-EM structures of PhPINK1 in unphosphorylated, dimeric, and phosphorylated active states with phosphorylation assays

    PMID:34933320

    Open questions at the time
    • Used Pediculus ortholog, not human PINK1
    • Context of the TOM complex absent from these structures
  8. 2022 High

    Mapping two distinct phospho-ubiquitin sites on Parkin clarified how phospho-ubiquitin separately controls Parkin localization and de-repression.

    Evidence ITC, NMR titrations, vinyl-sulfone activity assays and parkin chimera/mutagenesis

    PMID:35491809

    Open questions at the time
    • Kinetic coordination of the two sites in cells not resolved
    • Relative contributions of pUb versus pUbl in vivo not quantified
  9. 2024 High

    Demonstrating that PINK1 tethers TOM to TIM23 via its N/C extension–Tom20 interaction defined the supercomplex that holds active PINK1 in place and explained how certain PD mutations block mitophagy.

    Evidence Co-IP and native gels of the PINK1–TOM–TIM23 supercomplex with mutagenesis and mitophagy assays in dopamine neurons and midbrain organoids

    PMID:38416681

    Open questions at the time
    • Atomic detail of the tethering interface not yet resolved here
    • Stoichiometry within the supercomplex unclear
  10. 2025 High

    A near-atomic cryo-EM structure of dimeric human PINK1 on an endogenous TOM–VDAC array resolved how PINK1 engages the import machinery, providing a human structural framework for the activation model.

    Evidence 3.1 Å cryo-EM of endogenous human PINK1–TOM–VDAC complex with interface mutagenesis and mitophagy assays across cell systems

    PMID:40080546

    Open questions at the time
    • Dynamic transition from import-competent to fully active kinase not captured
    • Role of VDAC2 dimer in activation not functionally dissected
  11. 2024 High

    Linking SYNJ2BP/SYNJ2-mediated Pink1 mRNA tethering to insulin–AMPK signaling placed PINK1 production and activation under metabolic control, particularly in neurites.

    Evidence RNA-FISH/live imaging, RNA-IP, SYNJ2BP PDZ phospho-site mutagenesis and PINK1 kinase activity assays in neurons

    PMID:35216662 PMID:38504131

    Open questions at the time
    • Mechanism coupling mRNA release to kinase activation incompletely defined
    • In vivo contribution to neurodegeneration not established
  12. 2018 High

    Identifying STING-driven inflammation as the consequence of PINK1/Parkin loss extended PINK1's role beyond organelle turnover to innate immune restraint relevant to neurodegeneration.

    Evidence Pink1-/- and Prkn-/- mouse models with mtDNA-mutator and exercise stress, rescued by STING knockout

    PMID:30135585

    Open questions at the time
    • Molecular trigger of mtDNA release in PINK1-deficient cells not defined
    • Direct PINK1 substrate in this axis unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse non-canonical PINK1 functions—ER-phagy via Keap1, IP3R/ER calcium via CISD1, TUFm phosphoswitch, and cytoplasmic mTORC2/AKT signaling—are integrated with the core mitophagy program, and whether they share the same activation logic, remains unresolved.
  • Several non-canonical roles rest on single-lab Co-IP/overexpression studies
  • No unifying mechanism connecting canonical and non-canonical PINK1 activities

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
AMBRA1ATAD3ABNIP3PARK2PHB2TOMM20TOMM40VDAC2
Complex memberships
PINK1–TOM–TIM23 supercomplexTOM–VDAC array

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 PINK1 accumulation on mitochondria is regulated by voltage-dependent proteolysis: on healthy, polarized mitochondria PINK1 is kept at low levels, while mitochondrial damage (depolarization) causes rapid accumulation of full-length PINK1 on the outer mitochondrial membrane. PINK1 accumulation is both necessary and sufficient for Parkin recruitment to mitochondria, and PINK1 acts upstream of Parkin in the mitophagy pathway. Genetic epistasis (disease-causing mutations dissecting pathway steps), biochemical fractionation, fluorescence microscopy of mitochondrial PINK1 and Parkin localization in mammalian cells with uncoupler treatment PLoS biology High 20126261
2014 PINK1 directly phosphorylates ubiquitin at Ser65, homologous to Ser65 in the Parkin ubiquitin-like domain. Phospho-ubiquitin (pS65-Ub) activates Parkin E3 ubiquitin ligase activity in cell-free assays, and the phosphomimetic ubiquitin S65D binds and activates Parkin. Expression of non-phosphorylatable ubiquitin S65A inhibits Parkin translocation to damaged mitochondria, establishing a feed-forward activation mechanism. Mass spectrometry identification of endogenous phosphorylation site; in vitro kinase assay with recombinant TcPINK1 and ubiquitin; cell-free Parkin activation assay; phosphomimetic/phospho-dead ubiquitin mutant overexpression in cells The Journal of cell biology High 24751536
2015 PINK1 recruits autophagy receptors NDP52 and optineurin (but not p62) to mitochondria independently of Parkin to initiate mitophagy. Once recruited, NDP52 and optineurin recruit autophagy initiation factors ULK1, DFCP1, and WIPI1 to focal spots proximal to mitochondria upstream of LC3, placing PINK1-generated phospho-ubiquitin as the primary autophagy signal on mitochondria. CRISPR/Cas9 knockout of five autophagy receptors in HeLa cells; fluorescence imaging of receptor recruitment; epistasis analysis of receptor dependence for mitophagy flux Nature High 26266977
2013 PINK1 phosphorylates mitofusin 2 (Mfn2) on the mitochondrial outer membrane, and phospho-Mfn2 acts as a receptor for Parkin. Parkin binds Mfn2 in a PINK1-dependent manner and promotes its ubiquitination. Ablation of Mfn2 in mouse cardiomyocytes prevents depolarization-induced Parkin translocation to mitochondria and suppresses mitophagy. Co-immunoprecipitation; PINK1 in vitro phosphorylation assay with Mfn2; conditional cardiac Mfn2 knockout mice; mitophagy assays Science (New York, N.Y.) Medium 23620051
2018 The mechanism of Parkin activation by PINK1 involves large-scale domain rearrangement: phospho-Ubl (phosphorylated by PINK1 at Ser65) rebinds to the parkin core at the unique parkin domain (UPD) and releases the catalytic RING2 domain from autoinhibition. A conserved linker ACT element between Ubl and UPD mimics RING2 interactions to facilitate release. Crystal structure of phosphorylated human parkin at 1.8 Å reveals the phospho-Ubl binding site on UPD lined by AR-JP disease mutations. Hydrogen-deuterium exchange mass spectrometry of full-length human parkin during activation; 1.8 Å crystal structure of phosphorylated human parkin; structure-guided mutagenesis Nature High 29995846
2021 PINK1 is activated through a multi-step mechanism involving: (1) dimerization and trans-autophosphorylation captured in a cryo-EM structure of a symmetric PhPINK1 dimer; (2) conformational change upon autophosphorylation to an active ubiquitin kinase state; (3) an N-terminal helix orienting unphosphorylated PINK1 on the mitochondrial outer membrane. Regulatory oxidation of PINK1 also modulates its activity. Crystallography of unphosphorylated PhPINK1; cryo-EM structures of PhPINK1 dimer during trans-autophosphorylation and of phosphorylated active state; in vitro phosphorylation assays Nature High 34933320
2025 Cryo-EM structure at 3.1 Å resolution of dimeric human PINK1 stabilized at an endogenous TOM-VDAC array reveals: PINK1 enters mitochondria through the proximal TOM40 barrel guided by TOM7 and TOM22; TOM5 and TOM20 both bind PINK1 kinase C-lobes; a symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20. The N-terminal–C-terminal extension module of PINK1 interacts with the cytosolic domain of Tom20 to stabilize PINK1 at the TOM complex. 3.1 Å cryo-EM structure of endogenous human PINK1–TOM–VDAC complex; mutagenesis of PINK1–Tom20 interaction interface; mitophagy functional assays in cell lines, dopamine neurons, and midbrain organoids Science (New York, N.Y.) High 40080546
2024 Upon mitochondrial stress, PINK1 induces formation of a PINK1–TOM–TIM23 supercomplex in human cell lines, dopamine neurons, and midbrain organoids. PINK1 is required to stably tether TOM to TIM23; this tethering depends on an interaction between the PINK1 N-terminal–C-terminal extension module and the cytosolic domain of Tom20. Disruption of this interaction by designer or PD-associated PINK1 mutations inhibits downstream mitophagy. Co-immunoprecipitation and native gel electrophoresis of PINK1–TOM–TIM23 supercomplex; mutagenesis of PINK1 N-terminal module; mitophagy assays in dopamine neurons and midbrain organoids Proceedings of the National Academy of Sciences of the United States of America High 38416681
2018 PINK1 autophosphorylation (at Ser205 in TcPINK1, equivalent to Ser228 in human PINK1) is required for substrate recognition; autophosphorylated PINK1 binds the Parkin Ubl domain with ~10-fold higher affinity than ubiquitin via a conserved interface. Multiple PINK1 molecules autophosphorylate in trans prior to binding and phosphorylating ubiquitin and Parkin. Enzyme kinetics; NMR spectroscopy of PINK1–Parkin Ubl interaction; mass spectrometry mapping of autophosphorylation site; SAXS; hydrogen-deuterium exchange EMBO reports High 29475881
2018 Structural analysis of TcPINK1 kinase domain with non-hydrolyzable ATP analogue at 2.5 Å reveals a Ub/UBL-binding groove wider than the peptide-binding groove of PKA/PKC to accommodate the globular Ub/UBL head; crosslinking and structure-guided mutagenesis identified the PINK1-interacting surface on ubiquitin. 2.5 Å crystal structure of TcPINK1–ATP analogue complex; crosslinking mass spectrometry; structure-guided mutagenesis Scientific reports High 29991771
2016 PINK1 autophosphorylation in Drosophila at Ser346 (identified by LC-MS/MS) is required for Parkin mitochondrial recruitment and for PINK1 kinase activity toward Parkin. Phosphorylation of Parkin by PINK1 is dispensable for Parkin translocation but required for Parkin activation. Autophosphorylation-deficient PINK1 fails to rescue pink1 null phenotypes. LC-MS/MS mapping of Drosophila PINK1 autophosphorylation; site-directed mutagenesis; Drosophila photoreceptor neuron degeneration model; mitochondrial Parkin recruitment assays Cell death & disease Medium 27906179
2019 PHB2 (inner mitochondrial membrane scaffold protein) stabilizes PINK1 on mitochondria; PHB2 depletion destabilizes PINK1, blocking Parkin/ubiquitin/OPTN recruitment and inhibiting mitophagy. PHB2 interacts with and inhibits the PARL protease; upon PHB2 depletion, PARL is activated and processes PGAM5, reducing PINK1 stability. Thus PHB2-PARL-PGAM5 constitutes a novel upstream regulatory axis for PINK1 stabilization. Co-immunoprecipitation of PHB2 with PARL; siRNA knockdown of PHB2, PARL, PGAM5; immunofluorescence of PINK1, Parkin, ubiquitin, OPTN mitochondrial recruitment; overexpression rescue experiments Autophagy Medium 31177901
2021 AMBRA1 is recruited to the outer mitochondrial membrane upon mitochondrial depolarization and interacts with PINK1 and ATAD3A (a transmembrane protein mediating PINK1 import and degradation). AMBRA1 downregulation reduces PINK1 levels via enhanced LONP1 protease-dependent degradation, decreasing PINK1-mediated ubiquitin phosphorylation and Parkin recruitment. ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells. Co-immunoprecipitation of AMBRA1 with PINK1 and ATAD3A; siRNA knockdown of AMBRA1, ATAD3A, LONP1; immunoblotting of pS65-Ub and Parkin recruitment; mitophagy flux assays Autophagy Medium 34798798
2023 TIM23 (inner mitochondrial membrane translocase subunit) is identified by mass spectrometry as a component of the PINK1 complex. TIM23 downregulation decreases PINK1 levels and delays PINK1 autophosphorylation upon depolarization. TIM23 protects PINK1 from degradation by the mitochondrial protease OMA1; OMA1 inactivation rescues PINK1 accumulation defects caused by TIM23 downregulation and partially restores pathogenic PINK1 mutants that fail to interact with TIM23. Mass spectrometry of PINK1 co-immunoprecipitates; siRNA knockdown of TIM23 and OMA1; PINK1 autophosphorylation kinetics; co-immunoprecipitation of TIM23-PINK1 Cell reports Medium 37160114
2016 BNIP3 interacts with PINK1 at the outer mitochondrial membrane, suppresses PINK1 proteolytic cleavage, promotes accumulation of full-length PINK1, and thereby facilitates Parkin recruitment and PINK1/Parkin-mediated mitophagy. Inactivation of BNIP3 promotes PINK1 proteolytic processing and suppresses mitophagy. Hypoxia-induced BNIP3 expression increases full-length PINK1 levels. Co-immunoprecipitation of BNIP3 and PINK1; BNIP3 siRNA knockdown and overexpression; Parkin recruitment assays; Drosophila rescue experiments The Journal of biological chemistry Medium 27528605
2016 PINK1 and Parkin influence the cell cycle by sequestering TBK1 at damaged mitochondria during mitophagy, thereby preventing TBK1 from performing its physiological role at centrosomes during mitosis. Loss of PINK1 and Parkin accelerates cell growth. Genetic interaction screen; TBK1 localization imaging at centrosomes vs. mitochondria; PINK1/Parkin loss-of-function cell proliferation assays; epistasis analysis Cell reports Medium 31577952
2018 Loss of PINK1 and Parkin leads to mtDNA-driven STING-dependent type I interferon inflammation in mice. PINK1/Parkin-mediated mitophagy restrains innate immunity by preventing release of mitochondrial DAMPs; concurrent loss of STING completely rescues inflammation, dopaminergic neuron loss, and motor defects in aged Prkn-/-;mutator mice. Pink1-/- and Prkn-/- mouse models with exhaustive exercise and mtDNA mutator backgrounds; genetic rescue by STING knockout; cytokine measurement; dopaminergic neuron quantification Nature High 30135585
2009 PINK1 knockdown in SH-SY5Y cells induces mitochondrial fragmentation and mitophagy driven by mitochondrial ROS. Dominant-negative Drp1 inhibits both fission and mitophagy in PINK1-deficient cells, placing Drp1-dependent fission upstream of mitophagy in the PINK1 pathway. Overexpression of wild-type PINK1 suppresses toxin-induced mitophagy and increases mitochondrial interconnectivity. Stable shRNA PINK1 knockdown; mitochondrial morphology imaging; Drp1 dominant-negative epistasis; ROS measurement; autophagy marker quantification The Journal of biological chemistry Medium 19279012
2022 Neuronal Pink1 mRNA is cotransported with mitochondria and locally translated in neurites. The outer mitochondrial membrane protein SYNJ2BP and its binding partner SYNJ2 (via an RNA-binding domain) are required to tether Pink1 mRNA to mitochondria, enabling local PINK1 production for mitophagy activation far from the soma. RNA-FISH and live imaging of Pink1 mRNA in neurons; SYNJ2BP/SYNJ2 knockdown; RNA immunoprecipitation; local translation assays; mitophagy readouts in distal neuronal compartments Neuron High 35216662
2024 Insulin signaling activates AKT/mTOR and inhibits AMPK, which in turn prevents SYNJ2BP phosphorylation within its PDZ domain; this phosphorylation is necessary for SYNJ2BP interaction with the RNA-binding protein SYNJ2 and Pink1 mRNA tethering to mitochondria. Loss of mitochondrial Pink1 mRNA association upon insulin addition is required for proper PINK1 protein activation as a ubiquitin kinase in the mitophagy pathway, placing PINK1 function under metabolic/insulin control. ApoE4-induced insulin resistance retains Pink1 mRNA at mitochondria and impairs PINK1 activity particularly in neurites. AMPK inhibition/activation experiments; phospho-site mutagenesis of SYNJ2BP PDZ domain; RNA immunoprecipitation; PINK1 ubiquitin kinase activity assays; Pink1 mRNA localization imaging in neurons Nature metabolism High 38504131
2006 PINK1 protein localizes to mitochondrial membranes in normal human brain (all cell types, punctate cytoplasmic pattern). Subcellular fractionation of human and rat brain confirms mitochondrial membrane localization. PINK1 is detected in a proportion of Lewy bodies in sporadic Parkinson's disease. Immunohistochemistry and western blotting with anti-PINK1 antibodies; subcellular fractionation of human and rat brain tissue Brain : a journal of neurology Medium 16702191
2011 PINK1 localizes exclusively to mitochondria in cardiomyocytes. Pink1-/- mice develop left ventricular dysfunction and pathological cardiac hypertrophy by 2 months of age with increased mitochondrial ROS, impaired mitochondrial function, fibrosis, and cardiomyocyte apoptosis, demonstrating PINK1 is required for maintaining mitochondrial function and redox homeostasis in the heart. PINK1 immunofluorescence/fractionation in cardiomyocytes; Pink1-/- mouse cardiac phenotyping; mitochondrial function assays; ROS measurement Proceedings of the National Academy of Sciences of the United States of America Medium 21606348
2013 Synphilin-1 interacts with PINK1 and is recruited to mitochondria in a PINK1-dependent manner. Once at mitochondria, synphilin-1 promotes PINK1-dependent mitophagy independently of Parkin by recruiting SIAH-1 E3 ubiquitin ligase to mitochondria, where SIAH-1 promotes mitochondrial protein ubiquitination and mitophagy. PINK1 disease mutants fail to recruit synphilin-1. Co-immunoprecipitation of synphilin-1 and PINK1; siRNA knockdown of synphilin-1 and SIAH-1; LC3/Lamp1 mitochondrial co-localization imaging; Atg5 knockdown epistasis Human molecular genetics Medium 27334109
2003 PINK1/BRPK encodes a serine/threonine-type protein kinase capable of autophosphorylation, as demonstrated with recombinant protein. Recombinant protein expression; in vitro autophosphorylation assay Cancer letters Medium 14607334
2010 PINK1 activates AKT phosphorylation at Ser473 through activation of mTORC2, not PI3K. Rictor (mTORC2 component) is phosphorylated upon PINK1 overexpression. This cytoplasmic PINK1 activity promotes cell survival and motility independently of its mitochondrial functions. Overexpression of PINK1 in SH-SY5Y cells; immunoblotting for pAkt-Ser473; rapamycin and PI3K inhibitor controls; Rictor phosphorylation; cell motility assays The Journal of biological chemistry Low 21177249
2009 FOXO3a transcription factor directly controls Pink1 transcription in mouse and human cells subjected to growth factor deprivation through evolutionarily conserved FOXO binding elements in the Pink1 promoter. PINK1 induction by FOXO3a is required for lymphocyte survival upon growth factor deprivation. FOXO3a overexpression and knockdown; Pink1 promoter-reporter assays; chromatin immunoprecipitation; PINK1 siRNA cell survival assays Proceedings of the National Academy of Sciences of the United States of America Medium 19276113
2015 DJ-1 transcriptionally upregulates Pink1 by binding with Foxo3a and directly interacting with the pink1 promoter. DJ-1-null cells show decreased pink1 mRNA and Pink1 protein; the glycolytic and proliferative changes in DJ1-deficient cells are abrogated by Pink1 expression. RT-PCR and western blot of Pink1 in DJ1-null MEFs; chromatin immunoprecipitation of DJ1/Foxo3a at pink1 promoter; Pink1 rescue overexpression; metabolic assays The Biochemical journal Medium 25670069
2020 PINK1 phosphorylates TUFm (mitochondrial Tu translation elongation factor) at Ser222, creating a phosphoswitch: unphosphorylated TUFm promotes mitophagy via a Parkin-independent route, while p-S222-TUFm is exported to the cytosol where it inhibits mitophagy by impeding Atg5-Atg12 formation. This self-antagonizing PINK1/TUFm mechanism provides robustness to mitophagy regulation. Co-immunoprecipitation of TUFm and PINK1; PINK1 kinase assay with TUFm; phospho-site mutagenesis (S222A/D); subcellular fractionation of p-S222-TUFm; Atg5-Atg12 formation assay; Drosophila genetic validation Molecular cell Medium 33113344
2023 PINK1 regulates selective ER clearance (ER-phagy) in addition to mitophagy during Drosophila development. PINK1 acts upstream to regulate both Parkin-dependent mitochondrial clearance and Keap1/Cullin3-dependent ER clearance. PINK1 regulates a change in Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate ER removal. Parkin has the opposite function in ER clearance compared to mitochondrial clearance. Drosophila genetic epistasis (PINK1, parkin, keap1, cullin3, rtnl1 mutants); Keap1 localization imaging; Rtnl1 ubiquitylation assays; autophagy flux assays during development Cell Medium 37633267
2022 Structural basis for feedforward Parkin activation: phospho-ubiquitin binds to two distinct sites on Parkin—a high-affinity site on RING1 controlling Parkin localization and a low-affinity site on RING0 that releases autoinhibition. The RING0 site has higher affinity for phospho-ubiquitin than for phosphorylated Ubl in trans. Parkin activation by micromolar tetra-phospho-ubiquitin chains, and a Parkin chimera with Ubl replaced by ubiquitin, is activated by PINK1 phosphorylation; mutation of the RING0 binding site abolishes activation. ITC; NMR titrations; ubiquitin vinyl sulfone activity assays; parkin chimera construction and PINK1 phosphorylation assays; mutagenesis of RING0 site The EMBO journal High 35491809
2023 OPTN initiates PINK1/Parkin mitophagy through an unconventional pathway that does not require FIP200 binding or ULK1/2 kinases. Instead, OPTN uses the kinase TBK1, which binds directly to PI3KC3-C1 (class III phosphatidylinositol 3-kinase complex I) to initiate mitophagy. This is mechanistically distinct from NDP52-mediated initiation (which uses FIP200). Gene-edited cell lines lacking autophagy receptors and upstream initiation factors; in vitro reconstitution of TBK1-PI3KC3-C1 interaction; epistasis analysis of FIP200/ULK1/2 dependence Molecular cell High 37207627
2019 PINK1 associates with TRAF3 via its kinase domain and inhibits Parkin-mediated K48-linked TRAF3 proteasomal degradation, thereby positively regulating RLR-triggered innate immune responses. PINK1 also interacts with YAP1 upon viral infection and impairs YAP1/IRF3 complex formation. PINK1 knockdown reduces cytokine production and IRF3/NF-κB activation upon viral infection. Co-immunoprecipitation of PINK1 with TRAF3 and YAP1; PINK1 knockdown in macrophages; cytokine ELISA; IRF3/NF-κB activation assays; ubiquitylation assays of TRAF3 Frontiers in immunology Low 31139191
2019 PINK1 phosphorylates ubiquitin predominantly in astrocytes rather than neurons under basal and mitochondrial stress conditions, as determined by pS65-ubiquitin western blotting and immunofluorescence in primary cultures of neurons, astrocytes, microglia, and oligodendrocyte progenitor cells from wild-type and PINK1 knockout rats. pS65-ubiquitin western blotting and immunofluorescence in primary rat brain cell cultures; PINK1 KO comparison; CCCP/valinomycin mitochondrial stress treatment NPJ Parkinson's disease Medium 31840043
2023 PINK1 recruits PD-L1 to mitochondria for degradation via the mitophagy pathway. ATAD3A disrupts PINK1-dependent mitophagy-mediated PD-L1 degradation; paclitaxel increases ATAD3A expression to restrain PINK1-dependent mitophagy, causing PD-L1 to accumulate on the tumor cell membrane rather than being degraded at mitochondria. Co-immunoprecipitation; subcellular fractionation of PD-L1; PINK1 knockdown mitophagy assays; ATAD3A overexpression/knockdown; immunotherapy patient cohort correlative imaging Cell research Low 36627348
2011 PINK1 loss-of-function in substantia nigra dopaminergic neurons (PINK1 knockout mice) causes depolarized mitochondrial membrane potential, mitochondrial fragmentation, and increased basal and H2O2-induced ROS. Wild-type PINK1 overexpression restores mitochondrial membrane potential and morphology; PARK6 disease mutants (G309D, E417G, CΔ145) fail to rescue these defects. Confocal imaging of mitochondrial membrane potential (ΔΨm) and morphology; ROS measurement in PINK1 KO dopaminergic neurons; PINK1 mutant overexpression rescue Biochimica et biophysica acta Medium 21421046
2013 TRAP1 (TNF receptor-associated protein 1) acts downstream of PINK1 to maintain mitochondrial integrity. TRAP1 overexpression rescues Pink1 loss-of-function phenotypes in Drosophila and mitochondrial fragmentation/dysfunction after siRNA-mediated Pink1 silencing in human SH-SY5Y cells, but does not rescue Parkin deficiency phenotypes, placing TRAP1 specifically downstream of PINK1 (and parallel to/upstream of Parkin). Drosophila genetic epistasis (TRAP1 overexpression in pink1 and park2 mutants); siRNA knockdown of Pink1 in SH-SY5Y with TRAP1 rescue; mitochondrial morphology and function assays Human molecular genetics Medium 23525905
2018 PINK1/Parkin-mediated mitophagy suppresses mtDNA-driven STING inflammatory signaling; in Pink1-/- mice subject to intestinal Gram-negative bacterial infection, mitochondrial antigen presentation and autoimmune mechanisms are engaged, generating cytotoxic mitochondria-specific CD8+ T cells that cause dopaminergic axonal loss and motor impairment reversible by L-DOPA treatment. Pink1-/- mouse intestinal infection model; CD8+ T cell characterization; dopaminergic axonal density measurement; L-DOPA pharmacological rescue; flow cytometry Nature Medium 31316206
2015 pS65-ubiquitin (PINK1-phosphorylated ubiquitin) is barely detectable under basal conditions but is rapidly induced upon mitochondrial stress in cells; it is amplified by functional Parkin and is dependent on PINK1 kinase activity as confirmed in patient fibroblasts and postmortem brain samples with pathogenic mutations. pS65-Ub is reversible and accumulates as cytoplasmic granules in aged and diseased human brain. Novel anti-pS65-Ub antibodies; western blotting and immunofluorescence in cells, primary neurons, patient fibroblasts, and human postmortem brain; genetic confirmation with PINK1 patient mutations EMBO reports Medium 26162776
2018 The PINK1 p.I368N pathogenic mutation reduces binding to the co-chaperone complex HSP90/CDC37 and abolishes stress-induced interaction with TOM40, preventing PINK1 stabilization on the outer mitochondrial membrane. Structural modeling and functional assays confirm that p.I368N deforms the ATP-binding pocket and abolishes ubiquitin kinase activity. Patient fibroblast biochemical assays; Co-immunoprecipitation of PINK1 with HSP90/CDC37 and TOM40; structural modeling; ubiquitin kinase activity assays; pS65-Ub western blotting Molecular neurodegeneration Medium 28438176
2014 smARF (short mitochondrial ARF) depolarizes mitochondria and promotes PINK1/Parkin-dependent mitophagy in both cell lines and neurons, positioning smARF as an intrinsic signaling molecule upstream of PINK1 and Parkin in the mitophagy pathway. smARF overexpression in cell lines and neurons; Parkin/PINK1 knockdown epistasis; mitochondrial membrane potential measurement; mitophagy flux assays The Journal of biological chemistry Low 25217637
2023 Loss of PINK1 and Parkin leads to dysregulation of IP3R activity, robustly increasing ER calcium release. CISD1 (mitoNEET) functions downstream of Parkin to directly control IP3R. Genetic and pharmacological suppression of CISD1 restores increased ER calcium release in PINK1/Parkin null mammalian cells and flies, and rescues PD-related phenotypes (locomotor defects, dopaminergic neurodegeneration) in Drosophila. PINK1/Parkin null mammalian cells and Drosophila; CISD1 genetic and pharmacological suppression; ER calcium release measurements; Drosophila locomotor and dopaminergic neuron assays Nature communications Medium 37626046

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 2405 20126261
2015 The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 2290 26266977
2013 PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science (New York, N.Y.) 1080 23620051
2018 Parkin and PINK1 mitigate STING-induced inflammation. Nature 1074 30135585
2014 PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity. The Journal of cell biology 1052 24751536
2009 Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. The Journal of biological chemistry 811 19279012
2016 Deciphering the Molecular Signals of PINK1/Parkin Mitophagy. Trends in cell biology 593 27291334
2014 PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. The Journal of clinical investigation 521 25562319
2015 PINK1/Parkin-mediated mitophagy in mammalian cells. Current opinion in cell biology 494 25697963
2020 PINK1/PARKIN signalling in neurodegeneration and neuroinflammation. Acta neuropathologica communications 387 33168089
2019 Intestinal infection triggers Parkinson's disease-like symptoms in Pink1-/- mice. Nature 382 31316206
2019 PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 342 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 333 21606348
2018 Mechanism of parkin activation by PINK1. Nature 318 29995846
2014 Parkin and PINK1: much more than mitophagy. Trends in neurosciences 316 24735649
2024 The role of PINK1-Parkin in mitochondrial quality control. Nature cell biology 305 39358449
2011 Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxidants & redox signaling 298 21194381
2022 PINK1/Parkin-mediated mitophagy in neurodegenerative diseases. Ageing research reviews 291 36503124
2017 PINK1 and Parkin: emerging themes in mitochondrial homeostasis. Current opinion in cell biology 275 28437683
2006 PINK1 protein in normal human brain and Parkinson's disease. Brain : a journal of neurology 268 16702191
2016 Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond. Free radical biology & medicine 265 27094585
2018 PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol. BMC biology 254 29325568
2016 BNIP3 Protein Suppresses PINK1 Kinase Proteolytic Cleavage to Promote Mitophagy. The Journal of biological chemistry 237 27528605
2018 PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism. Developmental cell 224 30100261
2018 Deficiency of parkin and PINK1 impairs age-dependent mitophagy in Drosophila. eLife 176 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 159 17141510
2021 Activation mechanism of PINK1. Nature 157 34933320
2011 Regulation of PINK1-Parkin-mediated mitophagy. Autophagy 154 21187721
2015 (Patho-)physiological relevance of PINK1-dependent ubiquitin phosphorylation. EMBO reports 153 26162776
2016 The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway. Human molecular genetics 146 27334109
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 139 19276113
2016 Parkin and PINK1 functions in oxidative stress and neurodegeneration. Brain research bulletin 125 28017782
2022 Neuronal mitochondria transport Pink1 mRNA via synaptojanin 2 to support local mitophagy. Neuron 118 35216662
2009 The PINK1/Parkin pathway: a mitochondrial quality control system? Journal of bioenergetics and biomembranes 116 19967438
2020 The PINK1-Parkin axis: An Overview. Neuroscience research 115 31982458
2009 PINK1 function in health and disease. EMBO molecular medicine 115 20049715
2010 A new cytosolic pathway from a Parkinson disease-associated kinase, BRPK/PINK1: activation of AKT via mTORC2. The Journal of biological chemistry 110 21177249
2016 Mitochondrial quality control by the Pink1/Parkin system. Cell and tissue research 108 27586587
2023 Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria. Cell research 102 36627348
2018 PINK1 autophosphorylation is required for ubiquitin recognition. EMBO reports 100 29475881
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
2023 Unconventional initiation of PINK1/Parkin mitophagy by Optineurin. Molecular cell 96 37207627
2018 PINK1-PARK2-mediated mitophagy in COPD and IPF pathogeneses. Inflammation and regeneration 94 30386443
2019 Mechanisms of PINK1, ubiquitin and Parkin interactions in mitochondrial quality control and beyond. Cellular and molecular life sciences : CMLS 92 31254044
2020 PINK1: The guard of mitochondria. Life sciences 90 32805222
2016 A novel PINK1- and PARK2-dependent protective neuroimmune pathway in lethal sepsis. Autophagy 87 27754761
2013 Function and characteristics of PINK1 in mitochondria. Oxidative medicine and cellular longevity 81 23533695
2017 PINK1/Parkin-Dependent Mitochondrial Surveillance: From Pleiotropy to Parkinson's Disease. Frontiers in molecular neuroscience 80 28507507
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
2021 PTEN-induced kinase 1 (PINK1) and Parkin: Unlocking a mitochondrial quality control pathway linked to Parkinson's disease. Current opinion in neurobiology 75 34717133
2019 PINK1/Parkin Influences Cell Cycle by Sequestering TBK1 at Damaged Mitochondria, Inhibiting Mitosis. Cell reports 75 31577952
2021 PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis. Stem cell research & therapy 71 34823575
2011 Genetic mutations and functions of PINK1. Trends in pharmacological sciences 70 21784538
2021 AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability. Autophagy 69 34798798
2016 PINK1-dependent phosphorylation of PINK1 and Parkin is essential for mitochondrial quality control. Cell death & disease 68 27906179
2017 The PINK1 p.I368N mutation affects protein stability and ubiquitin kinase activity. Molecular neurodegeneration 66 28438176
2016 PINK1 in the limelight: multiple functions of an eclectic protein in human health and disease. The Journal of pathology 66 27701735
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 63 38416681
2014 PINK1 signalling in cancer biology. Biochimica et biophysica acta 57 25450579
2020 Paradoxical Mitophagy Regulation by PINK1 and TUFm. Molecular cell 55 33113344
2003 BRPK, a novel protein kinase showing increased expression in mouse cancer cell lines with higher metastatic potential. Cancer letters 54 14607334
2021 PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis. Protein & cell 51 34800266
2012 Involvement and interplay of Parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders. Free radical biology & medicine 49 22687462
2023 Structural Mechanisms of Mitochondrial Quality Control Mediated by PINK1 and Parkin. Journal of molecular biology 48 37054910
2023 PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development. Cell 48 37633267
2017 Hexokinases link DJ-1 to the PINK1/parkin pathway. Molecular neurodegeneration 47 28962651
2025 Structure of human PINK1 at a mitochondrial TOM-VDAC array. Science (New York, N.Y.) 44 40080546
2023 PINK1 and Parkin regulate IP3R-mediated ER calcium release. Nature communications 44 37626046
2022 PINK1-parkin-mediated neuronal mitophagy deficiency in prion disease. Cell death & disease 43 35184140
2020 PINK1 and Parkin: team players in stress-induced mitophagy. Biological chemistry 43 32297878
2021 PINK1: A Bridge between Mitochondria and Parkinson's Disease. Life (Basel, Switzerland) 42 33919398
2019 PINK1 phosphorylates ubiquitin predominantly in astrocytes. NPJ Parkinson's disease 41 31840043
2017 Mitochondrial quality control pathways: PINK1 acts as a gatekeeper. Biochemical and biophysical research communications 41 28647367
2015 DJ1 represses glycolysis and cell proliferation by transcriptionally up-regulating Pink1. The Biochemical journal 41 25670069
2009 Tickled PINK1: mitochondrial homeostasis and autophagy in recessive Parkinsonism. Biochimica et biophysica acta 41 19595762
2023 TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria. Cell reports 40 37160114
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
2018 Structural insights into ubiquitin phosphorylation by PINK1. Scientific reports 36 29991771
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
2025 Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1. Nature 34 39972141
2010 Enhanced vulnerability of PARK6 patient skin fibroblasts to apoptosis induced by proteasomal stress. Neuroscience 34 20045449
2024 Insulin signalling regulates Pink1 mRNA localization via modulation of AMPK activity to support PINK1 function in neurons. Nature metabolism 33 38504131
2022 The emerging multifaceted role of PINK1 in cancer biology. Cancer science 33 36071695
2020 N-degron-mediated degradation and regulation of mitochondrial PINK1 kinase. Current genetics 33 32157382
2012 Analysis of the regulatory and catalytic domains of PTEN-induced kinase-1 (PINK1). Human mutation 33 22644621
2021 PINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome. Cell reports 32 34077728
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
2022 Structural basis for feedforward control in the PINK1/Parkin pathway. The EMBO journal 31 35491809
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 Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy. International journal of molecular sciences 28 39000117
2023 PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems. EMBO reports 27 37334901

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