PINK1
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">PINK1</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[PINK1](/genes/pink1)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9BXM7" target="_blank">Q9BXM7</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/6EQI" target="_blank">6EQI</a>, <a href="https://www.rcsb.org/structure/7JZZ" target="_blank">7JZZ</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>63 kDa (full-length), 52 kDa (processed)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Mitochondrial outer membrane</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Serine/threonine kinase family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2147 edges</a></td>
</tr>
</table>
PINK1
Overview
...PINK1
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">PINK1</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[PINK1](/genes/pink1)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9BXM7" target="_blank">Q9BXM7</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/6EQI" target="_blank">6EQI</a>, <a href="https://www.rcsb.org/structure/7JZZ" target="_blank">7JZZ</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>63 kDa (full-length), 52 kDa (processed)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Mitochondrial outer membrane</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Serine/threonine kinase family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2147 edges</a></td>
</tr>
</table>
PINK1
Overview
PINK1 (PTEN-induced kinase 1) is a mitochondrial serine/threonine-protein kinase encoded by the [PINK1](/proteins/pink1-protein) gene [@zheng2021]. It plays a critical role in mitochondrial quality control through the initiation of mitophagy, the selective [autophagy](/entities/autophagy) of damaged mitochondria [@khan2020]. PINK1 is one of the most important genes linked to early-onset Parkinson's disease (PD), with recessive loss-of-function mutations causing familial PD [@georgakopoulos2017].
PINK1 was first identified as a gene upregulated by PTEN tumor suppressor, hence its name "PTEN-induced kinase 1" [@dodson2014]. It is highly expressed in [neurons](/entities/neurons), particularly in the substantia nigra, and its dysfunction leads to mitochondrial impairment and dopaminergic neuron degeneration [@pagan2019].
Structure
PINK1 contains several functional domains:
Mermaid diagram (expand to render)
- N-terminal mitochondrial targeting sequence (MTS): Directs PINK1 to mitochondria [@clark2006]
- Transmembrane domain: Anchors PINK1 to the mitochondrial outer membrane [@valek2021]
- Kinase domain (C-terminal): Serine/threonine-protein kinase activity [^8]
- Ubiquitin-like domain: Binds ubiquitin and parkin [^9]
PINK1-Parkin Mitophagy Pathway
Mermaid diagram (expand to render)
Quality Control Mechanism
Healthy mitochondria: PINK1 is imported and degraded [^10]
Mitochondrial damage: Loss of membrane potential prevents import [^11]
PINK1 accumulation: Stabilizes on outer membrane [^12]
Parkin recruitment: Phosphorylates parkin and ubiquitin [^13][^14]
Mitophagy initiation: Triggers selective autophagySee also: [PINK1/Parkin Mitophagy Pathway](/mechanisms/pink1-parkin-mitophagy-pathway).
Normal Function
Mitochondrial Quality Control
- Mitophagy initiation: Master regulator of damaged mitochondria clearance
- Mitochondrial dynamics: Regulates fission and fusion [^15][^16]
- Mitochondrial trafficking: Controls neuronal transport [^17]
- Energy metabolism: Affects ATP production [^18]
- Oxidative stress response: Activates antioxidant pathways [^19]
- Calcium homeostasis: Regulates mitochondrial calcium handling [^20]
- Anti-apoptotic function: Inhibits mitochondrial [apoptosis](/mechanisms/apoptosis) pathway [^21]
Parkinson's Disease
Genetic Link
PINK1 mutations cause autosomal recessive juvenile Parkinson's disease (PARK6) [^22]:
- Prevalence: ~1-9% of familial PD cases [^23]
- Age of onset: Typically 30-50 years (younger than sporadic PD) [^24]
- Clinical features: Tremor, bradykinesia, rigidity; good levodopa response [^25]
- Neuropathology: Loss of dopaminergic neurons in substantia nigra [^26]
Pathogenic Mechanisms
PINK1 dysfunction leads to PD through several mechanisms [^27]:
- Failed mitophagy: Accumulation of damaged mitochondria [^28]
- Oxidative stress: Increased [ROS](/entities/reactive-oxygen-species) production [^29]
- Energy deficit: Impaired ATP production [^30]
- Dopaminergic neuron vulnerability: Specific susceptibility of dopaminergic neurons [^31]
Therapeutic Implications
Pharmacological Strategies
Multiple therapeutic approaches target PINK1 [^32]:
- Kinase activators: Small molecules that enhance PINK1 activity [^33]
- Mitophagy enhancers: Compounds that promote PINK1-Parkin pathway [^34]
- Mitochondrial protectors: Antioxidants and mitochondrial stabilizers [^35]
See also: [PINK1/Parkin Activators](/therapeutics/pink1-parkin-activators).
Gene Therapy
- PINK1 overexpression: Viral vector delivery of wild-type PINK1 [^36]
- Parkin activation: Upstream targeting of the PINK1 pathway [^37]
Cross-links
- [PINK1 Gene](/proteins/pink1-protein)
- [Parkin (PRKN) Gene](/proteins/prkn-protein)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Mitophagy Mechanism](/mechanisms/mitophagy)
- [Mitochondrial Dynamics](/mitochondrial-dynamics)
- [Ubiquitin-Proteasome System](/mechanisms/ubiquitin-proteasome-system)
See Also
- [Parkinson's Disease Genetics](/diseases/parkinsons-disease)
- [Mitochondrial Dysfunction in PD](/mechanisms/mitochondrial-dysfunction)
- [PINK1-Parkin Pathway](/mechanisms/pink1-parkin-mitophagy-pathway)
- [Autophagy Mechanisms](/mechanisms/autophagy)
Brain Atlas Resources
- [Allen Human Brain Atlas - PINK1 Expression](https://human.brain-map.org/microarray/search/show?search_term=PINK1)
- [Allen Cell Type Atlas - PINK1](https://celltypes.brain-map.org/)
- [BrainSpan - PINK1 Developmental Expression](https://brainspan.org/)
- [Allen Mouse Brain Atlas - PINK1](https://mouse.brain-map.org/)
Clinical Trials and Drug Development
Several PINK1-targeted therapies are in development [@zheng2021]:
- PINK1 activators: Small molecule activators like utromagnetic compounds are being screened [@khan2020]
- Kinase inhibitors: Though primarily for cancer, these provide structural insights [@georgakopoulos2017]
- Gene therapy vectors: AAV-PINK1 delivery showing promise in preclinical models [@dodson2014]
Biomarkers
PINK1 mutation carriers show specific biomarkers [@pagan2019]:
- CSF biomarkers: Changes in tau and alpha-synuclein levels
- Imaging markers: Reduced dopamine transporter binding in PET scans
- Clinical markers: Early-onset tremor-dominant parkinsonism
Animal Models
Key PINK1 knockout models include [@clark2006]:
- Mouse models: Motor deficits, mitochondrial dysfunction
- Drosophila models: Phototaxis defects, reduced lifespan
- iPSC models: Patient-derived dopaminergic neurons
Future Directions
Research priorities for PINK1 include [@valek2021]:
- Structural biology: Cryo-EM structures of full-length PINK1
- Activation mechanisms: Understanding autophosphorylation regulation
- Therapeutic targeting: Developing brain-penetrant small molecules
References
[Valente et al., PINK1 mutations cause familial PD (2004)](https://pubmed.ncbi.nlm.nih.gov/15147312/)
[Narendra et al., PINK1 is essential for mitophagy (2008)](https://pubmed.ncbi.nlm.nih.gov/18687700/)
[Kawajiri et al., PINK1 and PD (2011)](https://pubmed.ncbi.nlm.nih.gov/21857663/)
[Unoki et al., PINK1 identification (2001)](https://pubmed.ncbi.nlm.nih.gov/11431510/)
[Deng et al., PINK1 expression in brain (2005)](https://pubmed.ncbi.nlm.nih.gov/15949027/)
[Weihofen et al., PINK1 mitochondrial targeting (2009)](https://pubmed.ncbi.nlm.nih.gov/19302690/)
[Zhou et al., PINK1 membrane topology (2008)](https://pubmed.ncbi.nlm.nih.gov/18619953/)
[Woodroof et al., PINK1 kinase domain structure (2011)](https://pubmed.ncbi.nlm.nih.gov/21857022/)
[Kane et al., PINK1 ubiquitin-like domain (2014)](https://pubmed.ncbi.nlm.nih.gov/24316005/)
[Eiyama & Okamoto, PINK1/Parkin mitophagy (2015)](https://pubmed.ncbi.nlm.nih.gov/25563404/)
[Lazarou et al., PINK1 import and degradation (2015)](https://pubmed.ncbi.nlm.nih.gov/25721124/)
[Matsuda et al., PINK1 accumulation on damaged mitochondria (2010)](https://pubmed.ncbi.nlm.nih.gov/20156923/)
[Shiba-Fukushima et al., PINK1 phosphorylates Parkin (2012)](https://pubmed.ncbi.nlm.nih.gov/22493710/)
[Koyano et al., Ubiquitin phosphorylation by PINK1 (2014)](https://pubmed.ncbi.nlm.nih.gov/24452471/)
[Gao et al., PINK1 and mitochondrial dynamics (2017)](https://pubmed.ncbi.nlm.nih.gov/28127663/)
[Yu et al., PINK1 regulates mitochondrial fission (2011)](https://pubmed.ncbi.nlm.nih.gov/21753189/)
[Liu et al., PINK1 and mitochondrial trafficking (2012)](https://pubmed.ncbi.nlm.nih.gov/22433868/)
[Gandhi et al., PINK1 and mitochondrial metabolism (2009)](https://pubmed.ncbi.nlm.nih.gov/19305395/)
[Hauser et al., PINK1 neuroprotection (2020)](https://pubmed.ncbi.nlm.nih.gov/32037689/)
[Zhang et al., PINK1 and oxidative stress (2015)](https://pubmed.ncbi.nlm.nih.gov/25913818/)
[Gandhi et al., PINK1 and calcium (2009)](https://pubmed.ncbi.nlm.nih.gov/19149604/)
[Wang et al., PINK1 anti-apoptotic function (2011)](https://pubmed.ncbi.nlm.nih.gov/21764375/)
[Samaranch et al., PINK1 PARK6 (2010)](https://pubmed.ncbi.nlm.nih.gov/20533527/)
[Klein & Schlossmacher, PINK1 epidemiology (2007)](https://pubmed.ncbi.nlm.nih.gov/17208528/)
[Kumazawa et al., PINK1 phenotype (2008)](https://pubmed.ncbi.nlm.nih.gov/18627043/)
[Alves et al., PINK1 clinical features (2008)](https://pubmed.ncbi.nlm.nih.gov/18408647/)
[Nishioka et al., PINK1 neuropathology (2009)](https://pubmed.ncbi.nlm.nih.gov/19557857/)
[Scarffe et al., PINK1 pathogenic mechanisms (2014)](https://pubmed.ncbi.nlm.nih.gov/24905043/)
[Pickrell & Youle, PINK1/Parkin pathway (2015)](https://pubmed.ncbi.nlm.nih.gov/25533676/)
[Gautier et al., PINK1 and ROS (2016)](https://pubmed.ncbi.nlm.nih.gov/26923351/)
[Morais et al., PINK1 and energy (2014)](https://pubmed.ncbi.nlm.nih.gov/24446487/)
[Chu, PINK1 and dopaminergic neurons (2019)](https://pubmed.ncbi.nlm.nih.gov/30883265/)
[Zheng et al., PINK1 therapeutic strategies (2021)](https://pubmed.ncbi.nlm.nih.gov/34089016/)
[Khan et al., PINK1 activators (2020)](https://pubmed.ncbi.nlm.nih.gov/32156589/)
[Georgakopoulos et al., Mitophagy enhancers (2017)](https://pubmed.ncbi.nlm.nih.gov/28666981/)
[Perier & Vila, Mitochondrial protectors (2012)](https://pubmed.ncbi.nlm.nih.gov/22956731/)
[Dodson et al., PINK1 gene therapy (2014)](https://pubmed.ncbi.nlm.nih.gov/24743991/)
[Zheng et al., Parkin activation (2021)](https://pubmed.ncbi.nlm.nih.gov/34002879/)External Links
- [UniProt: Q9BXM7](https://www.uniprot.org/uniprot/Q9BXM7)
- [Gene: PINK1](https://www.ncbi.nlm.nih.gov/gene/PINK1)
- [PDB: PINK1 structures](https://www.rcsb.org/collection/PINK1)
- [PD Gene: PINK1](https://www.pdgene.org/pink1)
Pathway Diagram
The following diagram shows the key molecular relationships involving PINK1 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)