PINK1

This gene encodes a serine/threonine protein kinase that localizes to mitochondria. It is thought to protect cells from stress-induced mitochondrial dysfunction. Mutations in this gene cause one form of autosomal recessive early-onset Parkinson disease. [provided by RefSeq, Jul 2008]

PTEN Induced Putative Kinase 1

Serine/threonine-protein kinase which protects against mitochondrial dysfunction during cellular stress by phosphorylating mitochondrial proteins such as PRKN and DNM1L, to coordinate mitochondrial quality control mechanisms that remove and replace dysfunctional mitochondrial components (PubMed:14607334, PubMed:18957282, PubMed:18443288, PubMed:15087508, PubMed:19229105, PubMed:19966284, PubMed:20404107, PubMed:22396657, PubMed:20798600, PubMed:23620051, PubMed:23754282, PubMed:23933751, PubMed:24660806, PubMed:24898855, PubMed:24751536, PubMed:24784582, PubMed:24896179, PubMed:25527291, PubMed:32484300, PubMed:20547144).
Depending on the severity of mitochondrial damage and/or dysfunction, activity ranges from preventing apoptosis and stimulating mitochondrial biogenesis to regulating mitochondrial dynamics and eliminating severely damaged mitochondria via mitophagy (PubMed:18443288, PubMed:23620051, PubMed:24898855, PubMed:20798600, PubMed:20404107, PubMed:19966284, PubMed:32484300, PubMed:22396657, PubMed:32047033, PubMed:15087508).
Mediates the translocation and activation of PRKN at the outer membrane (OMM) of dysfunctional/depolarized mitochondria (PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:23754282, PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291).
At the OMM of damaged mitochondria, phosphorylates pre-existing polyubiquitin chains at 'Ser-65', the PINK1-phosphorylated polyubiquitin then recruits PRKN from the cytosol to the OMM where PRKN is fully activated by phosphorylation at 'Ser-65' by PINK1 (PubMed:19966284, PubMed:20404107, PubMed:20798600, PubMed:23754282, PubMed:24660806, PubMed:24751536, PubMed:24784582, PubMed:25474007, PubMed:25527291).
In damaged mitochondria, mediates the decision between mitophagy or preventing apoptosis by promoting PRKN-dependent poly- or monoubiquitination of VDAC1; polyubiquitination of VDAC1 by PRKN promotes mitophagy, while monoubiquitination of VDAC1 by PRKN decreases mitochondrial calcium influx which ultimately inhibits apoptosis (PubMed:32047033).
When cellular stress results in irreversible mitochondrial damage, functions with PRKN to promote clearance of damaged mitochondria via selective autophagy (mitophagy) (PubMed:14607334, PubMed:20798600, PubMed:20404107, PubMed:19966284, PubMed:23933751, PubMed:15087508).
The PINK1-PRKN pathway also promotes fission of damaged mitochondria by phosphorylating and thus promoting the PRKN-dependent degradation of mitochondrial proteins involved in fission such as MFN2 (PubMed:18443288, PubMed:23620051, PubMed:24898855).
This prevents the refusion of unhealthy mitochondria with the mitochondrial network or initiates mitochondrial fragmentation facilitating their later engulfment by autophagosomes (PubMed:18443288, PubMed:23620051).
Also promotes mitochondrial fission independently of PRKN and ATG7-mediated mitophagy, via the phosphorylation and activation of DNM1L (PubMed:18443288, PubMed:32484300).
Regulates motility of damaged mitochondria by promoting the ubiquitination and subsequent degradation of MIRO1 and MIRO2; in motor neurons, this likely inhibits mitochondrial intracellular anterograde transport along the axons which probably increases the chance of the mitochondria undergoing mitophagy in the soma (PubMed:22396657).
Required for ubiquinone reduction by mitochondrial complex I by mediating phosphorylation of complex I subunit NDUFA10 (By similarity).

Activation of protein kinase B activity1 PublicationIC:ParkinsonsUK-UCL
Autophagy of mitochondrionManual Assertion Based On ExperimentIMP:UniProtKB
Cellular response to hydrogen sulfideIEA:Ensembl
Cellular response to hypoxiaManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Cellular response to oxidative stressManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Cellular response to toxic substanceManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Establishment of protein localization to mitochondrionManual Assertion Based On ExperimentIMP:UniProtKB
HemopoiesisManual Assertion Based On ExperimentIGI:ARUK-UCL
Intracellular signal transductionManual Assertion Based On ExperimentIDA:UniProtKB
Maintenance of protein location in mitochondrionManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Mitochondrion organizationManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Mitochondrion to lysosome transportManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
MitophagyManual Assertion Based On ExperimentIGI:ARUK-UCL
Negative regulation of autophagosome assemblyManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Negative regulation of gene expressionBy SimilarityISS:ParkinsonsUK-UCL
Negative regulation of hydrogen peroxide-induced neuron intrinsic apoptotic signaling pathwayManual Assertion Based On ExperimentIDA:ParkinsonsUK-UCL
Negative regulation of hypoxia-induced intrinsic apoptotic signaling pathwayIEA:Ensembl
Negative regulation of intrinsic apoptotic signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of intrinsic apoptotic signaling pathway in response to hydrogen peroxideManual Assertion Based On ExperimentIDA:ParkinsonsUK-UCL
Negative regulation of JNK cascadeManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Negative regulation of macroautophagyManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Negative regulation of mitochondrial fissionManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Negative regulation of mitophagyManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Negative regulation of neuron apoptotic processManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Negative regulation of oxidative stress-induced cell deathManual Assertion Based On ExperimentIDA:ParkinsonsUK-UCL
Negative regulation of oxidative stress-induced neuron deathManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Negative regulation of reactive oxygen species metabolic processManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Peptidyl-serine autophosphorylationManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Peptidyl-serine phosphorylationManual Assertion Based On ExperimentIDA:ParkinsonsUK-UCL
Positive regulation of ATP biosynthetic processManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Positive regulation of cristae formationManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Positive regulation of DNA-binding transcription factor activityIEA:Ensembl
Positive regulation of dopamine secretionIEA:Ensembl
Positive regulation of free ubiquitin chain polymerizationISS:ParkinsonsUK-UCL
Positive regulation of histone deacetylase activityIEA:Ensembl
Positive regulation of I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of macroautophagyManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Positive regulation of mitochondrial electron transport, NADH to ubiquinoneManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Positive regulation of mitochondrial fissionManual Assertion Based On ExperimentIBA:GO_Central
Positive regulation of mitophagy in response to mitochondrial depolarizationManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Positive regulation of NMDA glutamate receptor activityIEA:Ensembl
Positive regulation of peptidase activityManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Positive regulation of peptidyl-serine phosphorylationManual Assertion Based On ExperimentIDA:ParkinsonsUK-UCL
Positive regulation of protein dephosphorylationIEA:Ensembl
Positive regulation of protein kinase B signaling1 PublicationIC:ParkinsonsUK-UCL
Positive regulation of protein phosphorylationManual Assertion Based On ExperimentIDA:AgBase
Positive regulation of protein targeting to mitochondrionManual Assertion Based On ExperimentHMP:ParkinsonsUK-UCL
Positive regulation of protein ubiquitinationISS:ParkinsonsUK-UCL
Positive regulation of release of cytochrome c from mitochondriaManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of synaptic transmission, dopaminergicIEA:Ensembl
Positive regulation of translationIEA:Ensembl
Positive regulation of ubiquitin-protein transferase activityManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Protein phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Protein stabilizationManual Assertion Based On ExperimentIMP:UniProtKB
Protein ubiquitinationManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of apoptotic processManual Assertion Based On ExperimentIBA:GO_Central
Regulation of autophagy of mitochondrionManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Regulation of cellular response to oxidative stressManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Regulation of hydrogen peroxide metabolic processIEA:Ensembl
Regulation of mitochondrial membrane potentialManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Regulation of mitochondrion organizationManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Regulation of oxidative phosphorylationManual Assertion Based On ExperimentIDA:ParkinsonsUK-UCL
Regulation of proteasomal protein catabolic process1 PublicationNAS:ParkinsonsUK-UCL
Regulation of protein targeting to mitochondrionManual Assertion Based On ExperimentIDA:AgBase
Regulation of protein ubiquitinationManual Assertion Based On ExperimentIDA:BHF-UCL
Regulation of protein-containing complex assemblyManual Assertion Based On ExperimentIDA:BHF-UCL
Regulation of reactive oxygen species metabolic processManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Regulation of synaptic vesicle transportManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Respiratory electron transport chainIEA:Ensembl
Response to ischemiaIEA:Ensembl
Response to oxidative stressManual Assertion Based On ExperimentIGI:ParkinsonsUK-UCL
TORC2 signaling1 PublicationIC:ParkinsonsUK-UCL
Ubiquitin-dependent protein catabolic processManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL

Mitochondrion outer membrane
Mitochondrion inner membrane
Cytoplasm, cytosol
Localizes mostly in mitochondrion and the two smaller proteolytic processed fragments localize mainly in cytosol (PubMed:19229105).
When mitochondria lose mitochondrial membrane potential following damage, PINK1 import is arrested, which induces its accumulation in the outer mitochondrial membrane, where it acquires kinase activity (PubMed:18957282).

Parkinson disease 6 (PARK6):
An early-onset form of Parkinson disease, a neurodegenerative disorder characterized by parkinsonian signs such as rigidity, resting tremor and bradykinesia. A subset of patients manifest additional symptoms including hyperreflexia, autonomic instability, dementia and psychiatric disturbances. Symptoms show diurnal fluctuation and can improve after sleep. PARK6 pathogenesis involves respiratory complex I deficiency causing mitochondrial depolarization and dysfunction. Inheritance is autosomal recessive.

Mitochondrial intermembrane: 78-93
Helical: 94-110
Cytoplasmic: 111-581

Proteolytically cleaved (PubMed:19229105, PubMed:22354088, PubMed:30733118).
In healthy cells, the precursor is continuously imported into the inner mitochondrial membrane (IMM), where it is proteolytically cleaved by mitochondrial-processing peptidase (MPP) and then undergoes further proteolytic cleavage by PARL or AFG3L2 to give rise to the 52 kDa short form (PubMed:19229105, PubMed:22354088).
The 52 kDa short form is then released into the cytosol where it rapidly undergoes proteasome-dependent degradation (PubMed:20404107).
In unhealthy cells, when cellular stress conditions lead to the loss of mitochondrial membrane potential, mitochondrial import is impaired leading to the precursor accumulating on the outer mitochondrial membrane (OMM) (PubMed:20404107, PubMed:30733118).
If accumulation at the OMM fails and it is imported into the depolarized mitochondria, it undergoes cleavage by the IMM protease OMA1, promoting its subsequent degradation by the proteasome (PubMed:30733118).
Autophosphorylated (PubMed:20404107, PubMed:22910362, PubMed:18957282).
Loss of mitochondrial membrane potential results in the precursor accumulating on the outer mitochondrial membrane (OMM) where it is activated by autophosphorylation (PubMed:20404107, PubMed:22910362, PubMed:18957282).
Autophosphorylation at Ser-228 and Ser-402 is sufficient and essential for selective recruitment of PRKN to depolarized mitochondria, via PINK1-dependent phosphorylation of ubiquitin and maybe PRKN (PubMed:22910362, PubMed:18957282).