PINK1 (PTEN induced kinase 1; HGNC:14581, NCBI Gene ID 65018) is a human locus mapped to chromosome band 1p36.12 that encodes mitochondrial serine/threonine-protein kinase PINK1 (581 aa; EC 2.7.11.1). PINK1 acts in depolarized mitochondrial outer-membrane ubiquitin & Parkin (PRKN) Ser65 phosphorylation driving mitophagy, together with PRKN (Parkin E3 Ubiquitin Ligase Gene), PTEN Tumor Suppressor Gene, and Mitochondrion. Encodes the mitochondrial serine/threonine kinase PINK1 that senses membrane depolarization and recruits Parkin to initiate mitophagy.
Biallelic LoF mutations cause Autosomal Recessive Early-Onset Parkinson Disease 6 (PARK6); target of kinetin/MTK458 mitophagy enhancers
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 8-exon gene at chromosome 1p36.12 encoding a 581-amino-acid polypeptide with an N-terminal mitochondrial targeting sequence (MTS) and transmembrane stop-transfer segment followed by a cytosolic serine/threonine kinase domain containing three unique loop insertions.
Cellular & Tissue Expression Profile: Ubiquitously expressed across high-energy post-mitotic tissues including substantia nigra pars compacta dopaminergic neurons, cortical neurons, cardiac myocytes, and oxidative skeletal muscle fibers.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Acts as a molecular volt-meter for mitochondrial health: in healthy polarized mitochondria, PINK1 is imported across the TOM/TIM23 complexes, cleaved by PARL at Ala103, and rapidly degraded by the N-end rule proteasome pathway; when a mitochondrion loses its inner-membrane potential (delta-psi-m), import stalls and full-length PINK1 homodimerizes on the outer mitochondrial membrane (TOM complex), where it phosphorylates both Ubiquitin at Ser65 and the Ubl domain of Parkin (PRKN) at Ser65 to trigger selective autophagic clearance (mitophagy).
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations in PINK1 are the second most common cause of autosomal recessive early-onset Parkinson disease (PARK6, after PRKN), leading to accumulation of damaged, reactive-oxygen-species-producing mitochondria and selective degeneration of nigrostriatal dopaminergic neurons.
Therapeutic & Clinical Pharmacology: Small-molecule neo-substrates (kinetin riboside) and allosteric PINK1 activators (such as MTK458) stabilize active PINK1 dimers on damaged mitochondria to accelerate mitophagy in Parkinson disease, heart failure, and aging models.