NKF2, also known as PINK1. PTEN-induced kinase 1 (PINK1) is a mitochondrial serine / threonine protein kinase encoded by the PINK1 gene. It is thought to protect cells from stress-induced mitochondrial dysfunction. PINK1 activity causes Parkin to bind to depolarized mitochondria, thereby inducing those mitochondria to autophagy. PINK1 is processed and released by healthy mitochondria to trigger neuronal differentiation. Mutations in this gene cause an autosomal recessive, early-onset Parkinson's disease.
PINK1 is synthesized as a 63,000 Da protein, which is usually cleaved by PARL between the 103-alanine and 104-phenylalanine residues into a 53,000 Da fragment. PINK1 contains an N-terminal mitochondrial localization sequence, a putative transmembrane sequence, a Ser/Thr kinase domain, and a C-terminal regulatory sequence. The protein has been found to be localized to the outer membrane of the mitochondria, but it can also be found throughout the cytoplasm. Experiments have shown that the Ser/Thr kinase domain faces outward towards the cytoplasm, suggesting possible points of interaction with Parkin.
PINK1 is closely involved in mitochondrial quality control by identifying damaged mitochondria and degrading specific mitochondria. Healthy mitochondria maintain membrane potential, which can be used to introduce PINK1 into the inner membrane, which is then lysed by the parl and removed from the outer membrane. Severely damaged mitochondria lack sufficient membrane potential to introduce PINK1, which then accumulates on the adventitia. PINK1 then recruits Parkin to target damaged mitochondria for degradation by autophagy. Since PINK1 is present throughout the cytoplasm, it has been suggested that PINK1 acts as a "scout" to detect mitochondrial damage PINK1 can also control mitochondrial mass through mitochondrial fission. Through mitochondrial fission, many daughter mitochondria are produced, which are usually unevenly distributed in membrane potential. Strong membrane potential, healthy mitochondria fuse more easily than mitochondria with low membrane potential. Disturbance of the mitochondrial pathway leads to an increase in oxidized protein and a decrease in respiration. Without PINK1, Parkin cannot effectively localize to damaged mitochondria, and overexpression of PINK1 will cause Parkin to localize to even healthy mitochondria. In addition, mutations in Drp1, mitochondrial fission factor and PINK1 were fatal in the Drosophila model. However, overexpression of Drp1 could rescue subjects lacking PINK1 or Parkinella, suggesting that mitochondrial fission induced by Drp1 would reproduce the same effect of the PINK1/parkin pathway. In addition to mitochondrial fission, PINK1 is also related to mitochondrial movement. The goal of PINK1 accumulation and Parkinson's recruitment is to degrade mitochondria, while PINK1 may increase the degradation rate by preventing mitochondrial movement. Overexpression of PINK1 produces a similar effect to silencing Miro, a protein closely related to mitochondrial migration.
Another mechanism for mitochondrial quality control may be produced by mitochondrial-derived vesicles. Oxidative stress in mitochondria can produce potentially harmful compounds, including improperly folded proteins or reactive oxygen species. PINK1 has been shown to promote the formation of mitochondrial-derived vesicles that separate active oxygen and transport it to lysosomes for degradation.
Parkinson's disease is often characterized by degeneration of dopaminergic neurons and is associated with incorrectly folded protein and Lewy body accumulation. Mutations in the PINK1 protein have been shown to cause the accumulation of such incorrectly folded proteins in the mitochondria of Drosophila and human cells. Specifically, mutations in the serine/threonine kinase domain have been found in many patients with Parkinson's disease, where PINK1 fails to prevent stress-induced mitochondrial dysfunction and apoptosis.