PINK1 With Healthy Mitochondria
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PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the ''PINK1''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. It is thought to protect cells from stress-induced
mitochondrial A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
dysfunction. PINK1 activity causes the parkin
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
to bind to depolarized mitochondria to induce
autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...
of those mitochondria. PINK1 is processed by healthy mitochondria and released to trigger neuron differentiation. Mutations in this gene cause one form of autosomal recessive early-onset
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
.


Structure

PINK1 is synthesized as a 63000 Da protein which is often cleaved by PARL, between the 103-Alanine and the 104-Phenylalanine residues, into a 53000 Da fragment. PINK1 contains an
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
mitochondrial localization sequence, a putative transmembrane sequence, a Ser/Thr kinase domain, and a
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
regulatory sequence. The protein has been found to localize to the outer membrane of mitochondria, but can also be found throughout the cytosol. Experiments suggest the Ser/Thr kinase domain faces outward toward the cytosol, indicating a possible point of interaction with parkin. The structure of PINK1 has been solved and shows how the protein binds and phosphorylates its substrate ubiquitin.


Function

PINK1 is intimately involved with mitochondrial quality control by identifying damaged mitochondria and targeting specific mitochondria for degradation (
mitophagy Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described in 1915 by Margaret Reed Lewis and Warren Harmon Lewis. Ashford ...
). Healthy mitochondria maintain a
membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. It equals the interior potential minus the exterior potential. This is th ...
that can be used to import PINK1 into the mitochondrial inner membrane where it is cleaved by PARL and cleared from the outer membrane. Severely damaged mitochondria lack sufficient membrane potential to import PINK1, which then accumulates on the outer membrane. PINK1 then recruits Parkin to target the damaged mitochondria for degradation. Due to the presence of PINK1 throughout the cytoplasm, it has been suggested that PINK1 functions as a "scout" to probe for damaged mitochondria. PINK1 may also control mitochondria quality through
mitochondrial fission Mitochondrial fission is the process by which mitochondria divide or segregate into two separate mitochondrial organelles. Mitochondrial fission is counteracted by mitochondrial fusion, where two mitochondria fuse together to form a larger one. Fu ...
. Through mitochondrial fission, a number of daughter mitochondria are created, often with an uneven distribution in membrane potential. Mitochondria with a strong, healthy membrane potential were more likely to undergo fusion than mitochondria with low membrane potential. Interference with the mitochondrial fission pathway led to an increase in oxidized proteins and a decrease in respiration. Without PINK1, parkin cannot efficiently localize to damaged mitochondria, while an over-expression of PINK1 causes parkin to localize to even healthy mitochondria. Furthermore, mutations in both Drp1, a mitochondrial fission factor, and PINK1 were fatal in
Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
models. However, an over-expression of Drp1 could rescue subjects deficient in PINK1 or parkin, suggesting mitochondrial fission initiated by Drp1 recreates the same effects of the PINK1/parkin pathway. In addition to mitochondrial fission, PINK1 has been implicated in mitochondrial motility. The accumulation of PINK1 and recruitment of parkin targets a mitochondrion for degradation, and PINK1 may serve to enhance degradation rates by arresting mitochondrial motility. Over-expression of PINK1 produced similar effects to silencing Miro, a protein closely associated with mitochondrial migration. Another mechanism of mitochondrial quality control may arise through mitochondria-derived vesicles. Oxidative stress in mitochondria can produce potentially harmful compounds including improperly folded proteins or reactive oxygen species. PINK1 has been shown to facilitate the creation of mitochondria-derived vesicles which can separate reactive oxygen species and shuttle them toward
lysosomes A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
for degradation.


Disease relevance

Parkinson's disease is often characterized by the degeneration of
dopaminergic neuron Dopaminergic cell groups, DA cell groups, or dopaminergic nuclei are collections of neurons in the central nervous system that synthesize the neurotransmitter dopamine. In the 1960s, Dopaminergic pathways, dopaminergic neurons or ''dopamine neuron ...
s and associated with the build-up of improperly folded proteins and Lewy bodies. Mutations in the PINK1 protein have been shown to lead to a build-up of such improperly folded proteins in the mitochondria of both fly and human cells. Specifically, mutations in the serine/threonine kinase domain have been found in a number of Parkinson's patients where PINK1 fails to protect against stress-induced mitochondrial dysfunction and
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
.


Pharmacological manipulation

To date, there have been few reports of small molecules that activate PINK1 and their promise as potential treatments for Parkinson's disease. The first report appeared in 2013 when Kevan Shokat and his team from UCSF identified a nucleobase called kinetin as an activator of PINK1. Subsequently, it was shown by others that the nucleoside derivative of kinetin, i.e. kinetin riboside, exhibited significant activation of PINK1 in cells. Additionally, the monophosphate prodrugs of kinetin riboside, ProTides, also showed activation of PINK1. In December 2017, niclosamide, an anthelmintic drug, was identified as a potent activator of PINK1 in cells and in neurons.


References


Further reading

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External links


GeneReviews/NCBI/NIH/UW entry on PINK1 Type of Young-Onset Parkinson Disease
Parkinson's disease