PINK1

Key takeaways

PINK1 belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect PINK1 to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of PINK1 from memory before moving on to harder problems.

Reference excerpt

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 the parkin protein to bind to depolarized mitochondria to induce autophagy 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.

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 mitochondrial localization sequence, a putative transmembrane sequence, a Ser/Thr kinase domain, and a C-terminal 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). Healthy mitochondria maintain a membrane potential 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. In neurons, processed PINK1 released by healthy mitochondria activates signaling pathways that promote dendritic branching, spine maturation and synaptic function.

PINK1 may also control mitochondria quality through mitochondrial fission. 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 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. Regulation of mitochondrial fission by PINK1 modulates synaptic function. 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 for degradation.

Disease relevance Parkinson's disease is often characterized by the degeneration of dopaminergic neurons 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.

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. Another strategy to elevate PINK1 activity involves small molecule-mediated inhibition of PINK1 degradation, which confers protection in toxin and patient-derived models.

References

Illustrations

Worked examples

Example 1 — a first encounter with PINK1

Start with the simplest possible case. Write down what PINK1 claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to PINK1 before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about PINK1 ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of PINK1

In research: PINK1 appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses PINK1 in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: PINK1 is common in secondary-school and first-year university syllabi. It links to neighbouring topics Genes on human chromosome 1, Parkinson's disease, so understanding it makes those chapters shorter.
In everyday life: Look for PINK1 outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study PINK1 in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what PINK1 means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain PINK1 out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is PINK1 in simple terms?

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.

Why does PINK1 matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study PINK1?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on PINK1.