Rosa Rubicondior: Malevolent Design - How a Design Blunder Caused Parkinson's Disease

Malevolent Design

How A Design Blunder Caused Parkinson's Disease
Or Was It Malevolence?

Two PINK1 proteins are shown attached to the membrane of a mitochondrion for the first time.

Scientists solve decades-long Parkinson’s mystery | WEHI

One of the causes of Parkinsonism is the accumulation of defective mitochondria in neurone leading to the death of these cells and reduced neurotransmitter production. Under normal circumstances, a protein known as PTEN-induced putative kinase 1 (PINK1) attaches to the surface of damaged mitochondria and facilitates their destruction, but when a mutation causes PINK1 to malfunction, this cell hygiene mechanism fails.

The question for creationists is why this cell hygiene process is needed in the first place when an intelligent designer could have designed more robust mitochondria, and why does it depend on an error-prone process where a simple mutation is the gene for a key protein can cause the whole thing to fail?

In fact, of course, what we have here is an example of a layer of complexity being necessary because a fundamental process is suboptimal, when a well-designed process would need no such additional layer of complexity. Additional complexity simply multiplies that opportunity for failure, especially when the additional complexity is itself suboptimal.

As an example of putative intelligent design, the result is exactly what we would expect a mindless, unintelligent process to produce.

What information do you have on Parkinson's Disease and the role of the PINK1 protein in its progress?

Parkinson's Disease Overview

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms such as bradykinesia, resting tremor, rigidity, and postural instability. Non-motor symptoms, including cognitive decline, depression, and autonomic dysfunction, also significantly affect patients.

PD has both sporadic and genetic forms, with various genes implicated in its pathogenesis, including PINK1 (PTEN-induced putative kinase 1), PARKIN (PARK2), LRRK2 SNCA and DJ-1. Mitochondrial dysfunction, oxidative stress, and defective protein degradation pathways play crucial roles in disease progression.
The Role of PINK1 in Parkinson’s Disease

PINK1 Function in Mitochondrial Quality Control

PINK1 is a mitochondrial serine/threonine kinase that plays a crucial role in maintaining mitochondrial health. It is particularly involved in mitophagy, a process that clears damaged mitochondria.

Under normal conditions, PINK1 is imported into mitochondria and rapidly degraded.
When mitochondria become damaged (e.g., due to oxidative stress or membrane depolarization), PINK1 accumulates on the outer mitochondrial membrane.
PINK1 then phosphorylates ubiquitin and the E3 ubiquitin ligase Parkin leading to the recruitment of the autophagy machinery to degrade defective mitochondria.

PINK1 Mutations and Parkinson’s Disease

Mutations in PINK1 are associated with autosomal recessive early-onset Parkinson’s disease (ARPD), typically manifesting before the age of 50. These mutations often lead to:

Loss of kinase function, impairing PINK1’s ability to phosphorylate Parkin and initiate mitophagy.
Accumulation of defective mitochondria, leading to increased oxidative stress and neuronal damage.
Dysfunctional energy metabolism in dopaminergic neurons, which are particularly vulnerable to mitochondrial defects due to their high metabolic demand.

PINK1-Parkin Pathway in Neuroprotection

The PINK1-Parkin pathway is a key neuroprotective mechanism. It ensures the removal of damaged mitochondria before they release pro-apoptotic factors.
In PD patients with PINK1 mutations this pathway is disrupted, leading to mitochondrial dysfunction accumulation of reactive oxygen species (ROS), and neuronal death.
Several studies suggest that enhancing PINK1 function or mimicking its downstream effects (e.g., boosting mitophagy) could be a potential therapeutic strategy.

Therapeutic Implications of PINK1 Research

Gene Therapy Approaches

Restoring PINK1 expression in PD models has shown promise in preventing mitochondrial dysfunction.
Clinical trials are investigating viral vector-based PINK1 delivery to rescue mitochondrial quality control.

Small-Molecule Activators of Mitophagy

Compounds that stimulate PINK1-Parkin signaling or enhance mitochondrial clearance are being explored.
Mitochondrial-targeted antioxidants (e.g., MitoQ, SkQ1) are also under study to reduce oxidative stress.

CRISPR-Based Gene Editing

Emerging technologies like CRISPR-Cas9 may offer potential ways to correct PINK1 mutations in patients with hereditary PD.

Exercise and Lifestyle Interventions

Physical activity has been shown to enhance mitochondrial biogenesis and reduce oxidative stress potentially compensating for PINK1 dysfunction.

Summary

PINK1 is essential for mitochondrial quality control through mitophagy.
PINK1 mutations cause early-onset Parkinson’s disease by impairing mitophagy, leading to mitochondrial dysfunction and neuronal death.
Therapeutic strategies targeting PINK1 include gene therapy, small-molecule drugs, and neuroprotective interventions.
Ongoing research aims to restore mitochondrial function as a way to slow PD progression.

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How a defective PINK1 protein causes Parkinsonism is the subject of a paper by researchers from the Walter & Eli Hall Institute (WEHI), of Medical Research, Victoria, Australia and is explained in a WEHI news item:

Scientists solve decades-long Parkinson’s mystery
WEHI researchers have made a huge leap forward in the fight against Parkinson’s disease, solving a decades-long mystery that paves the way for development of new drugs to treat the condition.

At a glance

In a world-first, WEHI researchers have discovered what human PINK1 looks like and how it is activated.
PINK1 is a protein linked to Parkinson’s disease, the second most common neurodegenerative disease after Alzheimer’s. There is no cure for Parkinson’s.
This discovery, published in Science, is a huge leap forward in the fight against Parkinson’s with the hope that it will accelerate the search for a drug to stop the condition.

First discovered over 20 years ago, PINK1 is a protein directly linked to Parkinson’s disease – the fastest growing neurodegenerative condition in the world. Until now, no one had seen what human PINK1 looks like, how PINK1 attaches to the surface of damaged mitochondria, or how it is switched on.

In a major breakthrough, researchers at the WEHI Parkinson’s Disease Research Centre have determined the first ever structure of human PINK1 bound to mitochondria, in findings published in Science. The work could help find new treatments for the condition that currently has no cure or drug to stop its progression.

Parkinson’s disease is insidious, often taking years, sometimes decades to diagnose. Often associated with tremors, there are close to 40 symptoms including cognitive impairment, speech issues, body temperature regulation and vision problems.

In Australia, over 200,000 people live with Parkinson’s and between 10% and 20% have Young Onset Parkinson’s Disease – meaning they are diagnosed under the age of fifty. The impact of Parkinson’s on the Australian economy and healthcare systems is estimated to be over $10 billion each year.

Breakthrough after decades of research

Mitochondria produce energy at a cellular level in all living things, and cells that require a lot of energy can contain hundreds or thousands of mitochondria. The PARK6 gene encodes the PINK1 protein, which supports cell survival by detecting damaged mitochondria and tagging them for removal.

In a healthy person, when mitochondria are damaged, PINK1 gathers on mitochondrial membranes and signals through a small protein called ubiquitin, that the broken mitochondria need to be removed. The PINK1 ubiquitin signal is unique to damaged mitochondria, and when PINK1 is mutated in patients, broken mitochondria accumulate in cells.

Although PINK1 has been linked to Parkinson’s, and in particular Young Onset Parkinson’s Disease, researchers had been unable to visualise it and did not understand how it attaches to mitochondria and is switched on.

Corresponding author on the study and head of WEHI’s Ubiquitin Signalling Division, Professor David Komander, said years of work by his team have unlocked the mystery of what human PINK1 looks like, and how it assembles on mitochondria to be switched on.

This is a significant milestone for research into Parkinson’s. It is incredible to finally see PINK1 and understand how it binds to mitochondria. Our structure reveals many new ways to change PINK1, essentially switching it on, which will be life-changing for people with Parkinson’s.

Professor David Komander, co-author.
Walter and Eliza Hall Institute of Medical Research,
Parkville, Victoria, Australia.

Hope for future treatments

Lead author on the study, WEHI senior researcher Dr Sylvie Callegari, said PINK1 works in four distinct steps, with the first two steps not been seen before.

First, PINK1 senses mitochondrial damage. Then it attaches to damaged mitochondria. Once attached it tags ubiquitin, which then links to a protein called Parkin so that the damaged mitochondria can be recycled.

This is the first time we’ve seen human PINK1 docked to the surface of damaged mitochondria and it has uncovered a remarkable array of proteins that act as the docking site. We also saw, for the first time, how mutations present in people with Parkinson’s disease affect human PINK1.

Dr Sylvie Callegari, first author.
Walter and Eliza Hall Institute of Medical Research,
Parkville, Victoria, Australia.

The idea of using PINK1 as a target for potential drug therapies has long been touted but not yet achieved because the structure of PINK1 and how it attaches to damaged mitochondria were unknown.

The research team hope to use the knowledge to find a drug to slow or stop Parkinson’s in people with a PINK1 mutation.

The link between PINK1 and Parkinson’s

One of the hallmarks of Parkinson’s is the death of brain cells. Around 50 million cells die and are replaced in the human body every minute. But unlike other cells in the body, when brain cells die, the rate at which they are replaced is extremely low.

When mitochondria are damaged, they stop making energy and release toxins into the cell. In a healthy person, the damaged cells are disposed of in a process called mitophagy.

In a person with Parkinson’s and a PINK1 mutation the mitophagy process no longer functions correctly and toxins accumulate in the cell, eventually killing it. Brain cells need a lot of energy and are especially sensitive to this damage.

Abstract
Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson’s Disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial TOM and VDAC complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.

Sylvie Callegari et al. ,
Structure of human PINK1 at a mitochondrial TOM-VDAC array. Science 0, eadu6445 DOI:10.1126/science.adu6445

© 2025 American Association for the Advancement of Science.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.

Lots of things for creationists to ignore here:

Firstly, there is the question why the complexity of mitochondria to perform basic cell metabolic functions when an intelligent designer could have given cells that ability?
Secondly, there is the problem that these mitochondria get damaged because they aren't robust enough for their function.
Thirdly, there is the error-prone layer of complexity in the repair/removal mechanism for damaged mitochondria.
Fourthly, there is the avoidable suffering for the victim and their family from the resulting Parkinsonism.

Which of these should we regard as the product of a supremely stupid designer? Or can we resolve the paradox by assuming the designer is supremely intelligent but malevolent, so this outcome was carefully designed?

And why should we not regard this as the result of a mindless utilitarian natural process that settles on suboptimal solutions providing only that they give better short-term survival than their predecessors?

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