Rosa Rubicondior: Unintelligent Design - Another Failure By Creationism's Blundering Designer

Unintelligent Design

Another Failure By Creationism's Blundering Designer

Machine for repairing broken mtDNA.

AI-Generated image
(with apologies to William Heath Robinson)

The graphic shows images of a cell under mtDNA replication stress made using so-called Correlative Light and Electron Microscopy (for short: CLEM). The mitochondrial DNA (mtDNA, green) is ejected from the mitochondria (magenta) and taken up by a lysosome, which contains the retromer (cyan). The highlighted section was also analysed using 3D-CLEM to obtain volumetric information.

Fig.: HHU/David Pla-Martín.

Medicine: Publication in Science Advances

Yet Another Workaround for a Flawed Design.

Researchers led by Professor Dr David Pla-Martín of Heinrich Heine University Düsseldorf, alongside colleagues from the University of Cologne, have uncovered yet another complex but error-prone workaround—this time, to fix a problem that stems from an earlier design flaw.

They have identified a mechanism used to repair mitochondrial DNA (mtDNA) when it breaks. From an intelligent design perspective, mitochondria — once free-living bacteria—were supposedly the 'quick fix' to give eukaryotic cells the ability to efficiently convert glucose into adenosine triphosphate (ATP) using oxygen. ATP is the primary energy currency used in metabolic reactions, formed from adenosine diphosphate (ADP) and phosphate.

A truly intelligent designer, however, could have simply endowed cells with this biochemical machinery from the start—no need to incorporate foreign bacteria complete with their own DNA. But apparently, that would have been too simple.

This convoluted solution, predictably, comes with problems. Mitochondria often replicate their DNA imperfectly, or the DNA becomes damaged, leading to mitochondrial failure and a range of diseases. So, yet another layer of biological complexity has evolved to patch up the broken mtDNA. And, in classic Heath Robinson fashion, this repair mechanism is itself error-prone.

What are some of the diseases that can be caused by faulty mtDNA and failure of the repair mechanism?

Faulty mitochondrial DNA (mtDNA) and failures in its repair mechanisms can lead to a wide range of mitochondrial diseases, many of which are serious and often progressive. These diseases can affect multiple organ systems, especially those with high energy demands, such as the brain, muscles, heart, and liver.

Here are some notable examples:

Neurological Disorders

Leigh syndrome: A severe neurological disorder usually emerging in infancy. It causes progressive loss of mental and movement abilities, and typically leads to early death.
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes): Characterised by strokes, seizures, muscle weakness, and learning disabilities.
MERRF (Myoclonic Epilepsy with Ragged Red Fibres): Causes muscle spasms, epilepsy, ataxia, and hearing loss.
Alzheimer’s disease & Parkinson’s disease (suspected links): Mitochondrial dysfunction, including mtDNA mutations, is increasingly associated with the pathogenesis of these neurodegenerative conditions.

Muscle and Metabolic Disorders

Kearns–Sayre syndrome: Involves progressive external ophthalmoplegia (eye muscle weakness), pigmentary retinopathy, and heart block.
Pearson syndrome: Affects bone marrow and the pancreas, often fatal in infancy. Survivors may later develop Kearns–Sayre syndrome.
Chronic Progressive External Ophthalmoplegia (CPEO): A condition involving muscle weakness, especially of the eyes and eyelids.

Cardiovascular Disorders

Mitochondrial cardiomyopathy: Includes hypertrophic or dilated cardiomyopathy, where the heart muscle becomes abnormally thick or weak, respectively.
Arrhythmias and heart block: Especially in syndromes like Kearns–Sayre.

Endocrine and Metabolic Disorders

Diabetes mellitus and deafness (DAD): A mitochondrial disorder involving both diabetes and hearing loss, commonly linked to the m.3243A>G mutation in mtDNA.
Lactic acidosis: Caused by defective oxidative phosphorylation, leading to the accumulation of lactic acid in the body.

Visual and Auditory Disorders

Leber’s Hereditary Optic Neuropathy (LHON): Sudden vision loss in young adults, due to death of optic nerve cells.
Sensorineural hearing loss: A common symptom in several mtDNA-related syndromes.

Multisystemic Disorders

Mitochondrial DNA depletion syndromes (MDDS): A group of disorders caused by a significant reduction in mtDNA copy number, leading to organ failure, especially in liver, muscle, or brain.

Most of these diseases are inherited maternally, as mitochondria (and their DNA) are passed down from the mother. However, somatic mtDNA mutations — those acquired over time — are also implicated in ageing and some cancers.

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How this was discovered and its significance for medical science is explained in a Heinrich Heine University news article:

How cells repair their power plants
Damage to the mitochondria, the “power plants” of the cells, contributes to many diseases. Researchers from Heinrich Heine University Düsseldorf (HHU) and the University of Cologne led by HHU professor of medicine Dr David Pla-Martín, now describe in the scientific journal Science Advances how cells with defective mitochondria activate a special recycling system to eliminate damaged genetic material.
Damage to the genetic material of mitochondria – the mitochondrial DNA or mtDNA for short – can lead to diseases such as Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS), cardiovascular diseases and type 2 diabetes. Such damage also speeds up the ageing process. However, the cells are normally capable of identifying such damage and reacting.

Scientists from University Hospital Düsseldorf and HHU have – in collaboration with the University of Cologne and the Center for Molecular Medicine Cologne (CMMC) – discovered a mechanism, which protects and repairs the mitochondria. The research team, headed by Professor Pla-Martín from the Institute of Biochemistry and Molecular Biology I at HHU, has identified a specialised recycling system, which cells activate when they identify damage to the mtDNA.

According to the authors in Science Advances, this mechanism relies on a protein complex known as retromer and the lysosomes – cell organelles containing digestive enzymes. These special cellular compartments act like recycling centres, eliminating the damaged genetic material. This process is one of the mechanisms, which prevent the accumulation of faulty mtDNA, thus maintaining cellular health and potentially preventing diseases.

We have identified a previously unknown cellular pathway, which is important for mitochondrial health and thus for the natural defences of our cells. By understanding this mechanism, we can explain how mitochondrial damage can trigger diseases like Parkinson’s and Alzheimer’s. This could in turn form the basis for developing preventive therapies.

Professor Dr. David Pla-Martín, lead author.
Institute of Physiology
University Clinics and Faculty of Medicine
University of Cologne, Cologne, Germany.

In collaboration with the cell biologist Dr Parisa Kakanj from the University of Cologne, who is also a member of the CEPLAS Cluster of Excellence, Professor Pla-Martín was able to verify and extend the findings using fruit flies (Drosophila) as a model organism. Dr Kakanj showed that damaged mitochondrial DNA are eliminated much more quickly and that mitochondrial function improves significantly when the activity of the retromer complex – in particular the protein VPS35 – is increased.

Using Drosophila allowed us to confirm our initial findings in human cells and demonstrate clear improvements in mitochondrial health. This opens up exciting possibilities for therapeutic strategies for treating mitochondrial diseases and age-related conditions.

Dr Parisa Kakanj, first author.
Institute of Genetics
University of Cologne
Cologne, Germany.

Publication

Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollá, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín.
Retromer promotes the lysosomal turnover of mtDNA. Science Advances 11, eadr6415 (2025). DOI:10.1126/sciadv.adr6415

Abstract
Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria’s association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.

INTRODUCTION
Mitochondria are multifaceted organelles in charge of many essential cellular functions. Unique among cellular organelles, mitochondria contain their own genome, also known as mitochondrial DNA (mtDNA). Present in multiple copies per cell, the mitochondrial genome is organized within structures known as mitochondrial nucleoids. mtDNA is relatively small but encodes 13 critical proteins essential for the mitochondrial respiratory chain and a subset of RNAs and tRNAs required for mitochondrial protein synthesis. All these components are indispensable for maintaining mitochondrial function and cellular homeostasis (1).

One of the main subproducts generated during the coupling of the different mitochondrial pathways to produce adenosine triphosphate (ATP) are reactive oxygen species (ROS) (2). ROS, including superoxide anions, hydrogen peroxide, and hydroxyl radicals, are generated when electrons leak from the electron transport chain and react with oxygen molecules. ROS damages not only proteins and lipids but also the mtDNA, modifying the biochemical properties of the molecule, altering base-pairing properties, and affecting the maintenance of the mitochondrial genome, serving as a source for mutations (3, 4). These mutations impair respiratory chain complexes, increasing oxidative stress and triggering a self-amplifying cycle that results in mitochondrial dysfunction. Thus, the progressive accumulation of mtDNA damage influences many human diseases, accelerates aging, and, in marked cases, even leads to cellular death (5).

From energy production and ion exchange to metabolite synthesis, all mitochondrial functions depend on maintaining the integrity of the network through mitochondrial turnover. Since the discovery of selective degradation of mitochondria in mammals in the early 21st century, numerous parallel pathways have been identified (6). The PINK1-Parkin autophagy pathway targets large mitochondrial segments for degradation in response to acute damage or in situations requiring mitochondrial adaptation, such as during cell differentiation or changes in nutrient availability (7). Other complementary pathways work in parallel to selectively remove only dysfunctional mitochondrial pieces, thereby preserving the healthy portions of the network and maintaining cellular homeostasis (6).

The presence of mtDNA in autophagy-related structures, independent of other mitochondrial parts, suggests a specific selective quality control pathway for the mitochondrial genome (8). Several mechanisms have been proposed to explain how mtDNA is degraded in response to stress, including mitochondrial-derived vesicles (MDVs) (9) and piecemeal mitophagy (10, 11). Nevertheless, the exact mechanism seems to depend on the initial stress. Thus, upon fumarate accumulation, the mitochondrial genome appears encapsulated in TOM20−/PDH+ MDVs (9). Upon antimycin/oligomycin stress, the inner membrane and, eventually, the mtDNA are eliminated through lysosomal-dependent piecemeal mitophagy through VDAC1 pores (11). Furthermore, cells treated with low levels of ethidium bromide separate mitochondrial nucleoids into inner membrane subdomains, which, upon fission, are eliminated in autophagosome-dependent piecemeal mitophagy (10). In this context, the mitochondrial inner membrane PHB2 serves as a mitophagy receptor after the degradation of the outer mitochondrial membrane (10, 12). Independent of the specificities of each path, all of them point toward the separation of a mitochondrial piece and its degradation in recycling organelles.

Interfering with mtDNA replication leads to the accumulation of oxidative damage in the mitochondrial genome (13). The biochemical changes initiated by ROS modify the architecture of the mitochondrial membranes and allow the translocation of the mtDNA to the endosomal compartment, where it will be degraded within recycling organelles (13). We and others recently found that the extraction of the mtDNA responds to the coordination between mitochondrial membrane and vesicle trafficking proteins. The endosomal protein RAB5C physically interacts with Mitofusin 1 and Mitofusin 2 and assists in endosomal approach and mtDNA transfer (14). Similarly, proper disposal of mtDNA requires the mitochondrial membrane protein SAMM50 (13). Disturbance of this selective quality control pathway leads to the activation of the innate immune response with potential implications in aging and several human diseases (14–16).

In the current study, we sought to elucidate the mechanisms underlying the elimination of the mitochondrial genome upon mtDNA replication stress. By spatial proteomics of the mitochondria-endosome contact sites, we identified a group of lysosomal proteins involved in mtDNA turnover. Mitochondrial matrix components, including the mtDNA, exit the mitochondrial network assisted by the retromer, although they do not follow the same path. The accumulation of the mtDNA outside the mitochondrial compartment is BAX dependent and enhanced by lysosomal inhibition with chloroquine. Using correlative light and electron microscopy (CLEM), we demonstrate that the piecemeal removal of mtDNA from mitochondria occurs with direct transfer to a recycling organelle. The retromer assists this process by stimulating the lysosomal function and mitochondrial fragmentation. Furthermore, using a Drosophila model with a long deletion in the mtDNA (ΔmtDNA), we validated the role of the retromer in promoting mtDNA quality control in vivo. Our results reveal a mechanism for the degradation of the mitochondrial matrix, including the mtDNA, and highlight the lysosomes as the central organelles maintaining mitochondrial function.

Fig. 9. Proposed model for retromer function upon mtDNA stress.

The retromer enhances mitochondrial fragmentation and mtDNA turnover. mtDNA ejection occurs in a BAX-dependent manner, targeting RAB10-VPS35-positive lysosomes, and independent of MDVs. Stimulation of these pathways restores mitochondrial function and mitigates defects associated with mtDNA damage in vivo.

Cases like this continue to provide compelling evidence that life is not the product of a flawless intelligence but of a utilitarian, evolutionary process—one that works with what it has, under constraints, and produces suboptimal, compromise solutions. These solutions are riddled with inefficiencies and vulnerabilities, which then demand further layers of complexity to mitigate.

Yet despite these examples, creationists still insist that all of this is the handiwork of a supreme intelligence for whom nothing is impossible — and that evolutionary processes could never account for it. Exploiting their general ignorance of biology and unwillingness to fact-check, creationist cult leaders manage to obscure these details from their followers and continue to present complexity as evidence of intelligent design instead of the evidence against it that research such as this exposes.

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