Microscopic image. Magenta color shows the mitochondrial network in blood vessel endothelial cells. Green color shows mitochondria that are being degraded by the cells when they are stressed.
Image: Rehman Lab
In a paper recently published in the journal eLife, researchers at the University of Illinois Chicago report that proteins released from mitochondria during inflammation can activate the immune system in much the same way as proteins released by invading bacteria. The resulting recruitment and activation of neutrophils can amplify inflammation and contribute to tissue damage even when there are no living bacteria present.
Creationists, of course, frequently rely on a characteristic piece of circular reasoning: the human body must have been designed by a perfect creator, so it must represent perfect design; its supposed perfection is then offered as evidence for the existence of that perfect creator. As I have repeatedly shown in these blog posts and in my book, The Body of Evidence: How the Human Body Refutes Intelligent Design, the human body is nothing of the sort.
Evolution is not a progressive engineering process working towards an ideal solution. Natural selection preserves heritable variations that improve reproductive success under the conditions prevailing at the time. It cannot discard an organism's evolutionary history and begin again with a clean design. The result is a collection of modifications to inherited structures, together with compromises, constraints and vulnerabilities. Additional regulatory and protective mechanisms can evolve to reduce the harm caused by those vulnerabilities, but these mechanisms are themselves evolved systems and can also malfunction. The result is often an extraordinarily complicated biological arrangement capable of serious, and sometimes catastrophic, failure—not the elegant perfection expected of intelligent design.
Mitochondria are now understood to be the descendants of bacteria that entered into an enduring symbiotic association with a host cell, probably one belonging to an archaeal lineage, early in the evolution of complex eukaryotic cells. Over evolutionary time, the former bacteria became indispensable cellular organelles, transferring most of their genes to the host-cell nucleus but retaining a small genome and several features of their bacterial ancestry.
Mitochondria do not literally revert to behaving as invading bacteria. Instead, when some of their contents escape into the cell or bloodstream, the immune system can recognise their preserved bacterial characteristics as signs of infection. This new research therefore reveals a striking medical consequence of mitochondrial evolution: an organelle essential for human life retains molecular features that can cause the immune system to mistake material from our own cells for material from invading bacteria.
The discovery helps to explain one mechanism by which inflammation can continue or intensify after the original threat has been removed. Patients with bacterial pneumonia, for example, can remain seriously ill even after antibiotics have eliminated the bacteria because an overactivated immune response continues to damage lung tissue.
The clue lies in a chemical modification called N-formylation. Bacteria commonly begin the production of a protein with the modified amino acid N-formylmethionine. Human proteins manufactured by ribosomes in the cell cytoplasm do not normally carry this bacterial signature, but the 13 proteins encoded by mitochondrial DNA and translated by mitochondrial ribosomes begin in this way. One of these is a mitochondrial protein called ND6. When such proteins or fragments of them are released, their formylated ends can bind to formyl-peptide receptors on neutrophils—the same receptors that detect bacterial peptides.
PINK1 does not manufacture ND6 or attach its formyl group. That happens during normal protein production inside mitochondria. Instead, PINK1 acts as part of a quality-control system that identifies damaged mitochondria and initiates their removal by a process called mitophagy.
In healthy mitochondria, PINK1 is continually imported across the mitochondrial membrane, cleaved and degraded, so very little accumulates. During inflammation, however, the inflammatory signalling molecule tumour necrosis factor alpha (TNF-α) causes mitochondria in endothelial cells—the cells lining blood vessels—to lose their normal membrane potential. This prevents the usual removal of PINK1, which consequently accumulates on the outer mitochondrial membrane and marks the damaged organelle for destruction through mitophagy.
Unexpectedly, the researchers found that this PINK1-dependent mitophagy was accompanied by the release of mitochondrially encoded, formylated proteins such as ND6. PINK1 therefore regulates the process leading to their release; it does not cause their production or formylation. Precisely how the mitochondrial material passes from the cell into the circulation remains to be established. The authors suggest that different cells might release it through lysosomal exocytosis, extracellular vesicles or related disposal pathways.
TNF-α increased the amount of ND6 released by cultured human lung endothelial cells. Material from these cells, as well as a synthetic mitochondrial formyl peptide, activated signalling and migration in human neutrophil-like cells. In mice given bacterial lipopolysaccharide to produce acute systemic inflammation, selectively reducing Pink1 activity in endothelial cells decreased mitophagy, lowered the concentration of circulating ND6, reduced the early recruitment and activation of neutrophils in the lungs, lowered inflammatory signalling and substantially improved survival.
The researchers have therefore uncovered a potentially harmful feedback loop. Inflammation damages and depolarises mitochondria; PINK1 initiates their disposal; formylated mitochondrial material is released; neutrophils interpret that material as a bacterial signal; and the resulting immune response produces still more inflammation and tissue damage.
This response may sometimes be beneficial, priming neutrophils to confront bacteria at an injured or infected site. During severe or persistent inflammation, however, the same inherited bacterial recognition system can become a liability, causing the immune system to attack healthy tissue in response to molecules originating within the body's own cells. It is an understandable outcome of evolutionary history and evolutionary trade-offs, but a remarkably strange arrangement for any supposedly perfect and intelligently designed system.
Evidence for the bacterial origin of mitochondria. The endosymbiotic theory proposes that mitochondria are descended from bacteria that became incorporated into another cell early in eukaryotic evolution. Instead of being digested, the bacterium and its host formed a mutually beneficial association. Over many generations, the bacterium surrendered most of its genetic independence and evolved into an indispensable cellular organelle.The paper in eLife was accompanied by a news item in UIC Today:
This conclusion does not rest upon a single resemblance. It is supported by several independent lines of evidence:
- Mitochondria retain their own DNA. Mitochondria possess a small genome separate from the chromosomes in the cell nucleus. In humans and many other organisms, this consists of a circular DNA molecule, resembling the circular chromosomes of bacteria. Mitochondrial genomes in other eukaryotes have evolved more varied forms, including linear and branched molecules, but their genes are recognisably descended from bacterial genes.
- Genetic sequences reveal their ancestry. When mitochondrial genes and proteins are compared with those of bacteria and used to construct evolutionary trees, mitochondria consistently group with, or immediately beside, the Alphaproteobacteria. Different analyses disagree about their precise position and no living bacterium should be expected to be identical to their ancestor, but the bacterial relationship itself is not seriously disputed. One extensive phylogenomic analysis of 108 proteins of alphaproteobacterial origin placed mitochondria as the sister group of known Alphaproteobacteria.
- They retain bacterial protein-making machinery. Mitochondria contain their own ribosomes, transfer RNAs and other components needed to translate their remaining genes. Although mitochondrial ribosomes have changed considerably during approximately two billion years of evolution, their central machinery is derived from bacterial ribosomes, rather than from the larger ribosomes operating in the eukaryotic cell cytoplasm.
- Their proteins retain a bacterial chemical signature. Proteins encoded by mitochondrial DNA begin with N-formylmethionine, as bacterial proteins do. Proteins manufactured from genes in the human cell nucleus do not normally begin in this way. This retained bacterial characteristic is the reason mitochondrial peptides can activate the same formyl-peptide receptors that neutrophils use to detect bacteria.
- Some antibiotics affect both bacteria and mitochondria. Antibiotics that interfere with bacterial ribosomes can also inhibit mitochondrial protein synthesis because the two translation systems share a common evolutionary origin. This unintended effect can contribute to the adverse effects of drugs such as chloramphenicol, tetracyclines and some aminoglycosides.
- Mitochondria are surrounded by two membranes. Their double membrane is consistent with the incorporation of one cell into another. The inner mitochondrial membrane contains cardiolipin, respiratory-chain components and protein complexes related to those found in bacterial membranes. Some mitochondrial membrane proteins and the machinery that inserts them also have identifiable bacterial homologues. A double membrane alone would not prove endosymbiosis, but it agrees with the genetic and biochemical evidence.
- They arise only from pre-existing mitochondria. Cells do not normally construct mitochondria from nothing. Existing mitochondria grow, divide and fuse, and their DNA is copied separately from nuclear DNA. Their division is now controlled largely by proteins supplied by the host cell, but it retains aspects of the autonomous reproduction of their bacterial ancestor.
- Mitochondrial genes have moved into the nucleus. The ancestral bacterium must have possessed thousands of genes, whereas human mitochondrial DNA retains only 13 protein-coding genes. Most mitochondrial proteins are now encoded by genes in the nucleus, manufactured in the cytoplasm and imported into the organelle. Comparative genomics has identified many nuclear genes of bacterial ancestry that reached the ancestral eukaryotic genome through this process of endosymbiotic gene transfer.
- Gene transfer can still be observed. Fragments of mitochondrial DNA continue to enter nuclear chromosomes, producing sequences known as NUMTs—nuclear mitochondrial DNA segments. Most become non-functional molecular fossils, but their presence demonstrates that DNA can travel from mitochondria to the nucleus, providing an observable mechanism for the ancient transfer of mitochondrial genes.
- Even apparently mitochondria-free organisms bear evidence of them. Several anaerobic single-celled eukaryotes once thought never to have possessed mitochondria contain reduced mitochondrial derivatives called hydrogenosomes or mitosomes. These organelles retain mitochondrial proteins, biochemical pathways or protein-import systems. Genetic evidence has demonstrated, for example, a common evolutionary origin for mitochondria and hydrogenosomes.
- The exceptional absence of mitochondria is a secondary loss. The anaerobic protist Monocercomonoides appears to have lost its mitochondrial organelle completely, but its position within a group descended from mitochondrion-bearing ancestors shows that this was a later loss, made possible after it acquired a bacterial substitute for an essential mitochondrial biochemical pathway. It is therefore not a surviving example of a primitively mitochondria-free eukaryote.
The evidence also identifies the likely nature of the host cell. Many of the genes concerned with storing and processing genetic information in eukaryotes are most closely related to archaeal genes, whereas many metabolic genes have bacterial affinities. Genomic studies of the Asgard archaea have strengthened the evidence that the host belonged to, or was closely related to, an archaeal lineage.
Modern eukaryotic cells are therefore evolutionary chimaeras. Their information-processing machinery is predominantly archaeal in origin, while mitochondria and many associated metabolic genes originated with a bacterial endosymbiont. Exactly how the association began—whether through engulfment, metabolic cooperation or some other intimate relationship—and the precise identity of the partners remain subjects of research. These uncertainties concern the details of the event, not whether mitochondria evolved from bacteria.
Mitochondria are not merely structures that happen to resemble bacteria. They contain bacterial DNA, bacterial-derived genes, bacterial-type translation machinery, bacterial membrane components and proteins that molecular phylogenies trace to a bacterial lineage. The evidence is written into their genes, their chemistry and their cellular structure.
Ancient bacterial signals from cell powerhouses may fuel excessive inflammation
Mitochondria are often called the powerhouses of the cell. But their ancient origins may also make them drivers of inflammation.
Researchers at the University of Illinois Chicago have discovered that proteins released from mitochondria can activate the immune system in a similar way to invading bacteria. The findings suggest that remnants of mitochondria’s evolutionary past may contribute to inflammation in infections and autoimmune disorders.Listen to story summary
The research, published in eLife, sheds light on a longstanding question in biology: Why do immune cells continue to produce inflammation even after a threat has disappeared?
Inflammation emerges when our immune cells fight off infections. However, many diseases have an excessive inflammation component. For example, even after antibiotics eliminate the bacteria causing pneumonia, patients can remain very sick because their immune system doesn’t always switch off the inflammation.
Dr. Jalees Rehman, senior author.
Department of Biochemistry and Molecular Genetics
University of Illinois
College of Medicine, Chicago, USA.
The widely accepted scientific theory is that mitochondria originated billions of years ago, when an ancient cell engulfed a bacterium. Through evolution, the bacterium became the mitochondrion, an integrated part of a cell, but it kept some bacterial characteristics.
That evolutionary history inspired Rehman, the Benjamin J. Goldberg Professor and head of the Department of Biochemistry and Molecular Genetics at UIC, to ask if mitochondria could trigger inflammatory responses because parts of them still resemble bacteria.
One clue came from proteins produced by mitochondria. Mitochondrial proteins carry a chemical tag known as a formyl group. Bacterial proteins have the same feature.
The only proteins our body makes that have these formyl groups are proteins produced in mitochondria. The immune system uses formylated peptides as a signal that bacteria are present.
Dr. Jalees Rehman
This signal draws the body’s immune cells, particularly neutrophils, to the infection site to launch an attack.
Using mouse models of acute lung inflammation, the team found elevated levels of mitochondrial proteins circulating in the bloodstream even when no live bacteria were present. The researchers concluded that the proteins originated from the animals’ own mitochondria.
Further experiments revealed that inflamed blood vessel cells, known as endothelial cells, were releasing the molecules through a process regulated by a protein called Pink1. That protein helps clean up and remove damaged mitochondria.
The team then exposed human neutrophils to the mitochondrial proteins. Even in the absence of bacteria, the immune cells became activated and generated high levels of oxidative stress, a hallmark of tissue injury.
The reason we think they’re so harmful is that these neutrophils create a lot of oxidative stress. When bacteria are present, that response helps kill them. But if there are no bacteria, the same response can damage healthy tissues.
Dr. Jalees Rehman
When the scientists removed Pink1 from endothelial cells, they produced lower levels of circulating mitochondrial proteins, less neutrophil accumulation in the lungs and better survival.
The findings identify endothelial cells as an unexpected source of inflammatory signals and suggest that mitochondria can act as messengers that amplify immune responses during disease. The work may help explain excessive inflammation seen in conditions ranging from severe infections to other inflammatory disorders.
The researchers hope that future studies will determine whether drugs that block the release or activity of mitochondrial proteins could help patients suffering from high inflammation.
The study also highlights how events that occurred billions of years ago continue to shape human health today, Rehman said.
By understanding the evolution of cells, we can uncover new pathways to studying and treating diseases that are very impactful or detrimental for human health.
Dr. Jalees Rehman
Publication:Priyanka Gajwani, Li Wang, Koushik Debnath, Pierina Danos, Young-Mee Kim, Shubhi Srivastava, Zijing Ye, Sarah Krantz, Dong-Mei Wang, Chinnaswamy Tiruppathi, Peter T Toth, Sriram Ravindran, Jalees Rehman (2026)
Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses during inflammation
eLife 15: e82205 https://doi.org/10.7554/eLife.82205.
What the researchers have uncovered is precisely the sort of historical compromise that evolution predicts. Mitochondria retain bacterial-style protein synthesis because they are descended from bacteria; the immune system recognises formylated bacterial peptides because doing so helps it to detect infection; and PINK1-mediated mitophagy ordinarily protects cells by removing damaged mitochondria. Each component has an understandable function, yet their interaction can produce a dangerous result: the disposal of damaged mitochondria releases molecules bearing the same chemical signature that neutrophils interpret as evidence of invading bacteria.
This is not a system assembled afresh according to a rational plan. It is a collection of inherited components, each modified by natural selection from what already existed. Selection preserved mitochondrial formylation because it remains important for efficient energy production, while also preserving immune receptors that recognise formylated peptides because they provide an effective warning of bacterial infection. It could not anticipate that, under some circumstances, material released from our own bacterial-derived organelles would activate those same receptors and provoke an escalating cycle of inflammation and tissue damage.
The researchers suggest that this apparent defect may represent an evolutionary trade-off. Mitochondrial peptides released from damaged tissue might sometimes prime neutrophils before they encounter bacteria, strengthening the response to genuine infection. But a response that was beneficial often enough to be retained need not be harmless under every circumstance. During severe inflammation, the same mechanism can become a liability, with the damage caused by excessive neutrophil activity outweighing any defensive benefit.
It is difficult to imagine a more striking antithesis of intelligent design. A competent designer working without evolutionary constraints would hardly give essential cellular organelles the same molecular signature used to identify dangerous intruders, arrange for their quality-control system to release that signature into the bloodstream, and then equip immune cells to respond by producing substances capable of damaging healthy tissue. Evolution, however, explains this peculiar arrangement without difficulty: mitochondria still carry molecular relics of their bacterial ancestry, while the immune system has evolved to respond to precisely those relics.
There is another point here that creationists will probably prefer not to notice. The researchers did not encounter these findings and conclude that evolutionary theory had failed. On the contrary, evolution supplied the reasoning that led them to the discovery. Knowing that mitochondria evolved from bacteria and retain bacterial characteristics prompted them to ask whether mitochondrial proteins might activate the same immune pathways as bacterial proteins. That evolutionary hypothesis generated testable predictions, and their experiments produced results consistent with them.
Far from being a dogma imposed upon the evidence, evolution was the productive scientific framework that told the researchers where to look, what mechanism might be operating and how their observations could be understood. No appeal to intelligent design was required at any stage, because “design” would explain neither why mitochondria carry bacterial molecular signatures nor why a supposedly perfect immune system sometimes mistakes the products of our own cells for evidence of infection. Evolution explains both—and, in doing so, once again demonstrates why it remains indispensable to modern biology and medicine.
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