In another example of the ramshackle Heath Robinson design process that created humans, scientists today published their findings that show how when a cell process goes wrong, as it frequently does, the result can be a serious health condition, causing suffering and unhappiness.
And of course, it’s another example of how we can tell humans weren't intelligently designed by an omnibenevolent god who wants to minimise the suffering in the world, but by a mindless, amoral natural process that has no option but to settle for the sub-optimal as long as it’s better than nothing.
The discovery, by researchers at the Salk Institute and their colleagues at UC San Diego , is the way when mitochondrial DNA (mtDNA) goes wrong and the cell tried to dispose of it, some of it leaks out into the cell, the cell’s immune system treats it like the DNA of a parasitic organism and sets up an immune response which caused inflammation.
Given the origin of mitochondria in our Heath Robinson contraptions we call cells, this is hardly surprising since mitochondria started out, probably as the free-living bacterial prey of another prokaryote, possibly an archaeon. They then became symbiotic, providing the cell with free ATP in return for protection and nutrients in the form of sugar, water and oxygen. Because they need to provide a handful of enzymes to do this with, and they are self-replicating, they retained a small amount of their original DNA while giving up most of it to the host cell's nucleus.
Tell me all about mitochondria, what they do and how they originated as free-living prokaryote cells, please. Mitochondria are essential organelles found in the cells of eukaryotic organisms, including plants, animals, fungi, and protists. They are often referred to as the "powerhouses" of the cell due to their primary function of producing adenosine triphosphate (ATP), the molecule used by cells as a source of energy. Mitochondria are involved in various other cellular processes as well, including regulation of cell cycle and growth, cell signaling, and apoptosis (programmed cell death).What the researchers have found is a novel mechanism for removing malfunctioning mtDNA from inside the mitochondrion to outside it, where it then gets treated as hostile alien DNA.
Here's an overview of the structure and function of mitochondria:
- Structure: Mitochondria are double-membraned organelles, consisting of an outer membrane and an inner membrane. The outer membrane is smooth, while the inner membrane is highly folded into structures called cristae, which increase its surface area. The space enclosed by the inner membrane is called the mitochondrial matrix. Within the matrix, there are enzymes responsible for the various biochemical reactions that occur in mitochondria, including those involved in the citric acid cycle (Krebs cycle) and oxidative phosphorylation.
- Function:
- ATP Production: The primary function of mitochondria is to generate ATP through cellular respiration. This process involves the breakdown of carbohydrates, fats, and sometimes proteins, to produce ATP molecules, which cells use as a source of energy.
- Cellular Respiration: Mitochondria are involved in cellular respiration, which is a series of metabolic reactions that occur in the presence of oxygen. Cellular respiration includes glycolysis, the citric acid cycle, and oxidative phosphorylation.
- Calcium Regulation: Mitochondria also play a role in calcium signaling and regulation within cells. They can sequester and release calcium ions, which are involved in various cellular processes such as muscle contraction and cell signaling.
- Apoptosis: Mitochondria are involved in programmed cell death, or apoptosis. They release certain proteins that trigger apoptosis when cells are damaged or no longer needed.
- Synthesis of Certain Biomolecules: Mitochondria are involved in the synthesis of certain lipids, amino acids, and heme, a component of hemoglobin.
- Endosymbiotic Theory: Mitochondria are believed to have originated from a symbiotic relationship between an ancestral eukaryotic cell and an aerobic prokaryote, possibly a bacterium similar to modern-day alpha-proteobacteria. According to the endosymbiotic theory proposed by Lynn Margulis in the 1960s, an ancestral eukaryotic cell engulfed a free-living aerobic prokaryote, forming a symbiotic relationship in which the prokaryote provided ATP through aerobic respiration, while the host cell provided protection and resources. Over time, this symbiotic relationship became permanent, with the engulfed prokaryote evolving into the mitochondria found in eukaryotic cells today. Evidence supporting this theory includes the similarities between mitochondria and certain bacteria, such as their similar size, structure, and the presence of their own circular DNA (similar to bacterial DNA). Additionally, mitochondria replicate independently of the cell, similar to bacteria, and have their own ribosomes and machinery for protein synthesis.
The team have reported their findings in Nature Cell Biology where annoyingly, all but the abstract id behind a paywall. However, they also describe their research in a Salk Institute News release:
Faulty DNA disposal system causes inflammation
Salk scientists outline mouse cell inflammation pathway from mitochondrial stress to leaking endosomes to immune system initiation, revealing new potential therapeutic targets to reduce inflammation in aging and disease
Cells in the human body contain power-generating mitochondria, each with their own mtDNA—a unique set of genetic instructions entirely separate from the cell’s nuclear DNA that mitochondria use to create life-giving energy. When mtDNA remains where it belongs (inside of mitochondria), it sustains both mitochondrial and cellular health—but when it goes where it doesn’t belong, it can initiate an immune response that promotes inflammation.
Now, Salk scientists and collaborators at UC San Diego have discovered a novel mechanism used to remove improperly functioning mtDNA from inside to outside the mitochondria. When this happens, the mtDNA gets flagged as foreign DNA and activates a cellular pathway normally used to promote inflammation to rid the cell of pathogens, like viruses.
The findings, published in Nature Cell Biology on February 8, 2024, offer many new targets for therapeutics to disrupt the inflammatory pathway and therefore mitigate inflammation during aging and diseases, like lupus or rheumatoid arthritis.One of the ways our cells respond to damage and infection is with what’s known as the innate immune system. While the innate immune response is the first line of defense against viruses, it can also respond to molecules the body makes that simply resemble pathogens—including misplaced mtDNA. This response can lead to chronic inflammation and contribute to human diseases and aging.We knew that mtDNA was escaping mitochondria, but how was still unclear. Using imaging and cell biology approaches, we’re able to trace the steps of the pathway for moving mtDNA out of the mitochondria, which we can now try to target with therapeutic interventions to hopefully prevent the resulting inflammation.
Professor Gerald Shadel, co-corresponding author.
Director of the San Diego-Nathan Shock Center of Excellence in the Basic Biology of Aging
Audrey Geisel Chair in Biomedical Science
Salk Institute for Biological Studies, La Jolla, CA, USA
Scientists have been working to uncover how mtDNA leaves mitochondria and triggers the innate immune response, but the previously characterized pathways did not apply to the unique mtDNA stress conditions the Salk team was investigating. So, they turned to sophisticated imaging techniques to gather clues as to where and when things were going awry in those mitochondria.
The team discovered a process beginning with a malfunction in mtDNA replication that caused mtDNA-containing protein masses called nucleoids to pile up inside of mitochondria. Noticing this malfunction, the cell then begins to remove the replication-halting nucleoids by transporting them to endosomes, a collection of organelles that sort and send cellular material for permanent removal. The endosome gets overloaded with these nucleoids, springs a leak, and mtDNA is suddenly loose in the cell. The cell flags that mtDNA as foreign DNA—the same way it flags a virus’s DNA—and initiates the DNA-sensing cGAS-STING pathway to cause inflammation.We had a huge breakthrough when we saw that mtDNA was inside of a mysterious membrane structure once it left mitochondria — after assembling all of the puzzle pieces, we realized that structure was an endosome. That discovery eventually led us to the realization that the mtDNA was being disposed of and, in the process, some of it was leaking out.
Assistant professor Laura E. Newman, first author,
University of Virginia, Virginia, USA.
The researchers hope to map out more of this complicated mtDNA-disposal and immune-activation pathway, including what biological circumstances—like mtDNA replication dysfunction and viral infection—are required to initiate the pathway and what downstream effects there may be on human health. They also see an opportunity for therapeutic innovation using this pathway, which represents a new cellular target to reduce inflammation. Other authors include Sammy Weiser Novak, Gladys Rojas, Nimesha Tadepalle, Cara Schiavon, Christina Towers, Matthew Donnelly, Sagnika Ghosh, Sienna Rocha, and Ricardo Rodriguez-Enriquez of Salk; Danielle Grotjahn and Michaela Medina of The Scripps Research Institute; Marie-Ève Tremblay of the University of Victoria in Canada; Joshua Chevez of UC San Diego; and Ian Lemersal of the La Jolla Institute for Immunology.Using our cutting-edge imaging tools for probing mitochondria dynamics and mtDNA release, we have discovered an entirely novel release mechanism for mtDNA. There are so many follow-up questions we cannot wait to ask, like how other interactions between organelles control innate immune pathways, how different cell types release mtDNA, and how we can target this new pathway to reduce inflammation during disease and aging.
Assistant professor Uri Manor, co-corresponding author
Department of Cell & Developmental Biology
University of California, San Diego, La Jolla, CA, USA
AbstractLet's just recap what an 'intelligent' design creationist needs to believe here:
Mitochondrial DNA (mtDNA) encodes essential subunits of the oxidative phosphorylation system, but is also a major damage-associated molecular pattern (DAMP) that engages innate immune sensors when released into the cytoplasm, outside of cells or into circulation. As a DAMP, mtDNA not only contributes to anti-viral resistance, but also causes pathogenic inflammation in many disease contexts. Cells experiencing mtDNA stress caused by depletion of the mtDNA-packaging protein, transcription factor A, mitochondrial (TFAM) or during herpes simplex virus-1 infection exhibit elongated mitochondria, enlargement of nucleoids (mtDNA–protein complexes) and activation of cGAS–STING innate immune signalling via mtDNA released into the cytoplasm. However, the relationship among aberrant mitochondria and nucleoid dynamics, mtDNA release and cGAS–STING activation remains unclear. Here we show that, under a variety of mtDNA replication stress conditions and during herpes simplex virus-1 infection, enlarged nucleoids that remain bound to TFAM exit mitochondria. Enlarged nucleoids arise from mtDNA experiencing replication stress, which causes nucleoid clustering via a block in mitochondrial fission at a stage when endoplasmic reticulum actin polymerization would normally commence, defining a fission checkpoint that ensures mtDNA has completed replication and is competent for segregation into daughter mitochondria. Chronic engagement of this checkpoint results in enlarged nucleoids trafficking into early and then late endosomes for disposal. Endosomal rupture during transit through this endosomal pathway ultimately causes mtDNA-mediated cGAS–STING activation. Thus, we propose that replication-incompetent nucleoids are selectively eliminated by an adaptive mitochondria–endosomal quality control pathway that is prone to innate immune system activation, which might represent a therapeutic target to prevent mtDNA-mediated inflammation during viral infection and other pathogenic states.
Newman, L.E., Weiser Novak, S., Rojas, G.R. et al.
Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal.
Nat Cell Biol (2024). https://doi.org/10.1038/s41556-023-01343-1
© 2024 Springer Nature Ltd.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.
Firstly, that an intelligent designer would insert degenerate bacteria inside a cell so it could process glucose and oxygen to make ATP to power its metabolism, rather than giving the cell that ability. An example of the needless complexity of which William Heath Robinson would be proud, but which is the hall mark of bad, unintelligent design.
Then, because that overly complex process sometimes goes wrong, it gave the cell a mechanism for removing the faulty mtDNA to dispose of it, but that additional level of complexity also goes wrong and leaks mtDNA into the cell, where the immune system that is there to protect us, over-reacts and produces an immune response that results in inflammation that makes us sick.
To a creationist this unnecessarily complex, error-prone design is regarded as evidence that it was designed by a supreme intelligence, endowed with omnipotence and omniscience. But such an intelligence could and should have foreseen that this would happen and designed a better system.
In fact, or course, this 'design' is indistinguishable from one designed by an unthinking natural process working without a plan and unable to go back and start again, and it is exactly what we would expect to find if we were looking for evidence that there was no intelligence involved anywhere in the process.
The Unintelligent Designer: Refuting The Intelligent Design Hoax
ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
Available in Hardcover, Paperback or ebook for Kindle
The Malevolent Designer: Why Nature's God is Not Good
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
Illustrated by Catherine Webber-Hounslow.
Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
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