Review nature - A break in mitochondrial endosymbiosis as a basis for inflammatory diseases, Murphy et al, 2024

Abstract

Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered.

However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation.

This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs.

Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus.

Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases.

A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors.

Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities.

Thus, whereas mitochondria can be considered ‘the enemy within’ the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.

https://www.nature.com/articles/s41586-023-06866-z
(paywalled)

 

I think this is a puerile hyperbolic dramatised interpretation of observed mitochondrial activity.

Mitochondria have been symbiotic and more lately organelles of eukaryotes since well before the cambrian era, since some time in or before the paleoproterozoic era at least 2 billion years ago.

Evolution of protists is relatively fast, life cycles often measured in days if not hours, meaning hundreds of billions of generations worth of natural selection before you even get to mutlcellularity. If mitochondria were at war with their host cells their joint venture would soon be supplanted by better adjusted competitors.

In symbiosis as with multicellularity, cooperation is key. The activity of mitochondria should be viewed as having evolved under prevailing circumstances to be well harmonised with the evolutionary fate of the entire organism.

Dysregulation such as obesity is a result of changed conditions and anachronistic atavistic behaviours coupled to unhelpful balance of forms of nourishment. The rise in inflammatory disease likewise can be attributed in part to changes in our environment brought about by the partial success of the industrial revolution, not blamed on mitchondria.

However we should not view inflammatory health as originating in a garden of Eden either, where all was perfect and harmonious. Evolution is iterative trial and error and nature is reputedly red in tooth and claw, depending on your blood pigmentation and inflammation was always with us, shorter lifespans too. Much of it is a result of the battle between organisms, not so much between organelles and organism. That just sounds like a sensationalist misanalysis.

The causes of such problems are likely to lie outside the organism, the environmental context cannot safely be overlooked. That said we do need to understand how our organismal whole regulates itself in order to understand our maladies.

The opening of the mitochondrial cell pore is not rebellion, it is instigated at the cellular level by immunological control systems and is self sacrifice for the mitochondrion and leads to self sacrifice for the cell by releasing the ions notably calcium, which is sequestered in the mitochondrion.

Mitochondria are the powerhouse of the cell and opening the pore is pressing the self destruct button, because parasites have been detected and for the survival of the organism the parasite must not be allowed to feed on the powerhouse of cell metabolism and reproduce prolifically.

For the good of the whole, component cells must die. This is what multicellularity entails and when they die they must as a final act alert the rest of the body that there is a threat to the entire organism. That is not a breakdown of a relationship between organelles nor maladaptive as it evolved but where new interactions with pathogens and their products occur, inflammation can obviously become maladaptive until evolution sorts it out, the hard way (differential reproductory success).

The real cause of this modern malady is that our populations have become pools of pathogenicity. We live longer, thrive peacefully in urban proximity most of the time and travel all around the world on a yearly basis. As we age we harbour more and more of all the diseases humanity has ever known within our own bodies.

Today we survive in a state of immune overload whereas in the past our ancestors died before they were 30, which is why the knew diddly about diddly and their parasites died with them. They also didnt travel much lest they end up being sacrificed to other tribes' gods of fertility.

The solution to this is not depopulation by war, it is a new emphasis on hygiene, social distancing etc, a programme to eradicate these bugs and of course population management.

To return to the discussion of this article, the reproductory unit evolves, cells and organelles are subordinated to this reality. So organelle conflict is not an appropriate perspective or interpretation in this context. IMHO