Mitochondrial Rejuvenation and NIR

Rejuvenation of Mitochondria using Near Infra Red Light

Maybe I am just behind the times, but when my optician mails me with red-light treatment for my aging eyes (which will ‘stimulate and rejuvenate my mitochondria ) and in the same week a friend is having some one shining a red torch onto the backside of her horse, it is obviously time to do some internet searching.

What I found pretty quickly is that:

a) photobiomodulation therapy (PBM)  is everywhere and

b)  640nm LEDs are the cheap and easy reason for the ‘torches’ and variants on that theme

However, as my optician is no charlatan,  a bit more research was demanded which, after a long story, has resulted in me purchasing a 810nm high-powered LED complete with heat sink. Experiments will follow.

Below is ‘the story’ behind PBM and it’s very interesting.

Background:

1. Electrochemistry in mitochondria

The generation of chemical free energy by mitochondria is, broadly, in the form of the molecule ATP. ATP production depends on generating an electrochemical potential across a membrane and is mediated within that membrane by  a series of connected electron transporting proteins known as cytochromes.  The process is ultimately oxidative (hydrogen and oxygen combine to form water) and the cytochrome flash between oxidised and reduced forms as they play pass the parcel with an endless supply of electrons obtained from hydrogen.

2. Photochemistry of cytochromes

The clue as to their photo-sensitivity is in the ‘chrome’ part of their name. Light absorption is inevitable, as at their heart is the molecular ‘cage’ of a porphyrin ring which  embraces  a metal ion. This ion’s (usually copper) day job is to accept and release electrons thus becoming ‘reduced’ and ‘oxidised’ in turn. The ring’s structure though, being analogous to those molecules in plants which trap light for a living as part of the photosynthetic process means that light trapping is always ‘on the cards’/

It’s reasonable to assume then, that mitochondria’s photosensitivity is an atavistic legacy from a distant photosynthetic past inherited by their cytochrome structures. Even so, biology never lets an opportunity pass it by if it can be leveraged and scientists never let an opportunity pass that can be exploited!

Humans like most non-photosynthetic organisms are impermeable to light, but not all light.

The near infra-red penetrates skin well, it feels warm on the skin and carries on deeper into the tissues. This light can be seen as visible red light at the 600-700nm range becoming ‘dark’ by 800nm.

‘Bottom Line’

It has been long known and shown over and over, that mitochondria can and do absorb NIR light and that NIR can affect their activity either stimulating or inhibiting ATP production. And so onto its application and significance.

Red Light Therapy

‘Torches’ that emit red light at safe low levels at around 640nm ( the peak from standard IR LEDs) are routinely used as therapy to treat skin ailments and eyes. The theory goes that the mitochondria are stimulated, producing more ATP which promotes healing and performance ( rejuvenation). 

Naturally enough given their bogey-man status, the concomitant  increase in free radical production (ROS) is not mentioned, nor awkwardly, is the fact that some NIR wavelengths stimulate and other inhibit. 

Harder Science for practical application of NIR

NIR enhances mitochondrial activity by stimulating cytochrome c oxidase (COX) at 810nm. BUT it inhibits COX at 750nm and 950nm. 

I can find no such detailed data at red led’s 640nm. The absorption spectrum of COX shows that the stimulated oxidised form of its copper ion is at 670nm and 810nm. As a result I suspect  visible red light treatments may be less effective than ideal at when the main light source is at 640nm.

In any case, the conclusion is that the wavelength of NIR matters and that broad spectrum of wavelengths may cause inhibition as well as stimulation of mitochondria.

My interest rests at the 810nm absorbtion for which fortunately there is a powerful LED readily available. I have not carried out any experiments yet but the diode has arrived and works. 

What is the point of stimulating the mitochondria within say skin or eye tissue?

Retrograde signalling? 

In a previous blog I went into detail about mitochondrial control of ‘nuclear’ genes relevant to its own integrity. The mitochondrial response to NIR is another potential mechanism for signalling to the transcription factors in the nucleus. Firstly there are noted variations in the inner membrane’s electrical potential, secondly there is an associated production of nitric oxide and thirdly increased ROS production gas, all three are capable of communication with the nucleus. But what? if anything, they are talking about is a mystery.

Various theories exist as to environmental, natural responses to red light. Sunrise and sunset being cited as red-light rich cues. Dawn is proposed as a signal that a high UV session is coming. This seems fanciful and not persuasive. Another is that NIR stimulates  repair mechanisms. This is not so fanciful. The increased ROS production will cause mild inflammation signalling repair processes to increase. In this case ‘deep heat’ would be well served by sitting close to an open fire!.

The whole area of red-light therapy is fascinating and I am looking forward to trying it out. I am pretty sure that NIR at 810nm will stimulate mitochondria but what effect it will have and how deep is a question. Luckily I have my own sore muscles, joints and even an old horse to work on.

Covid, cholesterol and mitochondria

I will start this post with some one-line statements that are not controversial, simply collated recent published work from around the globe..:

In Covid infected patients showing an inflammatory response that led to hospitalisation, here are the following observations regarding mitochondria.:

• Mitochondrial DNA was present in plasma. This is known to trigger inflammation.
• Monocytes are found to have mitochondria that are depolarised and have altered morphology
•  In cells infected with Covid, oxidative respiration is low and anaerobic glycolysis predominates.
• Patients with severe infection may enter hospital with very low oxygen saturation but still be walking … a sign of glycolysis. Compromised lungs could not supply mitochondria with operational levels of oxygen even if the mitochondria were operational.
• Covid viral reproduction takes place within the mitochondria in a manner analogous to phage infection of bacteria

In Covid infected patients like those describe above the lipid profile ( lipidome) is affected as follows:

• Total lipids are reduced by infection. Increasing severity of infection maps to larger reductions.
• For patients that eventually do not survive, the decrease in lipid levels continues until death
• Patients entering treatment with low lipid levels at the start show markedly sharper fall in lipid levels than those with higher starting levels..
• The main lipids lowered by infection are cholesterol, LDL and HDL ... in that order.
• Lipid lowering medication is associated with weight gain and an increase in Type 2 diabetes (obesity and diabetes are associated with poor infection outcomes).
• Vitamin D deficiency is associated with severe symptoms (Vit D is synthesised from cholesterol).

• Use of lipid lowering drugs reached 49% in the over 80s by 2015.

I apologize for not citing the wide range of researchers in labs who have  produced these results within the past year but reading their papers is as interesting for the inter alia text other than the plain findings.

In the first set of results, the conclusion is rightly drawn that mitochondrial damage is very serious but it is hard to fathom a proposed therapy to mitigate it. One finding of low levels of CoQ10 elicited a suggestion that Q10 supplementation may help as it is a well known ‘go-between’ for anaerobic and aerobic respiration.  This is not surprising as few are proposing any mitochondrial ‘well being’ strategies currently

In the second set of results something sad is occurring. Manifestly the lowering of lipid levels is important in the progression of the disease but none of the authors could bring themselves to say that lipid lowering medication should be stopped, quite the opposite they state it should be continued!

This  is astonishing, and as I said above very sad. Clearly  medication used to lower cholesterol and LDL should be considered as something to stop in the light of the evidence above. 

The answer as to why not is I think as follows:

Many, maybe most people, who are capable of reasoning in the logical and rational sense along with those who are frankly not able to do so can fall back onto what is called ‘thematic reasoning’. A term, thirty years ago with which I was not familiar but was explained clearly by a politician ( whose name I don't recall) is the principal mode of thinking of the ‘voting public’. 

Thematic reasoning is simple; bad things cause bad things and vice versa. So for example in a survey on the causes of global warming ( a bad thing ) a random sample of the public were asked which of the following power generation systems caused global warming?  Gas fired power; coal fired power, nuclear power or wind power. Ans? Overwhelmingly the answer was ‘nuclear power’. Wrong of course but obvious in the thematic world, nuclear power is ‘bad’, global warming is bad and  ‘bad ‘causes ‘bad’.

And so it is with cholesterol. The ‘baddest’ of the bad in dietary terms. What lowers cholesterol? Statins, the life saving ‘good guys’ .  Nothing trumps the ‘badness’ of cholesterol in popular mythology and no-one dares challenge the ‘goodness’ of statin therapy.  

I think this must stop. 

Below is some abstracted material from my PhD thesis of forty years ago. We had a very rare colony of 300 rats that spanned the full life of a rat … 0 to 36 months. These colonies are long gone so some of our experiments will never be repeated. We worked on liver mitochondria.

I showed that the composition of the mitochondrion’s outer membrane reflected the levels of dietary cholesterol although as expected this did not occur for the inner membrane. 

In both old and young rat liver mitochondria cholesterol-enriched outer membranes produced less exogenous  Cytochrome C  under osmotic shock treatment than did untreated mitochondria. 

I had already shown that old mitochondria released more Cytochrome C than did young mitochondria and speculated that this was because the outer membrane was providing less of a barrier to the Cytochrome and /or that Cyt C was bound more weakly to the inner membrane.

In 1975 I was unaware that Cytochrome C was the mitochondrial signal to initiate the cascade of events leading to cell death or apoptosis as it is properly known.

 But to me now, and it has been so obvious for so many years, that low cholesterol levels risk compromising mitochondrial function by making the outer-membrane: 

a) leakier (risking apoptosis), 

b) less absorbent of free radicals (Increasing cellular damage).

So, if you have got this far, it will not be a surprise to anyone that I am convinced that cholesterol levels are important to mitochondrial health. Judging by the levels of current de-prescription of lipid lowering drugs in the over 75s, I am also convinced that the science community knows too.

update: December 2021

Below is a link to a mini-review on the relationship of Covid with mitochondria. It is worth reading.

Front. Pharmacol., 28 August 2020 | https://doi.org/10.3389/fphar.2020.578599

Mitochondria Targeted Viral Replication and Survival Strategies—Prospective on SARS-CoV-2

Priya Gatti, Hema Saranya Ilamathi, Kiran Todkar and Marc Germain1Groupe de Recherche en Signalisation Cellulaire and Département de Biologie, Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada

2Centre d’Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada

Covid 19 appears to actively target mitochondria and the parts of the smooth endoplasmic reticulum associated with the outer mitochondrial membrane. Like many cancer cells do, the virus down-regulates mitochondrial respiration and the cell-death cascade that mitochondria initiate to destroy malfunctioning cells.  

This tactic allows cancer cells to evade their destruction (which would be signalled by mitochondria) whilst having enough glycolytic energy to divide, and similarly viruses use the same tactic to buy time while they reproduce themselves. The phenomenon of 'living dead' walking into hospitals with incredibly low oxygen levels is clearly part of the story of deactivated mitochondria.

However, mitochondria are not silenced completely. A massive viral infection will set off a great amount of  mitochondrially-mediated cell death which can be seen in the massive sarcopenia in ICU Covid patients.

Once again mitochondria take centre stage and once again their well being is central.

The Pre-Cambrian Explosion: yes it was mitochondria 'wot' did it!

 

This post has taken a long time to gestate. It’s aim is to turn the idea of the mitochondrion as a symbiotic guest within the cell, a ‘slave’ under nuclear control, into the proposition that the mitochondrion is much, much more than a vestigial organism and may be the most successful genome ever to appear on this planet.

There is a huge amount to unpack from the paragraph above so I will break it down into its component stories.

Symbiont and ‘Guest’

It was in the 1960s that Lynn Margulis first proposed the idea that the organelles which possessed their own DNA were the descendants of once free living organisms. Both are energy transducing organelles; the chloroplast using light energy to split hydrogen from water and use it to build carbohydrate by reducing carbon dioxide; the mitochondrion conversely oxidised organic compounds ( carbohydrates and fats) to produce chemical energy in the form of ATP. 

The chloroplast and the mitochondrion have their own circular prokaryote-like DNA and the apparatus to transcribe and translate its code.Both are capable of replication, fusion and fission and both can senesce. In other words they look like many other bacteria-like organisms. Unfortunately it is obvious that in their DNA there is simply not enough genetic material to build a new organelle. Most of the genetic material for the building of these organelles is housed within the nucleus of the cell.

It is not a great step thereafter to propose that these organelles were once free living organisms that were ingested by chance into the host organism and have been taken over and fully integrated into the identity of their host organism. The host benefits from the ability of the organelles to generate free energy which is able to power the low entropy state that is a complex multicellular organism.

The host may have been itself once a large prokaryote- like phagocytic organism capable of metabolising the carbohydrates produced by ingested photosynthetic bacteria and so was bound to ingest the mitochondria which outside would have been oxidising hydrocarbon oily materials in their environment.

The paragraphs above briefly describe what is now, thanks to Margulis’ decades of argument, orthodoxy.

Why did mitochondria give up their DNA?

The answer is no one knows. It is easier to imagine ‘how’ since mitochondria and bacteria in general have circular plasmid DNA for which so called ‘horizontal transfer’, ie the passing of genetic material directly from one organism to another is the norm rather than the exception. But ‘why’ or even ‘when’ is a matter of speculation.

The answer may lie in the nature of the modern mitochondrion. It is capable of astonishing energy output in the form of ATP and Hydrogen ( in the form of reduced forms of NAD+ and FAD). It comes at a high price. Imagine a fast sports engine running at  red-line revs 24/7 spitting out bullets in all directions. Mitochondria are like this in the sense that at full power oxidative-phosphorylation, as it is called, spits out immense numbers of damaging free radicals. The cell’s cytoplasm contains a lot of resources for catching and dealing with these radicals, using anti-oxidants and specialised enzymes, not to mention the repair of anything that got in the way of a stray bullet. So imagine the potential damage to an internal genome, especially a large, naked and complex genome. Free living bacteria could not operate at this level of energy output as their genomes would soon be wrecked.

Mitochondria found themselves inside a cell which was living on carbohydrates, probably produced by ingested photosynthetic organisms. The biochemistry of glycolysis to metabolise these carbohydrates means that  the waste end products are acetyl units, or in other words simple pre-digested food for mitochondria.

. The end result would be  potentially  overfed, over stimulated  mitochondria.

If the new guests were to be able to ramp up energy output as above , their DNA would have to be shielded. So why not put the important bits of its genome somewhere safe? Behind a double membrane and coated with protein would be ideal.

The nucleus as a store room.

One of ideas with many adherents about the mysterious origin of the nucleus is that it was once basically a lysosomal-like storage zone for intrusive viral and bacterial DNA/RNA. A bag of alien junk genes safely stored behind a double membrane wall. This model would suit the mitochondrion ‘outsourcing’  its genes to a place where they won’t get wrecked by its supercharged metabolism. 

Conventionally, however this happened, the nucleus today controls the synthesis, repair and replication of mitochondria from a ‘central command’ model of the nucleus. However it is hard to imagine this being possible at the beginning. How would mitochondria reproduce and repair before the command and control nuclear model if their genes were locked away inside? Maybe gene transfer did not take place until the modern nucleus was up and running but if so how could mitochondrial DNA survive inside the high powered organelle? Possibly those chimeric cells that had increasing amounts of shielded mitochondrial DNA survived and vice versa.

One thing for sure, genes were transferred as mitochondria became hyper- energetic.

Retrograde signalling.

Recent developments have highlighted the fact that mitochondria and chloroplasts do not sit dumbly around awaiting orders from the nucleus. They have a complex signalling process that can ‘order up’ protein synthesis from the nuclear genes relevant to  themselves and to the needs of the wider cellular environment. They act as sensors for the intracellular world,

But the use of the word ‘sensors’ implies a subservient role and I would rather like to think of them being ‘sensitive’ to their environment. The reasons for this are in the following paragraphs.

The presence of retrograde signaling mechanisms, as yet only barely elucidated, means that in the past mitochondria could, using such signalling systems, potentially ‘outsource’ their DNA and still make use of it … safely stored in the proto-nucleus.

Grim reapers.

We have long been used to the idea of mitochondria initiating cell death.This is known as apoptosis. It occurs when mitochondria are badly damaged or senesce. Senescence is normal for mitochondria in aged post-mitotic cells. Failing or unused cells are destroyed by a chain reaction initiated by mitochondria leaking a  redox protein called Cytochrome C.

Mitochondria become leakier with age but will appear as a rejuvenated population if the cell undergoes mitosis, even in aged animals.

Mitochondria determine whether a cell lives or dies. But what about whether it reproduces?

Mitochondria and cell division.

Cell division requires a lot of energy. This is because there is a large decrease in the thermodynamic concept called entropy. Entropy can be driven in the negative direction with so-called Free Energy. Mitochondria provide 7.2 kj of Free Energy per molecule of ATP they produce.

It comes as no surprise that during cell division, scanning electron microscopy shows clearly that a large part of the  population of mitochondria has fused to form a network  of reticulate mitochondria seemingly bonded to the outer surface of the nucleus. The obvious inference is that a lot of energy is being supplied to drive the complex process of reproduction.

From a mitochondrial point of view,  the reproduction of a cell presses a reset button for the mitochondrial population … and so is a good thing from their point of view.

A new perspective.

All of the above is pretty mainstream stuff and not the source of hot debate. What I would like to do is to change how we view mitochondria. To me they are not slaves to act merely as producers of free energy and to act as environmental sensors for the mission control centre which is the mighty nucleus. To me mitochondria are still free-living and reproducing their genetic material in a world that is the eukaryotic cytoplasm. 

From a selfish-gene perspective mitochondria have distributed their genes throughout the entire biosphere of plants and animals. Cells without mitochondria are almost non-existent and certainly could not participate in the energy hungry multicellular world. And so the basic genetic building plan for mitochondria could be regarded as the most successful gene-machine of all time.

But there is  the small matter of the bewildering diversity of the multicellular world Mitochondria could not be responsible for this? No, not directly, but indirectly they certainly could. If in some imagined past there were mitochondria living in a host and they had outsourced their genes to the bag of DNA described earlier. Inevitably when powering-up their own cell division there would be unintended recipients within the store of DNA postulated as the proto-nucleus. Bizarre and unpredictable results of countless explosive forms would emerge to be nurtured or eliminated by natural selection. Eventually things would settle down and the pre-cambrian explosion 540 million years ago would fade into history.

There we have it, the ultimate mito-centric world. Not so much a useful passenger symbiont handily providing energy in an oxygen rich world, more a fundamental driver of multicelluar life as a result of it own genes’  ‘desire’ to survive

Mitochondrial DNA is no longer ‘stand-alone’ DNA. Xenobiotic transfer of mitochondria is possible between closely related species but it falls away with ‘genetic distance’. For example all of the mitochondrial DNA recovered from late Neanderthals is actually Homo Sapiens mtDNA, gorilla mtDNA will work in Chimp but embryos do not develop and so on.

This story is a classic ‘chicken and egg’ story for today the nucleus and mitochondria are intimately integrated. 

How that journey proceeded is unknown. But one thing's for sure, mitochondria were centre stage and still are:

Here is a potential timeline::

4 billion years ago = the start of life?

3.7 billion years ago. First photosynthetic life  Energy capture and transduction on the surface begins

2.7 billion years ago archea develop actin proteins and phagocytosis starts. Heterotrophic life begins

2.3 billion years ago  Cyanobacteria’s oxygen changes atmosphere, oils and carbohydrates accumulate

2.3 billion years ago free living proto-mitochondria oxidising hydrocarbons

600 million years ago chimeric cell  starts to ‘power-up’ mitochondria use endogenous acetyl groups and outsource genes to proto-nucleus Massive increase in transduction of energy originating from light

540  million years ago Cambrian explosion of extraordinary multicellular diversity. 

440 million years ago the first mass extinction.

 

Mitochondria and retrograde signalling ... mitos rule ok?

 Mitochondria rule the cell.

Are we humans merely the extended phenotype of a bacterium?

Introduction:

After nearly forty years I have re-read Richard Dawkins’ 1982 book ‘The Extended Phenotype’. The academically detailed sequel to ‘The Selfish Gene’ of 1976 is  for professional biologists really and, for those that have not ploughed through the arguments therein,  it makes the case once again for the ‘gene’ being the replicating ‘unit’ that is acted upon by natural selection. But there is a twist. The outward physical expression of a gene, or rather the collection of genes is the classic so-called  phenotype. A bird is a  bird with a beak and so on but he extends the idea beyond appearance to the products of the organism. An abstraction that extends the phenotype to the ‘works’ of the organism. So a bird’s nest is part of the extended phenotype. In the same way our AI systems would be part of our extended phenotypes as much as our behaviours and building.

Dawkins’ ideas  have survived and replicated just like one of his memes and is gaining currency again. For example in popular science reading this is well exemplified in ‘The Entangled Life’ by Merlin Sheldrake. To cut a very tangled long story short, the once sacrosanct idea of organisms as individuals, ‘them and us’ is melting away as the interconnectedness of all life is becoming more apparent, understood and elucidated. So, maybe now is the time to look  at the extended phenotype and the dissolving individualism of the organism together in a new, mitochondrial, context.

Mitochondria (and Chloroplast)s … rather special organelles.

As usual, these posts are about mitochondria and my drift has been towards what I shall call ‘intracellular ecology’. I may have invented this term  but I doubt it. Mitochondria and their plant counterparts chloroplasts are accepted today as ex-free-living  bacteria-like organisms that came to be part of the modern eukaryotic cell by some ancient happenstance probably involving phagocytosis by a larger prokaryote.

Although mitochondria and chloroplasts are able to replicate within the cell their small circular DNA is regarded as pretty much vestigial. It has few genes and limited internal apparatus for the synthesis of proteins and certainly not enough to build a replica of themselves. Nearly everything is carried out by genes found in the nucleus and its proteins are synthesised in the cytoplasm. Given these facts I always feel a sense of disappointment. It’s as if my beloved organelles ‘sold out’, and are now enslaved by a vast nuclear arsenal of genes, doing their work powering the cell and providing enough surplus energy to power multicellular evolution.

Maybe I was wrong, they didn’t get taken over.. We already know mitochondria have the power of life and death of a cell through the process called apoptosis. When a mitochondrion depolarises and starts to leak Cytochrome C, a cell is doomed. This is a big ‘responsibility’. Why cannot the nucleus take care of monitoring the cell’s health and initiate the process of apoptosis?

The answer, maybe, is that there is but one ‘organism’ and it’s inside the cell, the mitochondrion. The rest of the cell is ‘the environment’ … from its perspective. And it’s this unit of life which today is still exploiting its ancient ecosystem.

The question is quickly begged as if this is so, then why do mitochondria have such vestigial DNA, so little that they are such a long way from self-sufficient, let alone qualifying as a traditional organism.

But, what if mitochondria ( and chloroplasts ) have simply outsourced their genes to the nucleus?

The analogy with a first world power outsourcing its basic production facilities and data storage to other countries is obvious. No one expects the UK or even the US to be self-sufficient. So is that what mitochondria do?

Support to this idea is given by the discovery and exploration of so-called ‘retrograde signalling’. Here is an extract by Wang in 2020* to give a flavour of the work.

‘The biochemical, cellular and physiological reasons why mitochondrial and chloroplast retrograde signalling may be linked at several levels are worth considering. Organelle retrograde signalling provides feedback to anterograde signals that alters gene expression encoding proteins located in a variety of locations in the cell. Thus, chloroplasts and mitochondria have emerged as environmental sensors to ensure that the pipeline from gene expression to protein function is optimized relative to organelle function.’

‘Retrograde signalling’ Essentially this phrase, though cryptic,  is well described above.

Signalling is the same as ‘outsourcing’. Mitochondria may have simply outsourced their genes whilst retaining control of their new intracellular world. Dawkins’ extended phenotype notions would be entirely comfortable with this scenario.  Put simply mitochondria can ‘message’ the nuclear DNA store and get manufactured what they need when they need.

This may, ironically, be a good strategy for actually preserving mitochondrial genes. Inside the mitochondrion is a ferment of deadly free radicals spewed from the process of oxidative phosphorylation which provides the vast amount of energy consumed by eukaryote cells. So it would make sense for a gene to be stored somewhere safer to do its replication courtesy of energy provided by the ‘mothership’.

As an aside, I think, as do others, that back in the mists of time the ‘nucleus’ was a mere bag of junk DNA, probably viral in origin, and parcelled up somewhere where it could do no harm. So called horizontal transfer of plasmid DNA is normal in the prokaryote world and this store would be a good place to keep DNA away from damage. It would need to be supplied with energy and a signalling system that’s all.

The non-mitochondrial genes in the bag were then the accidental beneficiaries of the enormous supply of energy from the mitochondria and their own replication journey took off. You cannot help but think this when you see a nucleus undergoing division today literally wrapped in a reticulate net of fused tubular mitochondria. Replication requires energy.

An unparalleled source of energy and a bucket of random genes would be a great precursor for and explosion of forms, random, mad, hopeless but some ultimately successful.

Finally.

If the constructs of humans, physical or mimetic or computational can be  regarded as part of man’s extended phenotype and that the organism’ man’ is the extended phenotype of his genetic replicators. 

Then it is perfectly ok to regard an organism as the extended phenotype of a humble prokaryote! 

What a journey. From the cell’s batteries to their master. Long live retrograde signalling

 

*Philos Trans R Soc Lond B Biol Sci. 2020 Jun 22; 375(1801): 20190410.

Published online 2020 May 4. doi: 10.1098/rstb.2019.0410Linking mitochondrial and chloroplast retrograde signalling in plants