Mitochondria, immunity and Covid

 Mitochondria, immunity  and Covid

Just when I was thinking posts about mitochondria had dried up along comes a really intriguing finding. This intriguing finding concerned the effects of the Covid 19 Astrazenica vaccine and was published this January by Trinity College Dublin1.. In the Republic of Ireland AZ’s DNA vaccines were dropped in favour of the mRNA vaccines from Moderna and Pfizer due to the concerns raised about adverse responses to the vaccine amongst the young. TCD’s findings however have shown that recipients of the AZ DNA vaccine are showing long-term increased immunity to a wide range of so called ‘non-target’ pathogens. 

I picked up on this publication as anecdotally my wife and I ( both AZ recipients) had been puzzled by our lack of infections through the past two winters. Nothing, not a cold nor a sore throat. We would get the initial symptoms of various infections many times only to find six hours later they were gone. Repeatedly we had remarked on this oddity. 

Anyway, it turns out that it is all due to the innate immune system. I confess I was hazy on the very existence of a separate immune system to what I now know is the adaptive immune system. It also transpires that the training of the innate system is all the rage today. The innate immune system is very ancient and is a multifactorial defence against ‘non-self’ invaders found in most living creatures from insects to fungi. 

Our innate immune system, simplified, revolves around large white blood cells called monocytes. These are short lived cells capable of destroying bacteria and virus-filled infected cells by phagocytosis, in other words by eating them. They are also able to participate in so-called cross-talk communications with other parts of the immune system via the cytokine signalling network. The innate immune system has a good memory, possibly even inheritable. The monocytes are short-lived and it is supposed that the memory ( created by epigenetic modification of DNA) resides in the progenitor cells. These cells are similar to and derived from stem cells but can only give rise to one type of cell, in this case monocytes.

It gets very interesting when looking at the training of the innate system. In this context training means activating it to be on the alert for pathogenic changes such as bacteria or cancer-transformed cells. Regarding vaccination, the BCG vaccination and the Astrazenica vaccination have a training effect. The work on AZ is new but the off-target health benefits of BCG have been well known for many years. 

It is the simple molecules that activate the system, namely  beta-glycans (sugary molecules found in cereals) fumarate ( a TCA cycle intermediate) and squalene as from extra-virgin olive oils (EVO), from shark oil and now famously found in vaccine adjuvants.

At last this is where the mitochondria come in! Trained monocytes have, more, larger mitochondria with many cristae, high membrane potentials, multiple inter-mitochondrial fusions and higher ox-phos ratios than in non trained monocytes. Together these factors point to a powered up cell with deep reserves of energy.

Of the training agents, fumarate will stimulate mitochondrial TCA activity and so generate energy via the membrane electrical energy and squalene is a precursor of cholesterol which in turn is essential for the electrical integrity needed for the high inner membrane potentials and an effective free radical shield provided by the outer membrane. 

So, here we go again, chicken v egg. Trained immunity is dependent on mitochondrial performance because  training factors directly affect mitochondria: mitochondria are the watchdogs of cell health. 

Why? Because the cell is their home.

1. https://www.tcd.ie/news_events/articles/2023/research-indicates-wider-benefits-to-astrazeneca-vaccine/**

2. https://www.frontiersin.org/articles/10.3389/fimmu.2020.01715/full

The Mitochondrial Hegemony

 

Mitochondrial Hegemony

More on a mitocentric view of life.

A recent publication ¹ has shown that in the development of Parkinson’s Disease (PK), mitochondria switch to a situation where their substrate or ‘feedstock’ is from fatty acids rather than from  normal metabolism of glucose. 

This may sound esoterically biochemical and just a specific example from a particular disease, but it is of great significance. To me, it is another example of mitochondria ‘deciding’ the fate of cells. But this last sentence requires elucidation because it has been well known for many years that cell death, surely the ultimate example of a cell’s fate,  is initiated by mitochondria. 

Specifically, cell death is started by electrical depolarization of mitochondria followed by a release of the weakly-bound protein Cytochrome C from the inner mitochondrial membrane through the outer membrane which in turn sets off a cascade of reactions leading to cell death.

So what is significant about the first example which is observed in Parkinson’s disease?

What I want to posit is another shift in the 50yr scientific  journey of mitochondria from a mere structure, an organelle so called,  which is specialised in chemical energy transduction thence to modern orthodoxy (where it is now a symbiont) derived from free-living bacterial-like origins and living in subordinate partnership with its nucleated host cell. 

The next shift is to see the mitochondrion in a much more powerful role. A role which puts mitochondria at the very centre of life. Simply put, the mitochondria are ‘in charge’ of the cell not vice-versa. The mitochondria are living in a cellular ecosystem which they are able to reproduce into large trillion-cell organisms. 

 

A few supporting facts

Mitochondria provide the free-energy to maintain the low-entropy situation of a multicellular organism.

Multicellular undifferentiated clumps are possible without mitochondria². Typically as an example cancer-tumours have disabled their mitochondria (to prevent them initiating the cell death switch) but without the vast amounts of energy supplied by mitochondria the structure of the tumour is almost non existent and supplies of nutrients and disposing of waste prevents any viability outside host-victim.

Mitochondria have a fully functioning genome³

Few mitochondrial genes reside in the bacteria-like circular DNA within the mitochondria itself. What is there is highly redundant ( many gene copies ) which is unsurprising as mitochondria are in effect free-radical furnaces and gene damage highly likely. Most mitochondrial genes are to be found now in the relative safety of the host cell’s nucleus where it is tended and repaired but more importantly it is communicated with via a process called retrograde signalling. In other words mitochondria have outsourced their genetic information: stored it in the ‘cloud’ to use a modern analogy.

Mitochondrial energy-transduction biochemistry is ‘kludged*’ with its host’s energy -transduction biochemistry

The title above needs a fair amount of unpicking to make sense but can be appreciated maybe through an imaginative narrative well described nowadays and beautifully fleshed out in Wikipedia⁴:

Imagine free-living mitochondria emerging in a world that is becoming oxygen-rich as a result of photosynthetic activity. Imagine also vast pools of oil-like hydrocarbons resulting from decaying photosynthetic organisms. 

Mitochondria  fully oxidise a chemical we call acetyl. Essentially, acetyl consists of two carbon, three hydrogen and one oxygen atom. 

In my imaginary scene mitochondria are getting acetyl from free fatty acids (oily stuff) basically by chopping off two carbons at a time and hydrating them ( adding water) using a very complicated enzyme complex found on their inner membrane. They can still do this today and is coincidently described in the first paragraph of this essay.

Now imagine a bacteria-sized mitochondrion having been engulfed by a primitive, hunting amoebic-like cell … finding itself in paradise and being fed abundant acetyl, gratis! 

This is exactly what happens today. The ancient biochemistry we call glycolysis essentially takes sugars whose basic unit comprises six carbons and breaks them down to two, two-carbon units releasing a modest amount of free energy. Acetyl units for free.

The imaginary host cell above uses glycolysis to partly metabolise sugars without oxygen and the captured mitochondrion laps it up. Free food is rapidly fully oxidised to carbon dioxide and water and a powerhouse chimera is born. Over and over again and at some point the chimera persists and multiplies.

But, back to the title of this section, we have two alien biochemistries which are getting along fine but still have a long way to achieve glitch-free integration. My contention is that millions of years later with thousands of evolutionary modifications the junction between the two biochemistry has all the hallmarks of a kludge and should be seen as such and we often feel its effects even today.

 

To sumarise. What is this chimera? Is it a partnership of equals? Does one party dominate the other? Are ‘we-multicells’  just ‘Matrix-like’ hosts to the dominance of the mitochondria?

From a Dawkins’ selfish-gene perspective, for genes it is a win-win whatever your origin and as such a pointless distinction is being made. But from a physiological-health and longevity of organisms, ie ‘us’ the relationship between mitochondria and host does matter. 

Examples, just three of many relationships that matter:

For:  in the Parkinson’s example at the start of this article why has the junction failed, why have the mitochondria reverted to fat metabolism? 

Or; when we age we get fat disproportionately from sugar consumption as mitochondria fail to metabolise the acetyls and they are stored as fat

Or finally, during viral infection  whether oncogenic or simply a pathogen like Covid 19, mitochondria are in the front line destroying cells before they themselves are switched off.

By adopting a mitocentric view of life we may begin to see connections and causes overlooked in the past.

*kludge: an ill-assorted collection of parts assembled to fulfil a particular purpose.

1.    https://www.ebi.ac.uk/metabolights/MTBLS2266/descriptors

2.    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950268/#:~:text=Mitochondrial%20dysfunction%20induced%20by%20somatic,might%20contribute%20to%20cancer%20progression.

3.    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468901/#:~:text='%20Mitochondrial%20retrograde%20signalling%20is%20a,survival%2C%20drug%20resistance%20and%20metastasis.

4.    https://en.wikipedia.org/wiki/Symbiogenesis

5.    Biosystems. 2013 Jan; 111(1): 1–10.

 

Post script August 2024

During a person's lifetime, evidence has emerged that mitochondria insert their DNA in small blocks into the cell's nuclear DNA. This occurence has been discoverd in post mortem studies on the pre-frontal cortex of human brains. The insertions occur multiple times over a lifetime but occured more often in cadarvers that died at a younger age ... and vice versa.

No mechanism for early death has been put forward. But in the context of this article it is fun to speculate that the mitochondria 'sense' something in their cellular world is amiss, likely affecting their own health and are attempting to put something right.

Malfunctioning mitochondria will generate more free radicles and may hasten cell death as a result. What are the mitochondria signalling and why?

https://www.cuimc.columbia.edu/news/mitochondria-are-flinging-their-dna-our-brain-cells#:~:text=Their%20analysis%20showed%20that%20nuclear,than%20individuals%20with%20fewer%20NUMTs.

Dietary Cholesterol, a must.

 I have always been really puzzled by a dietary paradox. These are the undisputed  findings that foods either high in cholesterol or highly cholesterogenic are associated with good health in old age especially with regard to cognitive decline.

I repeat these findings are not in dispute. Foods highest in cholesterol are exemplified by  oily fish and seafood. It is difficult to find a voice dissenting from the health benefits of regularly eating these foods. Usually, despite there being no evidence to support it Omega-3 lipids are given the credit for the health plus.

Cholestero-genic foods, that is foods that have an ingredient that is readily and simply converted to cholesterol, are extra-virgin olive oil and fungi such as mushrooms of various types. The cholestero-genic ingredient in the former is squalene and in the latter, ergothionine.

Squalene is in highest concentrations in shark and ray oils so consumed mostly in the Japanese cultures. Squalene by the way is also the mysterious black-art ingredient of big-pharma’s vital vaccine adjuvants. Ergothionene is an antioxidant and so is given a ‘health plus’ press because of the assumption ( false at worst, unproven at best ) that anti-oxidants in the diet are good for you.

So why are these foods good for you? It is easy to explain why their cholesterol profile is not mentioned because anyone not branding  the ‘c’ word as the devil is an apostate by definition. I think dietary intake of cholesterol has now been rehabilitated since it is known to have little/no effect of serum levels of cholesterol, however it is a struggle to find a magic ingredient to explain the foods’ benefits.

The more you obtain cholesterol via the diet the less is made by the liver and vice-versa The liver can synthesize all or very nearly all the cholesterol required by the body and set it in any form from low to high density lipoprotein droplets (VHDL, HDLl ‘good cholesterol’, LDL ‘bad cholesterol’). 

Cholesterol is obviously and immediately  essential or there would be no such fall-back mechanism. I did read long ago that lab-monitored cholesterol-free diets, as in totally free had a bad effect on the trialists, but this is just a memory now, I cannot find it. I also cannot find whether the liver can make 100% of requirements or not.

The liver’s cholesterol from scratch bio-synthetic pathway is quite complex and energetically expensive starting from a simple two carbon molecule joined to a coenzyme called acetyl-coA. This molecule is the principle feed-stock for mitochondrial energetics in the production of ATP as well as being the building block of fat.

The pathway is very important at the complicated end of the pathway nearer the final steps to cholesterol as it branches and twines  into sterol based hormones or, at the very, end vitamin D which is made from cholesterol.

The ergothionines and squalenes are at the more complicated end and need little work to complete their sterol final destination.

IS requiring the liver to synthesize cholesterol a bad-thing? My guess is that it is.

Either the ‘good for you diets’ possess as yet unidentified ingredients that are ‘good’ or synergistic combinations common to animals, plants and fungi. Or, quite simply having to make your own cholesterol while possible is a bad thing.

Maybe the pathway being dedicated to cholesterol reduces energy available to mitochondria, maybe hormone production is unbalanced, maybe it damages the liver, maybe all sorts of things but I think this is where to look.

Cholesterol in the diet is good for you. Heresy for a while longer.

Ageing of Smooth Muscle 2

 

Introduction

Smooth muscle is the muscle that is found lining our hollow organs. That is to say, our intestines, bladder, blood vessels, uterus ( if applicable). It is also the muscle that closes sphincters (entry-exit to and from stomach, anus, urethra) and in the eye operates our iris and focuses the lens.

Smooth muscle, like cardiac muscle is not under our direct nervous control (as is skeletal muscle), it’s actions are, for the most part, autonomous and we are either unaware of its action (except during childbirth or intestinal or renal colic) Smooth muscle is also very strong, gramme for gramme when compared to skeletal muscle. Smooth muscle cells have mitochondria as do skeletal and cardiac muscle cells, and cell-death occurs in all these tissues using the same mechanisms.

Smooth muscle is not studied in any way comparable to skeletal or cardiac muscle but what has been carried out on the physiological and biochemical level does not suggest any fundamental difference in the tissues on the sub-morphological-histological level. It follows that it is reasonable to propose that smooth muscle will age as both cardiac and skeletal muscle ages.

It is also reasonable to propose that smooth muscle will be adaptive in a way analogous to hear and skeletal muscle. By this I mean that smooth muscle should respond to physiological demand in an adaptive sense, ie it can be conditioned, improved, by reasonable demand and use... ie exercised.

In old age a phenomenon with skeletal muscle called sarcopenia occurs when muscle mass is lost as mitochondria 'decommission’ old cells. This happens for a variety of reasons. The cells may be damaged or simply unused and have been marked ‘parked’ and have not been used for a long time, maybe due to illness, starvation or incapacitation.

For skeletal muscle we know that regular exercise, especially load bearing exercise, coupled with a good diet mitigates early sarcopenia. For skeletal muscle the 'use it or lose it' principle applies as old age encroaches. Cardiomyopathy does not exhibit sarcopenia with age but instead shows a thicken of non-functional muscle in the heart's cell walls. Again though physical activity benefits heart muscle seemingly through improving its uptake of oxygen and reducing stress hormones. In both cases the point is that these muscles respond to stressors* in a good way and adapt and condition as a result.

It seems, to repeat myself, unlikely to say the least, that smooth muscle cannot also be conditioned and de-conditioned through its physiological activity in respect to physical challenges.

The De-conditioning life-style

Let's take smooth muscle function tissue by tissue choosing four major groups..

1) Eyes. Pupil dilation and lens focus are controlled by the iris sphincter muscle and the lens' ciliary muscle, both are smooth muscles and not under our conscious control. A modern office worker will typically experience only regulated artifical light which will be similar if slighly less at home. In both cases the ambient light will be unchanging. In term of focal distance 'Work' and leisure today is heavily concentrated on screen focal distances be it phone, computer or TV. In other words these muscles are not called upon to do much work.

2) Guts. Motion through the gut and retention within the gut are carried out by smooth muscle. Three sphincters seal off the gut into compartments. Two enclose the stomach sealing it off while its muscles churn and emusifies food in a highly acidic environment. The third, the anal sphincter prevents waste from digestion being evacuated inconvenienty before water has been recalimed into the body. A 'mexican wave' of smooth muscle contraction known as peristalsis, moves liquids and semi-liquids and solids through the gut. De-conditioning these muscles is easy. Simpy put, food ingested approximates to pre-mastcated, pre-digested baby food. This is pretty much a description of many modern diets.

For example, a burger pattie is the norm today as the primary intake of meat. A pattie is basically macerated and emulsified meat and fat, saving the stomach substantial amounts of work. Carbohydrate intake is biased away from high fibre complex carbohydrates to oligosacharrides and simple sugars, again saving the gut work. Fat intake is overwhelmingly in what is termed 'hidden fat' rather than solid fat, obviating the need for active emulsfication by the gut's muscles.The modern gut has little to do when comapared to a hunter-gatherers gut.

Finally sphincters! Reflux and incontinence are common afflictions of age. These imperfectly closed and easily overhwelmed valves also need conditioning to retain their power in old age.

3) Lungs. Lungs have delicate envelopes of smooth muscle, they are inflated as a result of the lifting of the rib cage causing a reduction in pressure allowing air to enter the lungs. Positive pressures will damage the lung. Normal breathing is what is called 'tidal'. Only a small amount of air is ventilated when sedentary or even walking. The point is, deep breathing is reserved to hard exercsie or deliberate full inhalation. Sedentary workers do not make demands on the lungs smooth muscle.

4) Arteries. Arteries have muscular walls to their vessels. Major arteries such as the aorta have thick powerful layers of smooth muscle. Heavy work such as lifting objects increase blood pressure. It does so transiently but for instance it is not uncommon fo weightlifters to develop arterial pressures in excess of 400mmHg. Modern medicine and lifestyle works hard to maintain a near constant ideal blood pressure of 120/80mmHg ( systolic/diastolic) or even lower. NIR (near infra red light) causes apoptosis of vascular smooth muscle cells. This appears to be a good and a bad thing. Remodelling of blood vessels littered with quiescent ( unused ) smooth muscle cells benefit from a clear-out and remodelling. However for diseased vessels and atherosclerotic vessels there can be adverse effects including plaque rupture. 

Discussion

I think that the assertion that smooth muscle in modern urban man/woman is given a lot less work to do as a result of a carefully controlled environment and life style.

The question is does it matter? To answer this question we can look at some of the age-related woes that beset the examples above. All examples given will be multi-factorial, that is they cannot be attributed to smooth muscle alone even so it's worth a quick canter through some common disorders.

Night-vision acomodation slows with age; time to focus at distance increases; constipation or IBS increases with age; sphincters lose effectiveness as in acid reflux and incontinence;lung capacity, and shortness of breath are typical as we age; arteries bulge with aneurisms and even rupture.

On the flip side is there any suggestion that placing demands on smooth muscle ( in the Goldilocks zone) has a beneficial effect?

For eyes, I can only think of advice given to heavy screen time users to get away from screen and re-focus every twenty minutes; for guts we have the proposed benefits of fibrous food, whole foods and good fecal-biome; for lungs deep breathing exercises are highly recommended and finally for arteries resistance training is very popular.

Of course in the above list of 'good for you' we do not expect to see 'good for your smooth muscles' but indeed all of them would exercise just those muscles.

It's time for a new set of health guidlines, 'Look after your smooth muscle' Below is a program of 'exercise'forsmooth muscle health.

1) Daylight for eyes

2) Fibrous and raw food ( eg vegetables, mushrooms, whole meat, beans, pulses) for guts

3) Resistance work ( weights ) for arteries and sphincters.

4) Aerobic exercise for lungs

5) NIR light ( dawn and dusk light ) for vascular health

 

*As an aside it is important to point out that such stressors as exercise need to be 'not too much and not too little' ie they are in the Goldilocks Zone.

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.