Biochemistry Saves the World (again)

 

No-one can fail to be impressed by the development of

the mRNA technologies that have led to the successful production of

novel and effective vaccines against the Covid 19 corona-virus.

Undoubtedly, in the near future, controlled and directed protein synthesis

technologies will be employed in thousands of novel treatments

at the molecular level.

It all has happened because biochemists across the world had the skill, will and near unlimited funds to achieve a clear goal in record time. Such projects are a rarity. The Manhattan project to develop the ‘atom bomb’ and the space project landing men on the moon are the only two that come to mind. What has become clear to the world is equivalent technological power now wielded by biochemists in the world of molecular biology. 

All of the above having been said, do we have another pressing issue of the above kind?

Yes, of course we have the climate change threat and so the global project to ‘decarbonise’ our energy consumption is coming into focus. The question is, can the biochemists do it again?

Tucked away in the corners of research are the plant biochemists. Tucked away within this group are the plant bio-energeticists. Those scientists who study photosynthesis, the process by which green plants capture and transform the energy from sunlight by splitting water into hydrogen and oxygen. Oxygen is a waste product of plants but the hydrogen is used to generate the universal electrochemical potentials that power the processes that build all life.

Hold on, hydrogen, isn’t that the combustible gas that produces only water as a waste product? For over a century now biochemists have dreamed of harnessing the biochemical splitting of water on this very wet planet to provide a clean limitless fuel. It turns out to be tricky, but this is a new world with massive powerful bio-technologies. How far have our underfunded band progressed.?

I love the hydrogen-based technologies. Firstly you can burn the stuff so the internal combustion engine, so exquisitely engineered over so many years, remains a central technology. Secondly, via the fuel cell, hydrogen can make electricity directly and has done so for a hundred years, Thirdly it can be stored in tanks. What’s not to love?

A quick scan of the literature shows some emerging technologies for making hydrogen using photosynthetic mechanisms. 

‘Hybrid bio-photo-electro-chemical cells for solar water splitting’ is a title in Nature Communications from 2016. The paper illustrates the central problems in a nutshell:

1. Good science, small time funding

2. We depend on plants for food.

The latter point is the one that be-devils all bio-fuel projects. You need space to grow plants for bio-fuel and to. grow plants to eat. Who wins on a small planet with lots of people?

However it is clear that their plant-chemical hybrid works thanks to the amazing in-leaf modular apparatus known as the thylakoid stack which they isolate and hybridise with conventional chemical metal catalysts. It yields hydrogen.

In the paragraph above though is the holy grail, the so called thylakoid stack. These complex structures are isolated from chloroplasts in which they are found. Chloroplasts are found in leaves and so to scale the technology you need lots of leaves. Fortunately mostly in food sources we don't eat the leaves generally but in the big leafy crops we do. It's a step forward though from the ethanol-corn biofuel technologies though.

But what if you could make thylakoid stacks or their analogues?

Scroll forward to 2019 and move to China. ‘Artificial Thylakoid for the Coordinated Photoenzymatic Reduction of Carbon Dioxide’. And so on ..

I think the picture is clear whether or not you are a plant bio-energetics wonk. Minds are turning to photosynthesis as molecular technologies advance.

Imagine if the power of the molecular biologists and biochemists currently in pharma got the funding for this kind of green-startup?

I for one know that they could de-carbonise this planet. A Great Project = the will, the brains, the money and the goal.

Just don’t leave it too late.

Mitochondrial cholesterol: the shield is up

 Cholesterol, the noble fat’s self-sacrificial role in intracellular ecology....

or ...what is the point(s) of the outer mitochondrial membrane?

The mitochondrial outer membrane was, not so long ago, regarded as a vestigial relatively simple ‘candy-wrapper’ for the immensely folded, complex protein rich inner membrane which did all the heavy lifting for the complete oxidation of foodstuffs. The respiratory chain resides on the inner membrane and the chemiosmotic synthesis of ATP is now the hated stuff of undergraduate biochemistry. 

Today though, the outer membrane which resembles the other bounding membranes in the cell, is seen to have a literally a life or death role in the cell. The death of a cell is brought about swiftly when the outer membrane becomes permeable to Cytochrome C which itself is only lightly bound to the inner membrane. By the way, I showed forty years ago that in mitochondria from senescent rats Cytochrome C is even more easily detached. So,  woe betide a cell that is senescent, cancerous or virus-ridden if the outer membrane ‘decides’ to leak and so trigger cell death.

The point above is that it illustrates that our symbiotic energy-producing ‘guest’ organelle the mitochondria  has more in common with a ‘Chernobylesque’ nuclear power pack than it does with AAA batteries in terms of ‘risk to health’ versus energy benefits.

Along the lines of risk, mitochondria are the principle, if accidental, generators of so-called ROS species, free radicals that will oxidise (viz destroy) anything in their path. Dealing with free-radicals is naturally a major preoccupation of the cell and there are many signalling pathways to integrate with the valiant and lightning fast efforts of catalase and superoxide dismutase enzymes which mop up reactive species that escape to the cytoplasm. Mitochondria are high maintenance.

Now, if you had a ‘nuclear reactor’ in your house, you would take care to keep it in a box that  a) did not leak its chemicals  and b) mostly stopped radiation from getting out. So I was looking for what it is about the outer mitochondrial membrane that acts as a radiation shield, or more accurately a free-radical shield.

Mitochondria generate singlet oxygen, a very dangerous oxidising agent, but which singlet oxygen is short lived and travels only a short distance. Chemists exploit the electronic structure of our old friend cholesterol especially to trap singlet oxygen because it is so good at it. I think this utility of cholesterol  is in play in a biological context too.

My hypothesis is that the presence of cholesterol in the outer membrane, (which can be quite high and reflects dietary cholesterol levels), is less to do with regulation of membrane fluidity and permeability but is more part of shielding the ‘reactor’ against singlet oxygen emission. Cholesterol, by the way, assiduously traps singlet oxygen far better than the phospholipids’ double bonds in the membrane bilayer.

Cholesterol itself is oxidised by singlet oxygen and undergoes some complex free radical chemistry before it terminates the chain reaction.  Its oxidised products migrate from the membrane quickly to be replaced with fresh  cholesterol.

The cholesterol as a shield idea is just a hunch, but it is consistent with an emerging picture of the mitochondrion’s outer membrane. A membrane on a  journey from a ’candy wrapper’ to something that has an important role in keeping ‘everyone’  in the intra-cell ecosystem safe from this valuable but lethal guest.

 Post Script:

I confess to having in my mind a picture of the mitochondrion as ex-free living prokaryotes shorn of their tough outer coats and re-wrapped in the outer-membrane in the form as shown in every text book

I am not so sure now. Am I simply making an assumption, not unreasonably, from the appearance of  mitochondria obtained in isolates and as shown on conventional transmission electron micrographs that this is how mitochondria are actually in vivo.?

The outer-membrane is almost continuous with smooth ER and its lipid composition reflects this intimately. Mitochondria themselves are well known to fuse and split continually, forming every shape from tube-like structures sometimes extended into reticulate arrangements to small, almost spherical, units which can zoom through the cytoskeleton streams to all parts of the cell.

Sometimes the conventional mitochondrial model is obvious, especially when mitochondria are parcelled up for the muscle sarcoplasm or stacked to power the motors in spermatozooa.

When mitochondria are 'parcelled up' it is when they are required to produce maximum yields of energy in short bursts. When they are in their least recognisable forms they are tubular and reticulate. In this case, as in cell division they are required to produce large amounts of energy of a long period of time.

I wonder in terms of the shield article above whether the morphology is important. High energy equals high shield needs.

Mitochondria and Symbiosis: Just who is running this show?

This post, which ends as usual as an account of another amazing aspect of mitochondria, started life wondering why the possession of Neanderthal genes made those with them more susceptible to Covid19 than those without. It seems clear now that Africans, who do not have Neanderthal DNA, become less seriously ill with Covid19 than most of the world who do. 

Amongst the possessor of these genes South Asians seem to have drawn the shortest straw possessing more Neanderthal genes which have been particularly associated with pathogen vulnerability. Australian aboriginals also have Neanderthal DNA but uniquely they also have DNA from the mysterious Denisovans who co-existed with modern man and neanderthal but left little trace of themselves before becoming extinct. The aboriginal groups in Australia seem to have avoided the worst of Covid19 but not through any evidence of innate immunity and so nothing can be said about the Densovan DNA in this context. 

  The Joy of Surfing 

Whilst surfing such topics I came across the most extraordinary revelation ( to me at least). Neanderthal populations according to the fossil records ultimately possessed no neanderthal mitochondrial DNA at all! It was modern human mtDNA, the same as us. 

It looks like an African female (a modern human) seeded the neanderthal population with ‘our’ mitochondria about 200,000 or so yrs ago. Via her offspring, over the following millenia that seed population of mitochondria wiped out neanderthal mtDNA even though her original seed nuclear genes (nDNA) would have been near infinitely diluted through interbreeding amongst the neanderthal populations. Paradoxically then, nearly all humans outside Africa including Australian aborigines possess nuclear neanderthal DNA (nDNA) but no neanderthal mitochondrial DNA (mtDNA). Also, incidentally, the mtDNA from the Denisovan is also lost today despite the appearance of nuclear genes in the aboriginal population. 

Are we looking at a mitochondrial ‘land-grab’, a take-over bid for the endoplasmic-ecology of homo? Is this what mitochondria do? 

The next line of thought was xenobiotic. Human xenomitochondrial cybrids to be precise! Quite simply, how goes trans-species mitochondrial transplants? ‘Topping up’ the quota of human cell mitochondria is a well known experimental technique used to ‘supercharge’ underperforming myocytes after cardiac arrests. It works, for a while and then the population of mitochondria drops to normal levels with no harm done. 

But how about xeno biology? What is the fate of transplanted chimpanzee or gorilla mitochondria? Such transplants work too. Well in vitro they does, but there is some ‘push-back’ from the host as there are deficiencies in various enzyme complexes in the respiratory chain. The interplay between the host nDNA and mtDNA is complex and unpredictable. 

In the lucrative world of animal cloning ( horses, cows, sheep) xenobiology is deeply investigated. To cut a long story short it is easy enough to introduce (say) bovine mitochondria into sheep oocytes (eggs) which can readily proceed to the blastocyst but invariably the cybrid cell fails to implant in the host and develop normally. Similar findings have been found with mice oocytes acting as host to bovine mitochondria.

Mitochondria in mammals are inherited only through the female line via her eggs ( oocytes) so it is relatively easy to inject mtDNA, mitochondria or cytoplasm containing mitochondria into them and produce cybrids but by and large it is not successful from an intra-species perspective. It seems mitochondrial and nuclear DNAs are too subtly integrated to allow a crude transplant even within mammals. This is a shame as I always wanted to read about bat-human cybrids on account of the superb performance of the former’s mitochondria. 

In the homo story above though no alien mitochondria are introduced into an egg. 

The ‘mother’s’ mitochondria receive no challenge from the sperm of the male which carry no mitochondria and so no mtDNA. However, to replace over time the indigenous population’s mtDNA as in the case of the neanderthals it must follow that reproductive success ( from embryo implant to full term to survival) must have been enhanced for the neanderthal by the presence of modern human mitochondria. The story of the neanderthal mtDNA creates a fascinating picture of mitochondria as semi-autonomous populations able to move between creatures that can successfully interbreed. 

It is already well known that mitochondria which are reproducing can be selected for within a cell by energetic demands or even through senescence in terms of numbers, size, ROS production and efficiency. Now it seems, they have a bigger Darwinian ‘landscape’ to operate within, limited only by the species barrier. In this case mitochondrial populations will be selected for on the basis of the successful reproduction of their hosts. 

 The question that is begged is: does this mean morphologically quite different creatures which eventually end up using the same power-plant will converge phenotypically? Or will, like cars with identical engines see one succeed and the others fail. In other words are mitochondria limiting species differentiation? 

Just who is running this show?

Mitochondria, Covid19 and Goldilocks

 

This post is a further exploration as to why bats can live with Covid and we cannot ... or can we?

In the UK at least 13-15% of the population have been found to be asymptomatic carriers of Covid19 and only shed virus ( ie are infective)  from time to time. In other words much like the bats from which the virus came, only as yet a smaller proportion of the population. 

Worldometer’s statistics show in the UK approx 40,000 deaths from 400, 000 symptomatics out of a population of 66,000,000. Whereas Uganda reports approx 80 deaths from 4,000 symptomatics and a population of 40,000,000.  This is an astonishingly smaller proportion of deaths.

Nothing, no mental gymnastics, no adjustments for reporting,  age and testing regimes will convince me that this difference is not showing a fundamentally different immune response to the virus in these populations. I also suspect that the virus is present in the population in vast amounts but that asymptomatic is the norm not the exception.

I suspect that the bats and the asymptomatic humans have one thing in common and that is a response to infection by this virus that falls into the ‘Goldilocks Zone’. That is just enough to keep the virus in check but not so much as to trip a cytokine storm. And, as is well known now, it is the cytokine storm that kills and that old age, obesity and high blood sugar that predisposes individuals to that fate.

Anyone who reads my posts knows that the role of mitochondria inevitably takes centre stage and this one is no exception. Forty year ago we were establishing the roleof mitochondria in bioenergetics which having been established eclipsed the signalling and control roles of mitochondria in the endo-ecology of the cell. I always wondered how the immune system knew a virus was inside a cell and doing its dastardly reproduction until finally bursting out of the lysed cell. Having done so this virus is in the bodily fluids, the animal is infectious and the immune system has some work to do … on the back foot so to speak.

I had not known about the signalling power of mitochondrial DNA (mtDNA). To cut a long story short some mitochondria develop a ‘hernia’. Herniated mitochondria as they are actually called have holes in their outer membranes which allow blebs of inner membrane to protrude and form vesicles which contain mtDNA probably in fragments. These migrate through the cytosol and are released into the surrounding fluids. Here they set off a chain of pro-inflammatory events leading to the formation of the ‘inflammasome’ which alerts the immune system. So far so good one can imagine a well ordered setup where the immune system deals with infected cells before metaphorically it all kicks off and starts the response which usually creates symptoms of illness.

It has been known for a very long time that mitochondria in senescent cells are more fragile and more leaky that those in younger cells ( I was 'blowing up' mitos with hypotonic shock in 1977!)  It is also well known that in middle age onwards in sedentary humans that a great many rarely used or unused muscle cells are ‘parked’ awaiting cell destruction (apoptosis) mediated by the mitochondria. The apoptosis is triggered by release of the contents of the mitochondria ( weakly bound Cytochrome C) via a complex set of signals.

It seems to me that viral infection into senescent and ‘limbo’ cells would quickly cause the mitochondria to leak drastically ending in apoptosis and mtDNA release. The most likely outcome of which would be a cataclysmic emergency response of the immune system.

So why are we in the UK so badly hit by this virus? Simply put we are older, fatter and more idle than our african dwellers. Older, equates to senescent leaky mitochondria, idle life styles equate to muscle cells in limbo ( sarcopenia is a common outcome of Covid19 patients)

Finally, obesity and diabetes equate to higher blood sugar which separately to the above is part of its own pro-inflammatory pathway. 

It looks like a ‘perfect cytokine storm’ is the price of  the modern life.

ps Intriguingly, a scenario as described above would paint an interesting picture for the very old but well individuals. They have experienced already substantial sarcopenia and so most senescent cells have gone. Also they have little body fat. I would love to know how many of them fail to succumb to the virus but the data has not yet fine-grained what is meant by old.

Extinction's Rebellion: Nature's last laugh

 I suspect we are all amateur virologists now that Covid 19 has tormented us so initimatey.

In previous posts I have been fascinated as to why bats and birds in particular can host, apparently without harm, so many viruses. Such musing begs the question as to what viruses do we host without pathological signs.

This question takes centre stage with a new obsession with the  ‘symptomless carriers’ of Covid19 as to whether they are infectious or not and how long they host the virus. Clearly some are infectious some are not and no-one knows for how long they will test positive or whether they will test positive sometimes in the future or not. 

In reading for this post I have learned of the human ‘virome’, that is our endemic biome of viruses.  Suffice it to say there are many and at least five can be detected simply by sampling likely sites on the body and these include HPV, Herpes 6 and 7. The trouble is that these are sampled from bodily fluids which is the part of the virome ecology in a situation where viruses are being shed from a dormant phase within the cell into their surrounding fluids. This is the so-called lytic phase as opposed to the latent phase.

As a non-virologist I do not know what tips the balance between latent and lytic phases or indeed whether low level non-pathogenic release of viruses is ‘normal’ or infectious to others.

I do know that under stress the lytic phase causes the release of countless viruses which having so to speak ‘gone too far’ may elicit an immune response from the body along with pathogenic symptoms but in any case crucially has the ability to infect others. Anyone with Herpes knows what stresses will bring on an outbreak of symptoms.

This post however is in response to the dreadful data on the extinction of wildlife since the 1970s. Two thirds by one estimate and largely due to habitat loss. Habitat loss is the most effective and obvious stressor for wildlife and it is now well known that certainly in bats and birds this tips their viromes into a massive, shedding, lytic phase. 

It is well known today that viruses such as SARS, Covid19, and the deadly Ebola have bat hosted reservoirs. It looks like the HIV pandemic had its origins in primates as the simian immuno virus.

Close contact with wild-life viral reservoirs provides the opportunity for the species jump.It is a rare occurrence fortunately and usually is a wrecking-ball to the new hosts as they struggle to find an accommodation with the new virus. One thing is for sure and that is as we drive species to extinction, stealing and destroying their habitats as we move in on them that they are under stress! 

My guess is that whatever viruses they have will be being released like there is no tomorrow ( for them there is no tomorrow) and we will come across more of them and be infected by them.

How ironic if our drive to wipe out these creatures means that we sign our own death warrants thanks to viruses that one lived in peace. 

Why Bats can live with Coronavirus and we cannot .. an hypothesis

It has long been known that bats and birds can host a wide range of viruses which appear for most of the time to do  them no harm. Famously and recently, wide spread infection of humans resulting from a viral ‘species jump’ from the above animals has shown how badly humans can respond to the infections viz the current coronavirus pandemic.

It has been shown in bats that despite the presence of the viruses, an inflammatory response is not induced and there is little evidence of significantly elevated antibodies. It is speculated that vigilance by their own killer T cells keeps the virus loaded infected cells low.
The animals usually only shed the viruses ( ie get ill ) during stressful times such as food scarcity, loss of habitat and reproduction.

Below is an hypothesis that I have from the perspective of a biochemist and gerontologist to explain the mystery of the difference between humans and say bats with regard to susceptibility to Coronavirus.

Once a virus enters an organism, by whatever root, its ‘goal’ (in a teleological sense) is to reproduce. To do so it needs access to the full synthetic apparatus present in every cell which it will hijack for viral reproduction.

Entry into a cell is in itself a tricky process and viruses have a range of binding and injecting strategies which are subject to a dynamic and fluid battle between the ‘burglar and the household’ using a dazzling array of  molecular ‘picks and locks’.

If successful, the cell will be turned over to virus production and will eventually burst and release its payload. Here a second level of defence comes into action. The increase in viruses will alert the immune system which will cause inflammation ( basically increased transport pathways to infected areas), the production of antibodies which can clump viruses into easy to eat lumps, and the emergence of T-cells and other phagocytes which set about the killing infected cells and removing inactivated  viruses.

If the response above is extreme, usually due to sudden high viral loads the response itself can be life threatening as seen so often with critically ill Covid patients. But what about bats?
Are they just being  ‘laissez faire’ about virus reproduction? Are the locks on their cells unpickable?

I have another hypothesis.

I think the 'tipping point' between 'latent' and 'lytic', the virologists' terms for the emergence of viruses that can stay present but hidden for long periods ( herpes or HIV would be well nown examples), occurs through events inside the cell.

What happens to the nuclear material ( DNA or RNA) that gets into a cell? It is naked, that is unlike our DNA which has a coating of protein. It is exposed. The Corona Virus RNA is particularly vulnerable being the longest RNA genome discovered. As a result it fragments easily. Indeed sensitive PCR tests pick up RNA fragments from Covid19 long after active ( ie whole genome ) viruses have gone.


When this material enters a cell it is potentially entering a maelstrom of free-radicals released via mitochondria during oxidative metabolism. For a really energetic cell like those in bird or bat muscles it is a veritable firestorm. Damaged DNA is useless to the virus and will float around until it is recycled. It cannot hijack the cells apparatus as the code to do so is damaged.

Using the reasoning above, what would be good ‘victims’ for the virus. The answer is cells that have all the equipment to make viruses but are pretty much powered down.
For example storage cells like adipose tissue (fat), unused muscle cells ‘parked and marked for destruction’ in the old or simply sedentary, would be ideal targets for the virus.
Also hypoxic cells, or cells with poor sugar regulation would be vulnerable as here mitochondria can be turned down and anaerobic respiration is significant. All of the above are ideal for a virus ‘free for all’ and all are very characteristic of the modern human.

In summary I am hypothesising (guessing) the focus on the immune system’s response to infection is partly a red herring. The immune system’s panic comes from an understandable reaction to full scale viral production.


Part of  the answer to our vulnerability and the bats’ indifference may then actually be due to processes inside the cell rather than the response of the immune system.
60 years ago, globally, there were vastly fewer obese, inactive humans many kept alive into morbid old age by drugs. Would they have suffered quite so badly from the pandemic?


Our Prime MInister will do well to keep active and lose that flab.

Statins and Covid19

Currently there is much interest in the possible relationship between low Vitamin D serum levels and mortality figures from Covid19 infection. The hypothesis being that low Vit D levels are likely to be associated with those living largely indoors or with dark skins. Both conditions would prevent sunlight-mediated synthesis of Vit D.  Vit D is synthesised from cholesterol and this is important as will become clear later.

In other words, the conditions described above would predominate in the elderly and BAME communities which both are represented disproportionately in Covid19 related deaths..

Vit D can be obtained from dietary sources such as eggs, butter, oily fish, offal and red meats but consumption has been reducing nationally as people follow ‘healthy diets’ low in these foodstuffs.  Largely vegetarian diets expose the person to higher risk of Vit D deficiency as few vegetable  food-stuffs ( except UV-treated mushrooms) contain Vit D unless artificially supplemented.

Vit D is known to reduce cardio-vascular inflammation and is purported to improve immune response and so given all of the above it is not surprising that the medical world is following up any links with low Vitamin D levels and Corvid mortality.
The data will soon show whether there is a link with low Vit D  levels. It may then be added to other clearly risky medical conditions that contribute to Covid mortality, such as diabetes.

Sarcopena and cachexia ( muscle wastage ) are common  severe complications of serious Covid illness and are major contributors to mortality. Myelgias ( nerve pains ) are also common, though the latter do not seem to contribute to mortality. These traits described above have a familiarity about them.

The paragraph above reminded me of the adverse effects experienced by those who react poorly to statin drugs. It also reminded me that South Asians in particular are well known to be predisposed ( compared to Caucasian whites) to diabetes and cardio-vascular problems.  South Asians who react poorly to statins also are predisposed to early onset diabetes.

What is occurring to me is essentially a ‘perfect-storm’, a basket of disaster centred around the obsession with cholesterol and cardio-vascular disease. My hypothesis is that covid-related mortality outside of the frail and elderly population revolves around the cholesterol obsession.

I will guess that South Asians in particular will be disproportionately prescribed statins due to their CV risk profile, will have low dietary intakes of Vit D due to an avoidance of high cholesterol foods and will not have the exposure to sunlight generated Vit D.

Infection with Covid19 probably sets off a cascade of processes leading to apoptosis (cell-death) and hyper-inflammation in a system which has the ‘pump-primed’ so to speak. And yes, I do think that statin use, even for those who are not displaying obvious reactions to the drug will figure in the risk of Covid19 mortality.

If I can think this way then so can others, I do wonder if the search for the Vitamin D link will, or has already, uncovered the statin link. If so I am sure you will never hear about it. Or maybe the statin love affair is so embedded it will never be seen.


Post script October 2024:  The messianic prescribing of statins by GPs and prosylesing articles in the Press has all but disappeared.  A link between an uptick of shingles with statin use has been established.

I am due for my free Covid, Shingles and Flu jab next week. Conclusion: 'they' know and Humpty Dumpty has a lot of sellotaping to do.

Covid19, bats, birds and mitochondria

As an avowed mitochondriac I see the little organelle’s hand in a lot of pies and so may it be for Coronavirus in particular and viruses in general.

A relationship between mitochondrial performance and Corvid susceptibility is a real possibility. Below are the facts that present themselves for the ‘joining of the dots’ as one might say.

Birds, swallows and crows are reservoirs for influenza viruses as bats are for coronaviruses. None are hosts to these viruses specifically as they live happily enough with a wide range of viruses and normally show no symptoms of illness from any of them.

In recent years the mystery of just why these creatures can tolerate high viral loads and only occasionally shed them is being unravelled. They appear under normal conditions only to mount a mild immune response to these infections but under stress (food shortage, reproduction, habitat loss) they can become unwell and shed the viruses. All of the above is well known as is the ability for these viruses to jump across species into humans when they are being shed.

The ‘dots’ I would like to join would be to link known human susceptibilities to Coronavirus in particular and to the bat or bird host’s biochemistry.

Human susceptibility to Coronavirus increases with age. This is the number one vulnerability followed by diabetes and obesity. All three conditions are characterised by chronic inflammation. Indeed ageing can be described as an inflammatory disease. Hence there has been for years intense interest in both anti-inflammatory drugs and in anti-oxidant foodstuffs since these purport to mitigate the effects of pro-inflammatory ‘free-radicals’ within the cell.

Within a cell the chief source of free-radicals is the mitochondria and the cell takes great steps to mitigate their damage by capturing the radicals and rendering them harmless using extremely abundant and fast acting enzymes as well as simple chemicals. Even so, the damage is substantial and repair of proteins and DNA is ongoing throughout life. With age, poorly functioning mitochondria, degenerating back up systems and repair failures tip the balance towards inflammation.

The mitochondria in birds and bats are radically different to those in man and mice. Size for size, and despite having ultra-energetic lifestyles ( flying ) birds and bats have very long lives. Pigeons live for 20+ years, Parrots 100+.  A tiny bat can live for 40 years; the Pipistrel bat more than 15 years. Compare this with 2 years for a mouse and 40 for a human ( in the wild condition not modern medicalised society).

Why? Simply they have much better mitochondria. Bat and avian mitochondria produce far fewer free radicals, they are simply better built and place lower oxidative stress on their cell host. Early in life, when the bats start flying,  weaker mitochondria are apparently weeded out and only the smaller better ones reproduce within the cell. Eventually their mitochondria populations are much ‘fitter’ than for animals that don’t fly.

Conversely, for mammals that don’t do very much at all, (maybe think modern sedentary worker) there is no pressure to select for the best, after all, demands such as flying will not be made.

The key here is to see mitochondria within an organism as a reproducing population subject to evolutionary selective pressures within a cell, in the same way as this would apply to free living organisms in the outside environment. They can all be nearly as good as their best or exist in populations able to tolerate less than perfect versions.

Another fact to add to the mix is that mitochondria are not sugar-eaters (saccharophiles) so much so that cancer cells which survive almost exclusively on sugar effectively inhibit mitochondrial replication. Diabetic and pre-diabetic conditions are associated with mitochondria-unfriendly high sugar levels.

Another clue that mitochondria are figuring in the Covid context is reported extreme sarcopena ( muscle wastage)  for those on ventilators with Covid19. This is a sure sign of mitochondrial-mediated apoptosis ( cell death) of muscle cells. Sarcopena from middle age is ‘waiting to happen’ depending on how much activity is being demanded of the muscles.

It follows that amongst the old, the diabetic and the obese it is highly likely that their mitochondria are as un-bat-like as they can be.

So regarding Coronavirus human vulnerability, it tracks mitochondrial capacity in a way that feels more than coincidental. Conversely, human ‘invulnerability’ is associated with the youngest most active population which will naturally have the ‘best’ mitochondria.

In conclusion joining the dots is not the same as providing an explanation but there feels like there is a link between mitochondrial well being and viral tolerance. Just what it is is unknown but I’m off to the gym to practise flying and am keeping off the sugar.

Tuning the Cell’s Mitochondria

Tuning the Cell’s Mitochondria

In a previous post ‘Mitochondria the beating heart of the cell’ I described mitochondria as oscillators. The reasoning behind this was that mitochondria behave as capacitors in an electronics sense in which they are charged by electrons supplied from substrates as they ‘descend’ in redox potential through the so called respiratory chain of redox enzymes.

In turn they are discharged by the collapse ( partial ) of the electro-potential across their inner membrane, the energy of which is used to drive the synthesis of molecules such as ATP or to reduce nicotinamides or flavins ( NAD, FAD).

All the above is known to all students of biochemistry, many of whom are reluctant physical chemists and for sure not electrochemists or electronics geeks. When these ideas were first mooted and referred to as the Mitchell Hypothesis in the late 1960s the ‘wet bio-chemists’ reacted badly and it took many years for electro-mitochondria to gain a foothold. Indeed it was absent completely from A level text books well into the 1980s.

This was understandable as biology-organic chemistry was forced to encounter topics such as redox and Gibbs free energy. Concepts they did not meet normally …  and they certainly were not going into the territory of distinctions between enthalpy, entropy and the Nernst equation. A kind of truce settled after a while and the stuff got taught and then ignored.

However what seemed to be the case is that the silo that is science managed to keep well clear of interference from the rapidly developing world of micro-electronics. The circuit folk made little contribution to the bio-energetics world which had refined its physical chemistry and now well understood the movement of electrons up and down energetic pathways.

I have always been an advocate of the next steps and to reiterate a previous blog: 

Since  mitochondria hold charge and this charge can be used on demand they are acting like simple capacitors. And as capacitors:

1. They have a measurable capacitance which will vary according to  the dielectric properties of their membranes, the medium that surrounds them and their surface area.
2. They will have a ‘smoothing effect’ on chemical reactions that require electrons ( ie reducing reactions ( anabolic-biosynthetic, as opposed to oxidations which provide electrons) by providing a reservoir of charge above the threshold potential required for synthesis.
3. They will pulse or oscillate with defined frequencies if there is a time discrepancy between the rate of charge and discharge. This is likely because discharge occurs in discrete free energy ‘lumps’ larger than the supply-side electron donation from substrates.

When cells senesce mitochondria enlarge and have fewer inner-folds of membrane ( cristae). In other words they have a lower capacitance. This can be explained as follows:

A reduction in surface area means that it takes less charge to reach its working potential ( voltage). If, as seems the case, the dielectric of the membrane has decreased with age, that is in  biochemical terms it is ‘leaky’ with regard to ion porosity, then a reduced surface area allows, to use a simile, ‘the bath can be filled faster than it empties’.

For a long time I could not work out why the mitochondrion should enlarge also. I now think it is to maximise the ratio of ‘electron supplying’ matrix-located  reactions ( TCA mostly ) ) to the surface to be supplied.

The logical consequence of this response which seems adaptive to membrane integrity is that the mitochondrion will carry on ‘working’ but with reduced reserves. In the parlance the critical membrane depolarisation threshold is ever closer.

This concords with everyday observations of senescent mammals. They can’t keep   going, they run out of puff!

Finally, something of an intrigue for me is the oscillation of the charge that must occur. Oscillators have resonant frequencies, tuned circuits have resonance Resonance allows for transfer of energy and resonance energy transfer is well know in the photosynthetic electrochemical processes. 

Do mitochondria react to external electromagnetic resonant frequencies and if so what? Are cells ‘tuned’ systems? I won’t find out that’s for sure but every New Age ‘energy-field’ buff will just love it