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.

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

 

*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.