Linoleic Acid and Mitochondrial Dysfunction

A Dispatch From the Heart of Hell

In the beginning, old-time endocrinologist Broda Barnes detected an epidemic of hypothyroidism sweeping across the United States.

It does not show up on modern thyroid hormone level tests, it can be diagnosed only by symptoms. If you have a classical presentation of hypothyroidism, but there's no disturbance to the hormone levels, then what you'll end up with is one of the 'dustbin diagnoses': Chronic Fatigue Syndrome, Fibromyalgia, Major Depression, the list goes on and on, and they all look roughly the same.

Broda Barnes, Gordon Skinner, and John Lowe all claimed to be able to fix these things using thyroid drugs.

Somewhat more recently, Sarah Myhill proved pretty much beyond doubt that Chronic Fatigue Syndrome is a dysfunction of the mitochondria.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

That's why chronic fatigue syndrome looks like classical primary hypothyroidism, a gland dysfunction where the thyroid gland doesn't release enough thyroid hormones.

The function of the thyroid hormones is to stimulate the mitochondria.

On that basis I fixed my own chronic fatigue with thyroid hormones.

This worked very well indeed, and has carried on working very well for several years.

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When I first heard the 'Seed Oil Hypothesis', one of my first thoughts was 'Ooooooh I bet it's not a good idea to use the wrong sorts of fats in cell membranes'.

I am ashamed of how long it took me to get to: 'Hang on, don't mitochondria have lipid membranes too?'.

I was ever so pleased with my new theory:

Excess Dietary Linoleic Acid -> Excess Linoleic Acid in the Body -> Excess Linoleic Acid in the Mitochondrial Membranes -> Mitochondrial Dysfunction

It explains everything.

In particular, it explains why over the nine months or so since I have abominated the polyunsaturated anathema, the dose of thyroid drugs I have needed to stay functional has trended slowly and predictably and continuously downwards. Almost, one might suppose, as if the lack of linoleic acid was allowing my mitochondria to work better, and slowly to need less and less external stimulation to perform in the way God intended.

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So imagine my surprise, annoyance, astonishment, vexation when someone with a clue informed me that the inner mitochondrial membrane is made of linoleic acid.

What's more, it's supposed to be made of linoleic acid. It's made of linoleic acid in wild creatures on whom the polyunsaturated curse never fell.

Death of Theory

A beautiful hypothesis slain by an ugly fact. Many such cases. Oh well.

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But it's a paradox.

As every schoolboy bright enough to manage to tie his shoelaces can tell you, the mitochondria are the powerhouse of the cell.

But I think perhaps that there are schoolboys who do not fully appreciate the accuracy of that metaphor.

Mitochondria are ferocious places. The electric voltage across the inner membrane is absurdly high. The membrane is swimming in hideously reactive oxidising compounds.

That's how it works, the Krebs Cycle. The literal burning of fats and sugars to cause impossible electric charges which drive little motors to make ATP, the universal fuel of life.

The whole thing is a place of fire and lightning. A power station indeed. The inner membrane is the burning core and the alternator combined.

The structure is highly evolutionarily conserved.

You fuck with that membrane in any way, all hell will break loose.

A man would not want all hell to break loose in his mitochondria.

What in hell is linoleic acid doing in the inner membrane?

Linoleic acid, the easily oxidized, the unstable.

Linoleic acid the unstable, traditionally used as a varnish because it reacts with the air and hardens into a plastic sheet. When I have talked about the difference between chips fried in food, and chips fried in varnish, my slight is not mere idle diss.

Linoleic acid the rare, a trace element in the natural food of most creatures, traditionally available only in tiny tiny amounts, and yet essential. Without it you will die.

Why would you build the inner mitochondrial membrane out of a rare substance so reactive that it practically catches fire on contact with air?

It's as if the powerhouse of the cell were built of precious Cedar of Lebanon, rather than, say, cheap and stable plastic.

And what's worse, it needs to be. Attempts to make it of cheaper and more stable things have obviously repeatedly failed.

If it were not so, it would not be so. Uncounted squillions died when they tried to do it differently. That's what it means to be highly evolutionarily conserved.

A Paradox. A Paradox. A Sharp and Vicious Paradox.

Why, God? Why?

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So imagine my joy, as innocently I wandered aimless on the endless waves of words, to come all unawares upon this work of genius:

https://www.sciencedirect.com/science/article/pii/S2213231723001751

These guys think that linoleic acid's tendency to oxidize into varnish is what it's there for!

Obviously, obviously correct. It cannot be otherwise. One of those answers that in hindsight was staring us all in the face all along.

There are many ways to oxidize. You might split into burnt fragments and poison your surroundings, as, I think, all talk of the oxidization of seed oils assumes.

Or you might polymerize.

The Cedar of Lebanon, exposed to the fire and the lightning, becomes a stable plastic. The inner membrane is not a gentle film of soft lipids which might catch fire at any time.

It is hard stable polymerized plastic. That's why we need rare and precious unstable linoleic acid in the heart of hell. To varnish. To have a plastic cat in hell's chance of making a membrane which can endure the fire.

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Now I wonder, will this let me bring my membrane-contamination theory back from the dead?

Possibly. But it will require a sea-change.

Most cardiolipin (membrane-stuff) has four linoleic acid tails.

But not all.

It's rare to find saturated fats in the cardiolipin. But you do find other unsaturated fats.

Wiki learns me the following table:

https://en.wikipedia.org/wiki/Cardiolipin

In the hearts of cows, immune to the seed oil curse by virtue of rumination, and probably the place where you find the best cardiolipin in the world, half the cardiolipin is all-four 18:2 (linoleic acid).

About a fifth of it is three 18:2s and an 18:3 (either gamma or alpha-linolenic acid, position isomers with three double bonds instead of two, more polyunsaturated than the polyunsaturated, more unstable than the unstable)

And about a seventh of it is three 18:2s and an 18:1 (oleic acid, a monounsaturated fat)

So a mix of unstable (18:2), mildly unstable (18:1), and very unstable fats(18:3). But mostly unstable.

Lord have mercy on me, my chemistry is so weak that I do not know whether 18:3 and 18:1 polymerize at all, let alone what sort of polymerization we would see here in such a mixed membrane.

But I do know that messing with the diet can change the ratios of the various fats found in cardiolipin.

And you do not fuck with highly evolutionarily conserved.

Too much 18:2 in the diet, absurdly large quantities by historical standards, can maybe change the balance of these three fats.

And that might change the physical characteristics of the crucial membrane that holds back the fire and the lightning.

Imagine, if you will, a second rate constructor using a slightly dodgy grade of plastic in a furnace, or in an alternator. A plastic with slightly different physical or electrical properties. Too hard, too soft, too liquid, too conductive. Almost any change is bad.

What might go wrong?

Perhaps nothing catastrophic, at least at first.

But maybe a slight loss of performance, a few strange leaks, a few chemicals that aren't supposed to be around, being around. Perhaps a fire occasionally breaks out.

Someone, I think, might be well advised to look at cardiolipin in various animals.

Humans, say, living on various diets. Maybe try and measure how well the various mitochondria work.

Sarah Myhill gave us a method for doing that, a long time ago. A method which was good enough to detect chronic fatigue by looking at mitochondria alone. So that might be a thing to try.