Have you thought about electron transporting flavoprotein dehydrogenase and its substrate electron transporting flavoprotein?

This is not really a post. I just want somewhere to place a concept, outside of the original post in which it is embedded, where it is more easily recognisable and findable.

It's worth noting that this paper:

The CoQH2/CoQ Ratio Serves as a Sensor of Respiratory Chain Efficiency

describes the process of remodelling the ETC in great detail, especially down regulation of complex I when there is an high input from other sources to the CoQ couple. It's mediated by reverse electron transport and it happens fast.

The basic TLDR is that if you take fat adapted mitochondria they will be using mtETFdh to generate a significant proportion of their maximal oxygen consumption for ATP generation. This means that complexes I and II will be down regulated, so supplying electrons to these complexes cannot match the oxygen consumption which would be generated if mtETFdh was maximally active. We have no available direct supplies of electron transporting flavoprotein to supply FADH2 in the way that beta oxidation does. "Dysfunction" is actually an artefact of not inputting adequate electrons to the CoQ couple via mtETFdh.

This applied both to studies on high fat diets and studies on fasting. It implies extreme caution if one is to decide that high PUFA diets, when high in overall fat, do actually cause *any* mitochondrial dysfunction, if only tested using inputs from glutamate/malate or succinate.

So this has major implications as a generic "how to read a paper" factor.

The insight is based on the oxygen consumptions in this paper where "disrupted bioenergetics" are claimed.

Rapeseed oil‑rich diet alters hepatic mitochondrial membrane lipid composition and disrupts bioenergetics

I wrote this in the post about the above paper:

There is nothing wrong with these mitochondria. Bioenergetic are *not* disrupted, as suggested by the title of the paper. Let's dig deeper.


What is happening is that the study is taking mitochondria from fat-adapted rats and feeding them on either a complex I input or a complex II input. Fatty acids, even LA, make significant use of electron transporting flavoprotein (ETF) dehydrogenase as their input to the CoQ couple. Mitochondria adapt their electron transport chains to the substrates available. If mitochondria from rats fed 40% of calories from fat are significantly dependent on mtETFdh for input to the CoQ couple, and have down regulated both complexes I and II, then feeding the preparation on substrates specifically aimed at complex I or II will obviously produce sub-maximal oxygen consumption. Which is what happens under either state 3 respiration or FCCP uncoupling.


Under the "tickover" conditions of state 4 respiration the uncoupling from PUFA shows clearly.


Obviously, to restore visibly normal mitochondrial function, what's needed is a supply of reduced ETF to use as a substrate for mtETFdh. As supplied by beta oxidation. Sadly you can't just buy reduced electron transporting flavoprotein from Sigma Aldridge, so you end up with artifactual mitochondrial "dysfunction".

Another aside: that is exactly what is happening here too

Prolonged Fasting Identifies Skeletal Muscle Mitochondrial Dysfunction as Consequence Rather Than Cause of Human Insulin Resistance

discussed here

Will fasting destroy your mitochondria? (No).

It *appears* as if mitochondria adapted to high input from mtETFdh are dysfunctional if you fail to supply them with adequate electron transporting flavoprotein! The study did try to get around this by using octanoyl-carnitine (50μmol/l) as a lipid input to generate reduced ETF but clearly even 50μmol/l of palmitate will provide twice the ETF of 50μmol/l octanoate and the chaps in the study were running total FFAs of up to 3000μmol/l, not 50μmol/l, at the time that the muscle biopsies were taken. Utilising 3000μmol/l of FFAs provides a lot of ETF. So "dysfunction" is really an experimental artefact induced by lack of metabolic substrate for mtETFdh (secondary to using an homeopathic level of octanoate in this case or no mtETFdh substrate at all in most studies).

That is all.

Peter