Podcast with Dr Paul Saladino (2)

Part two is up, mostly about the glycerophosphate shuttle...

Peter

Protons (65): Fatty acids vs glucose and ROS generation

I've had this paper for some time:

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

It really grabbed me as it was one of the earlier references to supercomplex assembly of electron transport chain components, failure of C57Bl/6 mice to manage this correctly due to a truncated supercomplex assembly protein and the deconstruction of excess complex one when electrons were fed in to the ETC via electron transporting flavoprotein dehydrogenase. So it's a great paper of enormous scope.

But there is more. Dave Speijer has a great discussion of why mitochondrial preparations are so hard to interpret because they are so far away from the in vivo situation and preparation artefacts are massively influential of results. It's in here on page 4110 if you'd like to browse.

Back to the Guarás paper. They got out of the problems of using isolated mitochondria by using intact fibroblast, treating them with a cell permeant dye which becomes fluorescent on exposure to ROS, followed by flow cytometry to assess ROS production. Then they could treat the cells with glucose or fatty acids +/- very low dose rotenone, which blocks RET without having the unacceptable off target effects of higher doses.

This is what they got. Glucose was 5mmol/l and FFAs, mixed types, were supplied bound to albumin at 1000micromol/l. Both quite physiological. Here is what they got (Fig 6, section H), we can ignore the galactose results:

So mixed FFAs produce roughly twice the ROS produced by physiological glucose. The effect is markedly reduced by inhibiting RET through complex I.

Sadly no one has done the experiment to compare saturated fatty acids, MUFA or PUFA on the generation of ROS. Still less to look at the effects of background glucose elevation to represent the immediate post prandial period, with or without insulin. But the basic proof of concept is there.

Nice paper.

Peter

Here we go in to Lockdown 2

This is the number of daily positive PCR tests (rather than genuine cases) in the UK, via Worldometers, graphed from the UK government website data. I've added an arrow to indicate the start of Lockdown 2 for those of us living under peak incompetence.

And here are the ICU admissions for the current wave, in orange. Ignore the dramatic drop at the end of this line, it probably represents under reporting because it takes time to update the database for the last 24h and these stats come out at teatime every Friday. Again these are data for time immediately before Lockdown 2:

Will it Lockdown 2 work?

Pretty safe bet it will because PCR positive test numbers have already plateaued, ICU admissions have plateaued and are probably falling, both over the week pre lockdown.

Overall it looks like we continue to head towards herd immunity despite all attempts to stop this and in the face of minimal protection for the vulnerable. Deaths have not plateaued yet, that will lag a few weeks behind the peak in positive test results.

Any modelling scenario which did not have these data as a future possibility when it was run at the start of October should perhaps have its validity questioned. That'll be the one with the 4000 deaths per day as a possible scenario, in particular.

Listening to the modellers is like listening a cardiologist espousing the benefits and "death-preventing" effects of statins. Except for lockdowns there is no equivalent to the easy option of dropping your statin prescription in the bin.

Will Lockdown 2 end on the 2nd of December?

Hahahahahahahahahaha

Peter