Fruit Flies and NDI1

The Protons thread originated when I asked myself: What is the difference between fat oxidation and glucose oxidation? This rapidly led to the redox state of the CoQ couple as a driver for reverse electron transport (RET) through complex I, superoxide generation and the benefits of ROS signalling. It was a period of deep insight, especially about electron transporting flavoprotein and its dehydrogenase. Core to the Protons thread is the redox state of the CoQ couple and the generation of reverse electron transport.

In amongst the recent flurry of blogging about calorimetry and associated physiology Mike Eades forwarded this text to me:

Mitochondrial ROS Produced via Reverse Electron Transport Extend Animal Lifespan

Mostly on the basis of its title, I think. It's a very complex paper, drosophila based, couched in terminology which is probably completely routine if you work with flies but as clear as mud if you don't. I think we can reduce the paper to its title, discussion headings and three diagrams, one of which I'm going to butcher, the way you do. It's free full text if anyone wants to bend their brain.

Those titles:

ROS Production Increases with Age and Correlates with a Decrease in Complex I-Linked Respiration

Over-Reduction of the CoQ Pool Increases ROS Production and Extends Lifespan

CoQ-Mediated ROS Signalling Can Rescue Pathology Induced by Oxidative Stress

Loss of CoQ-Mediated ROS Signalling Accelerates Ageing

I mean, to a superoxidophile, what more could you ask? Just so long as the superoxide is RET derived from complex I...

OK, now the images. This one is core. It's taken from the Graphical Abstract and looks to be hand drawn in pencil. Note the NDI1 super-fly logo on the chest. This research group is crazy. I like that:

We've met NDI1 before. Its a small NADH oxidase from yeasts which reacts the reducing equivalents from NADH with oxygen to give water, reducing the CoQ couple in the process. It drives, given an adequate delta psi, RET through complex I. Inserting the gene for this protein in to a fly does this to life span:

Obviously, the line off to the right represents the NDI1 positive flies. NDI1>daGAL4, as "fly people" might say. They then went on to use an almost infinite supply of other tricks, in other flies, to show that it really is RET through complex I via CoQ reduction that extends life via site specific ROS generation. I won't slog through the arguments, you now know where the paper is!

And here is the lamb to the slaughter picture, presented as part of Figure 2:

There's NDI1 in blue, using NADH to reduce the CoQ couple and generate ROS. The main thing I dislike about this image is that the ROS seem to be popping out of the CoQ couple. They actually come from RET through complex I, so let's change it so it really looks that way:

That's better. Now I, personally, don't have and don't really want to have an NDI1 sitting on the matrix side of my inner mitochondrial membrane. Perhaps there is some similar enzyme available? Ah yes, let's mentally substitute ETFdh:

And of course, if we want to drive this process, we need FADH2, transported to ETFdh via electron transporting flavoprotein, generated by the first step of beta oxidation of saturated fats. Any double bonds mean this step gets skipped and all we supply is NADH. If we want FADH2 it's palmitate and stearate all the way:

I have absolutely no idea whether using FADH2 from beta oxidation will do, in mammals, what NDI1 does in fruit flies. But I like the paper, and I like that idea.

And the fly doodle of course!

Peter

The addendum; because this post is not totally irrelevant to my recent blogging ideas:

Veech doesn't like fatty acid oxidation. He has little time for acetoacetate but loves beta hydroxybutyrate because it, specifically, reduces the NAD+/NADH couple while oxidising the CoQ couple, increasing the redox span. ie BHB oxidises the CoQ couple.

Kwasniewski is very pro saturated fat and rather anti ketosis. He wants FADH2 driven metabolism which enters the ETC by reducing the CoQ couple. He has a disturbing habit of being correct without providing any science.

The flies suggest going with Kwasniewski rather than buying bulk BHB by the tanker-load when it eventually hits the market as an affordable ketone ester. But they're only flies...