Protons (33) The mtG3Pdh knockout mice

These mice keep asking me more questions that I'm comfortable with so the post is down subject to further thinking!


Time for a Christmas break methinks! Best wishes all round.

Peter

OK, I've stopped trying to cover every aspect of these mice, some of the more exciting bits really need a whole series on their own. So here we have the slightly truncated version of the original post.



Repost.

Before we come to the consequences of excessive superoxide generation in complex I I'd just like to run through a small part of this rather neat paper on what happens if you virtually eliminate it.


Take a mtG3Pdh knockout mouse and feed it on a very low fat standard style lab chow and it will grow pretty well normally. Bear in mind that both of the diets in the study are very, very low in fat.

Ultra low fat means that dietary fat, especially when PUFA based, is not going to generate any insulin resistance based on electron transferring flavoprotein dehydrogenase reducing the CoQ couple. It's going to have to be mtG3Pdh which controls insulin facilitated calorie delivery. This particular model may not behave as simply on a higher fat diet. There are stacks of unknowns about this model.

Before we come on to anything else, what happens when you inject any old mouse with exogenous insulin?

Simple so long as you have the dose rate carefully chosen, blood glucose falls, cells develop insulin-induced insulin resistance, mouse survives. You have to be modest in your dose but it's not too difficult. We talked extensively about the Somogyi effect back in the Zombie days.

The mice in the present study happen to have been fed a high sucrose/minimal fat diet for 6 months. The two top lines are the wild type and heterozygous knockouts for mtG3Pdh. The lower, terminated, line represents the full knockouts.

The line is terminated at around 30 minutes because all of the mice were terminated, ie they died of hypoglycaemia. They needed to develop insulin-induced insulin resistance and, without mtG3Pdh, it never came. RIP.

The paper also goes on to show many, many other fascinating things about these mice but the more I try to cover all of these features the more it obscures the main finding. For insulin resistance on a ultra low fat diet you need mtG3Pdh up and running. It may be worth coming back to the effects of fructose and oxygen consumption from this paper but that's another set of ideas.

That's all for today. I just wanted to link these mice to the normal physiological insulin resistance generated by mtG3Pdh (when glucose/fructose is the primary metabolic fuel) and the protons ideas. They all fit together.

Core message: For hyperglycaemia, exogenous insulin or fructose to induce insulin resistance you need mtG3Pdh for effective reverse electron flow through complex I to generate (essential) superoxide/H2O2. This is important. So is going over the top with this normal physiological function, which looks to be rather bad for you.

Peter