[Science/Neurosciences] Mole rats running on…..fructose!

You may have heard about this paper from Park TJ and colleagues (Park TJ et al., Science 2017) on how mole rats were showing extreme compliance to anoxic (0% oxygen) level, no? It made the news these last couple of weeks and finally was able to put my hand on. You can access to it here (need to have a Science subscription though) but I read it and it is really interesting for many reasons, especially because I try to think how can we translate it as a therapeutical strategies for hypoxemic pre-terms babies or even as a stroke fighting-drug.

First, mole rats. Oh mole rats! Not the prettiest mammals out there. They are naked, they have long teeth and look all wrinkled. But they are underground dwelling animals like moles. Underneath, oxygenation is scarce and these animals have developed formidable adaption to hypoxia. We as humans can barely survive 8% oxygen (thats about the Mount Everest). At 6% oxygen (thats what would happen if a aircraft cabin undergo a depressurization), you die within minutes.

In this experiment, they went fairly extreme, they put the animals into anoxia (0% O2) and looked how long the animals would survive. They used a common mouse strain as a control. Mice rapidly died at 100% rate at 5% O2 and died twice faster (based on the number of breaths) at 0% O2. In opposite, mole rats went 30 times longer than mice and still were doing fine (0% deaths). Were mice died within 60 seconds, molerats died over 1000 seconds of anoxia. One possible reason is their ability of their heart to beat much longer than mice.

Now what is interesting is how the authors came to fructose. Mammalian cells run on glucose through the following biochemical pathway (see below):

glycolysis-10-steps-explained-steps-by-steps-with-diagram

I will spare you the Krebs cycle but this is what every since healthcare and life scientist have to learn. Glucose is broken down into many intermediates and at the end becomes pyruvate. From pyruvate, you can enter the Krebs Cycle and produce a significant amount of ATP (the fuel cell of every living organism) needed to provide energy for any biological process. Krebs cycle is very good at it and provides an ATP yield of 36ATP/glucose consumed. However, the Krebs cycle stall under hypoxia and forces the cell to adapt. In particular, it needs to regenerate NAD+ (from NADH) in order to keep the system flowing and producing energy. One way mammalian cells solved it is by converting pyruvate into lactate. Thats allow cells to produce some energy (2ATP/glucose) and regenerate its NAD+. However lactate has tendency to accumulate and develop adverse effect (the famous muscle cramps any runners have experienced).

Fructose is not much different from glucose, it has the same composition but just a little difference in the molecular structure.  We get fructose from our daily diet made of fruits and vegetables, but also from refined sugar (sucrose or HFCS, same deal).

17693

Now fructose can bypass and feed the glycolysis at different steps:
fructolysis-pic-ca333

Fructose can produce glyceraldehyde-3-P (GA3P) and dihydroxyacetone-P (DHAP) and enter the rest of the glycolysis. Now like glucose, fructose needs a transporter to enter inside the cells. Glucose has a myriad of glucose transporters (GLUTs and SGLTs) that can provide glucose inside the cells. But not fructose. These transporters have very poor affinity for fructose. In that case, fructose has one transporter called GLUT5 that prefers fructose over glucose.
Now this is where it becomes interesting, mole rats show much higher levels of fructose than mice during anoxia in many organs and in blood. Now the interesting fact is the high prevalence of it as fructose-1-P in the brain, only this form. How it goes in? I don’t know but mole rat brains have a higher GLUT5 expression than mice. Where this transporter is expressed? I don’t know either but it would interesting to look at this transporter at the BBB.

What is interesting is the difference in how mole rats  brain and heart differ from mice in terms of fructose activity. When administered fructose over glucose, mole rats organs know to switch between the two sugars to gets its energy. In the other hand, mice organs fail to switch and result in decrease their activity.

Now the question I have (since I am working on glucose transport across the BBB and its impact in kids suffering from GLUT1 deficiency) is: does human express GLUT5? If yes, which brain cells express it and if these cells can adopt fructose as a source of energy?

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