OK
@JaimeS, I have just been taking my best brain fog-clearing supplements, in order to try to think this issue through! As a result, I think that you are likely right: I think that anaplerotically adding to the Krebs cycle intermediates can in some (but not all) cases supply energy to the Krebs cycle (although I suspect this is not a very efficient process, so you won't get much energy throughput via this route).
What I have realized is that from the energy perspective, the Krebs cycle is not really a cycle at all, but is best thought of as a cascade of events, starting at the top and ending at the bottom — a cascade analogous to water flowing down a mountain stream, or a ball rolling down a hill.
The diagram below is very instructive: it displays the energy levels associated with each of the 8 steps of the Krebs cycle — or the "
Krebs cascade," which I think would be a better name for the Krebs cycle, when you look at it from the energy angle.
As you can see in the diagram, citrate is the first molecule of the Krebs cascade, and has the highest energy. In our mountain stream analogy, you can think of citrate as like a certain quantity of water placed at the source of a mountain stream: this quantity of water at the top of the stream has a lot of potential energy, by virtue of the fact it is so high up. And as that water starts flowing down the mountain stream, you can harness the energy in its flow by means of a series of water mills, placed at different locations along the mountain stream.
This "mountain stream with watermills" is useful analogy to understand energy in the Krebs cycle, or the Krebs cascade as I am going to call it here. In the Krebs cascade, you don't have water, but a series of molecules (intermediates) that are sequentially converted from one to another, with each subsequent molecule being lower down on the energy hill than the previous molecule. Energetically, as these Krebs molecules convert from one to the next, it is like water flowing down a hill.
At various points in the Krebs cycle / Krebs cascade you have "water mills" that extract the energy: these "water mills" extract the energy from the Krebs cascade in the form of NADH, FADH2 or ATP (these "water mill" points of energy extraction are marked with arrows in the diagram below).
Energy Levels for the 8 Steps of the Krebs Cycle (Right in Blue),
and the 10 Steps of Glycolysis (Left in orange)
The vertical axis indicates how much energy is contained in each of the
8 intermediates of the Krebs cascade. Citrate is the first molecule of the
Krebs cascade, and this contains the highest amount of energy.
Source:
here
The Krebs cascade ends up with oxaloacetate, the final product of the 8 steps of the Krebs cycle. Oxaloacetate contains no usable energy, because it is like water that has flowed down to the lowest point of the stream: sea level.
However, this is where acetyl-CoA comes in: acetyl-CoA is like a bucket that picks up water from sea level at the lowest point of the stream, and brings that water back to the top and source of the mountain stream, so that the water can once again flow down the mountainside.
Acetyl-CoA acts like such a bucket in the Krebs cascade, because acetyl-CoA converts oxaloacetate back to citrate. And this is why acetyl-CoA supplies so much energy to the Krebs cycle, because in one fell swoop, it acts to convert the lowest energy molecule, oxaloacetate, back to the highest energy molecule, citrate.
Viewing the Krebs cycle in this way, in terms of an energy level cascade, helps understand how adding intermediates to the Krebs cascade can supply energy. The eight Krebs intermediates are, in their correct order:
Eight Krebs intermediates:
- Citrate
- Isocitrate
- Alpha-ketoglutarate (aka: oxoglutarate)
- Succinyl-CoA
- Succinate
- Fumarate
- Malate
- Oxaloacetate
In terms of inputs to the Krebs cycle, where you can add to and replenish the Krebs intermediates, there are only 4 such inputs, and these 4 are shown in green above. See:
Anaplerotic reactions - Wikipedia.
Now, if you added some alpha-ketoglutarate to the Krebs cycle, that I think would add energy, because it would be like carrying a bucket of water from sea level, and placing that water not very far down from the source of mountain stream (since alpha-ketoglutarate is in the 3rd position down from the source of the mountain stream, with citrate being in the 1st position, at the very top and source of the stream).
But if you added some fumarate to the Krebs cycle, that would supply less energy, because fumarate is quite a long way down the mountain stream, in 6th position. It would be like unloading your bucket of water in the stream at a position already quite a long way down the mountain, close to the end of the stream.
And if you added oxaloacetate to the Krebs cycle, that would not supply any energy at all, as oxaloacetate is at the very bottom sea level position of the stream, so cannot provide any energy.
So as far as I can see (and assuming my analysis is correct), the answer seems to be that replenishing the Krebs intermediates can provide energy to the Krebs cycle, but you get more energy if you replenish the intermediates that are higher up on the Krebs cascade.
So if you are thinking of replenishing the Krebs intermediates in order to boost energy, I think you'd want to go for the intermediates that are towards the top of the Krebs cascade, such as alpha-ketoglutarate (alpha-ketoglutarate replenishment is achieved in the mitochondria by the reaction of glutamate and NAD+, and is catalyzed by glutamate dehydrogenase).
As far as I am aware, the alpha-ketoglutarate supplements that you can buy cannot be directly utilized by the mitochondria, so I suspect these will not work to replenish the Krebs alpha-ketoglutarate intermediate.
If in ME/CFS, alpha-ketoglutarate is being used in order to supply energy to the Krebs cycle, it could explain why in an
Australian study, glutamate was found to be low in ME/CFS. Cort wrote
an article about this.