If the body wasted glucose in OXPHOS, protein catabolism would occur and lead to rapid death. So aerobic glycolysis in cancer cells is not a result of mitochondrial dysfunction. Cancer cells are in essence functioning as a wound and attempting to recycle lactose for systemic processes.
I really liked your thought on Warburg metabolism. Quick Q to make sure I have my understanding right -- why would pushing pyruvate through OXPHOS result in protein catabolism? I'm not sure I understand why it would trigger gluconeogenesis (if that's what you are implying).
You have to think of this in the evolutionary as well as whole-body context. Evolutionarily stress may involve things like serious infection, starvation, breaking a leg, etc that prohibit nutrient acquisition. Nowadays we have our family bring us pizza or whatever and there's no shortage or calories. Not every organism has had that luxury though and so insulin resistance is a highly conserved stress response mechanism to conserve glucose and protein for the acute phase response. It's not that pushing pyruvate through OXPHOS itself causes protein catabolism, it's that glucose depletion causes protein catabolism. Fat can not produce net glucose and glucose is mandatory for the pentose phosphate pathway and associated pathways and so glucose depletion inevitably results in peripheral protein catabolism to fulfill those needs (hence muscle wasting in starvation). Protein depletion almost always outpaces fatty acid depletion so conservation is critical. So what happens is that loss of insulin signaling results in the phosphorylation and inhibition of pyruvate dehydogenase, diverting pyruvate away from oxidation and towards anaplerosis via pyruvate carboxylase and the formation of oxaloacetate. This way no carbon is lost from glucose as CO2 but rather it is lost via beta-oxidation->OXPHOS. So each round (assuming intermediates are not used) will result in the input of one molecule of oxaloacetate from glucose and the output of one molecule of oxaloacetate which can then be recycled to glucose if needed. If glucose undergoes full oxidation, then you lose a glucose molecule for every 3 rounds of OXPHOS and that's less glucose available for the acute phase response.
During stress response insulin resistance triggers gluconeogenesis. So for the cells that are not proliferating, they are largely burning fatty acids without burning glucose. For the cells that are proliferating, they are fluctuating between the pentose phosphate pathway and aerobic glycolysis. This allows them to produce necessary ATP as well as massive amounts of NADPH without wasting glucose as lactate can enter the Cori cycle for gluconeogenesis and maintain glucose status
Hopefully that answers it and without any serious errors. This kratom man... :P
So if you take the infectious disease model i proposed you basically end up in a scenario like this... Say something like a spirochete gets into the blood stream, stimulates endothelial damage as it tries to dip out of the blood stream where the majority of immune cells are circulating. Inflammation is stimulated generating insulin resistance, VLDL secretion, cholesterol synthesis, lipoprotein lipase activity. Lipoproteins start circulating with endotoxin binding proteins, mopping up immunogenic materials from the endothelial tissue and bringing them back to the liver. So then that spirochete is going to use a host of matrix proteinases to move its way through the extracelluar matrix and say, enter the brain where it may penetrate a neural cell. Like most parasites it down regulates apoptosis mechanisms and immuno surveillance of damaged cells through redundant mechanisms, effectively immortalizing those cells and ensuring its persistance. So your immune cells are now using that glucose that the body was preserving to proliferate and generate massive amounts of reactive oxygen and nitrogen species against these pathogens via NADPH. If youre lucky the infection is cleared. If not these reactive species over time damage DNA strands and lead to tissue death. So now you have a scenario where the tissue is genetically damaged and interspersed by immortalized cells. In order to heal the tissue the surrounding cells coordinate the secretion of growth factors, angiogenic growth factors and so on to encourage healing. Dividing cells again utilize aerobic glycolysis and the pentose phosphate pathway for glutathione reduction, DNA synthesis, etc using up massive amounts of glucose and secreting lactate (i realize i said lactose before :P). Ultimately the gene damage adds up causing the immortalized cells to respond inappropriately to proliferative and migratory immune signals leading to tumorigenesis and metastesis along chemotactic pathways. Just a vague example of where I'm going with this...
Edit: I realize I've been flagged for "needs references". This is a compilation of my understandings from reading literature on diverse subjects. I did this for myself and my own health journey and do not have one single reference or even a pocketfull that i keep on hand. This is my understanding, my model of interpreting the science. That said much is just basic metabolism interpreted in a different light. If one has any uncertainties about something I say or wishes me to try and find a reference for a particular point I'm more than glad to try. But obviously there is a teleological argument which is my own.
Edited by Psilociraptor1, 29 June 2016 - 05:02 AM.
