Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies

Abstract

The Krebs cycle in cells that contain mitochondria is necessary for both energy production and anabolic processes. In given cell/condition, the Krebs cycle is dynamic but remains at a steady state. In this article, we first aimed at comparing the properties of a closed cycle versus the same metabolism in a linear array. The main finding is that, unlike a linear metabolism, the closed cycle can reach a steady state (SS) regardless of the nature and magnitude of the disturbance. When the cycle is modeled with input and output reactions, the “open” cycle is robust and reaches a steady state but with exceptions that lead to sustained accumulation of intermediate metabolites, i.e., conditions at which no SS can be achieved. The modeling of the cycle in cancer, trying to obtain marked reductions in flux, shows that these reductions are limited and therefore the Warburg effect is moderate at most. In general, our results of modeling the cycle in different conditions and looking for the achievement, or not, of SS, suggest that the cycle may have a regulation, not yet discovered, to go from an open cycle to a closed one. Said regulation could allow for reaching the steady state, thus avoiding the unwanted effects derived from the aberrant accumulation of metabolites in the mitochondria. The information in this paper might be useful to evaluate metabolism-modifying medicines.

The unbroken Krebs cycle. Hormonal‐like regulation and mitochondrial signaling to control mitophagy and prevent cell death

“…The need of fast-acting regulation mechanisms in mitochondria TCA cycle is very robust and has inertia; the concentration of cycle intermediates is accommodated to keep the flux with little variations. [7] The cycle is both anabolic and catabolic and, therefore, there are reactions that produce metabolites of the cycle and reactions that extract metabolites from it, they are known as anaplerotic reactions. In muscle mitochondria, during exercise, fumarate supply from an anaplerotic reaction and increased availability of acetyl-CoA lead to a significant increase in cycle flux, when the muscle stops working, the initial steady state is progressively restored.…”

“…A recent paper shows that the TCA cycle has inertia and is robust in the sense that it is prone to attain a new steady state with simple adjustment of metabolite concentrations and limited changes in flux. [7] If only the activity of one enzyme of the TCA cycle increases/decreases, the change in flux is usually low unless other parameters change substantially, for example, ADP/ATP ratio, NAD + /NADH ratio and/or acetyl-CoA supply/concentration. In a given circumstance TCA cycle is in steady state, that is, both the flux and the concentrations of metabolites of the TCA cycle remain constant.…”

“…Any acute increase in the concentration of oxalacetate is quickly reduced and "absorbed" by mass distribution among all intermediates of the cycle. [7] Actually, the view that increases in oxaloacetate would interrupt/stop the cycle by converting oxaloacetate to malate, fumarate, and succinate (i.e., part of the cycle goes counterclockwise)…”

“…The increase of citrate and of succinate in the “broken” cycle is explained by the impossibility in such a broken cycle to go from citrate to α‐ketoglutarate. [ 95 ] According to the model described elsewhere, [ 7 ] the reported decrease of isocitrate dehydrogenase in such “broken” Krebs cycle in M1 cells [ 95 ] does not prevent the cycle to be fully functional. Even magnifying the reported reduction of the activity of isocitrate dehydrogenase, citrate does not accumulate in the “open” TCA cycle model described elsewhere.…”

“…Even magnifying the reported reduction of the activity of isocitrate dehydrogenase, citrate does not accumulate in the “open” TCA cycle model described elsewhere. [ 7 ] In fact, a one‐fold decrease in the activity of the enzyme leads to an approximately 50% reduction of flux without significant variation in [citrate]. The reported increased drainage from citrate to itaconate would also go against citrate accumulation.…”