Bistability in fatty-acid oxidation resulting from substrate inhibition

Current understanding of fatty-acid β-oxidation does not fully explain how flux states are maintained in mitochondria. Prior research has shown that mitochondrial enzymes follow distributive kinetics, but the role of CoA conservation in pathway stability remains unclear. This gap motivated a deeper investigation into how substrate inhibition might influence metabolic flux. No prior work had resolved how multiple steady states could arise in fatty-acid oxidation. Established models often assume a single flux state, but this paper introduces the possibility of bistability. The study addresses how enzyme kinetics and metabolite conservation might interact to produce switch-like behavior. This research builds on computational approaches to explore metabolic hysteresis. The findings aim to clarify how flux transitions might be regulated in disease contexts.

The goal of this work was to explore whether fatty-acid β-oxidation could exhibit bistable behavior under certain conditions. The specific problem addressed is the lack of understanding about how flux states are regulated in mitochondrial metabolism. The motivation comes from the need to explain how low- and high-flux states might coexist. The study aimed to identify the biochemical mechanisms that could lead to hysteresis behavior. The authors sought to determine if substrate inhibition could cause multiple stable states. They also aimed to test interventions that might shift the system toward a healthy flux state. The study's design focused on computational modeling of enzyme kinetics. The results could inform strategies for metabolic interventions in disease.

The researchers used a computational model of fatty-acid β-oxidation validated by experimental data. They analyzed the parameter space to find regions where bistability could occur. A modular kinetic approach was applied to trace the causes of hysteresis behavior. The model incorporated distributive kinetics and CoA conservation in the last rounds of β-oxidation. Three interventions were simulated to assess their impact on flux states. These included activating MCKAT via p46-SHC, adding a thioesterase, and using SCFAs. The model tracked how each intervention affected the number of stable states. The simulations revealed how pathway activation could eliminate bistability.

The model identified a region in parameter space with two stable and one unstable steady state. The low-flux state was associated with disease and the high-flux with health. Bistability originated from distributive kinetics and CoA conservation in the final β-oxidation rounds. Activating MCKAT via p46-SHC increased flux toward the high state. Adding a thioesterase acted as a safety valve to reduce substrate accumulation. SCFA activation of multiple enzymes also shifted the system toward high-flux. High SCFA concentrations eliminated bistability by promoting a single stable state. These findings suggest that pathway activation could prevent low-flux states in disease.

The authors propose that bistability in fatty-acid oxidation arises from distributive kinetics and CoA conservation. They suggest that substrate inhibition in the final rounds of β-oxidation causes hysteresis behavior. The model indicates that activating MCKAT via p46-SHC could shift the system toward a healthy flux state. Adding a thioesterase reduces substrate accumulation and stabilizes high-flux behavior. SCFA activation of multiple enzymes also eliminates bistability. The study suggests that dietary or pharmacological interventions might target these mechanisms. The findings may lead to strategies for treating or preventing metabolic diseases. The authors emphasize the need for further research to validate these computational predictions.