Logical modelling reveals the PDC-PDK interaction as the regulatory switch driving metabolic flexibility at the cellular level

Abstract

Background: Metabolic flexibility is the ability of an organism to switch between substrates for energy metabolism, in response to the changing nutritional state and needs of the organism. On the cellular level, metabolic flexibility revolves around the tricarboxylic acid cycle by switching acetyl coenzyme A production from glucose to fatty acids and vice versa. In this study, we modelled cellular metabolic flexibility by constructing a logical model connecting glycolysis, fatty acid oxidation, fatty acid synthesis and the tricarboxylic acid cycle, and then using network analysis to study the behaviours of the model. Results: We observed that the substrate switching usually occurs through the inhibition of pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinases (PDK), which moves the metabolism from glycolysis to fatty acid oxidation. Furthermore, we were able to verify four different regulatory models of PDK to contain known biological observations, leading to the biological plausibility of all four models across different cells and conditions. Conclusion: These results suggest that the cellular metabolic flexibility depends upon the PDC-PDK regulatory interaction as a key regulatory switch for changing metabolic substrates.