Modelling pyruvate dehydrogenase under hypoxia and its role in cancer metabolism

Abstract

Metabolism is the only biological system that can be fully modelled at genome scale. As a result, metabolic models have been increasingly used to study the molecular mechanisms of various diseases. Hypoxia, a low-oxygen tension, is a well-known characteristic of many cancer cells. Pyruvate dehydrogenase (PDH) controls the flux of metabolites between glycolysis and the tricarboxylic acid cycle and is a key enzyme in metabolic reprogramming in cancer metabolism. Here, we develop and manually curate a constraint-based metabolic model to investigate the mechanism of pyruvate dehydrogenase under hypoxia. Our results characterize the activity of pyruvate dehydrogenase and its decline during hypoxia. This results in lactate accumulation, consistent with recent hypoxia studies and a well-known feature in cancer metabolism. We apply machine-learning techniques on the flux datasets to identify reactions that drive these variations. We also identify distinct features on the structure of the variables and individual metabolic components in the switch from normoxia to hypoxia. Our results provide a framework for future studies by integrating multi-omics data to predict condition-specific metabolic phenotypes under hypoxia.