Abstract
Hypoxia induces the expression of genes that alter metabolism through the hypoxia-inducible factor (HIF). A theoretical model based on differential equations of the hypoxia response network has been previously proposed in which a sharp response to changes in oxygen concentration was observed but not quantitatively explained. That model consisted of reactions involving 23 molecular species among which the concentrations of HIF and oxygen were linked through a complex set of reactions. In this paper, we analyze this previous model using a combination of mathematical tools to draw out the key components of the network and explain quantitatively how they contribute to the sharp oxygen response. We find that the switch-like behavior is due to pathway-switching wherein HIF degrades rapidly under normoxia in one pathway, while the other pathway accumulates HIF to trigger downstream genes under hypoxia. The analytic technique is potentially useful in studying larger biomedical networks.
Highlights
Molecular oxygen is the terminal electron acceptor in the mitochondrial electron transport chain
It is very likely that reactive oxidative species (ROS), which are a byproduct of mitochondrial respiration, are involved in oxygen sensing by neutralizing a necessary cofactor, Fe2þ, for the hydroxylation of HIFa by a prolyl hydroxylase (PHD) [7,8,9,10]
We note that similar methods, such as flux balance analysis (FBA) and elementary modes analysis, have been developed in other contexts [17
Summary
Molecular oxygen is the terminal electron acceptor in the mitochondrial electron transport chain. The key element in this network, hypoxia-inducible factor (HIF), is a master regulator of oxygen-sensitive gene expression [4,5,6]. HIF is a heterodimeric transcription factor which consists of one of the three different members (HIF-1a, HIF-2a, and HIF-3a) and a common constitutive ARNT subunit which is known as HIFb. The system includes an enzyme family: prolyl hydroxylases (PHDs), which directly sense the level of oxygen and hydroxylate HIFa by covalently modifying the HIFa subunits. It is very likely that reactive oxidative species (ROS), which are a byproduct of mitochondrial respiration, are involved in oxygen sensing by neutralizing a necessary cofactor, Fe2þ, for the hydroxylation of HIFa by a PHD [7,8,9,10]. The hydroxylated HIFa is targeted by the von Hippel-Lindau tumor-suppressor protein (VHL) for the ubiquitination-dependent degradation
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