Abstract
Intracellular levels of redox molecules, such as hydrogen peroxide (H2O2), glutathione (GSH), and NADPH etc., and their electron transfer are controlled by redox network with nuclear factor-E2 p45-related factor (Nrf) 2 regulation. Electron transfer fluxes of redox molecules were numerically calculated using our constructed model of redox network by biochemically-based modeling using literature data under H2O2 stress. The reaction rate of glutathione peroxidase (GPx) - glutathione reductase (GR) - glucose-6-phosphate dehydrogenase (G6PD) pathways was greatly increased in oxidative condition. Core regulatory mechanism was considered as follows: cytosolic H2O2 was elevated by huge influx of extracellular H2O2, and showed superlinear threshold increase with GSH depletion caused by saturation of negative feedback loop via GR reaction. NADPH regeneration simultaneously increased for keeping GSH homeostasis by negative feedback loop via G6PD reaction, but it could not prevent GSH depletion. Then subsequent adaptive response rescued GSH depletion by induction of GR, glutamate-cysteine ligase (GCL) and G6PD through Nrf2-dependent gene network to prevent H2O2 elevation. This model provided basic regulatory mechanism of redox network and allowed long-term simulation under wide range of H2O2 stress.
