Multistability maintains redox homeostasis in human cells.
Jo-Hsi HuangHannah K C CoYi-Chen LeeChia-Chou WuSheng-Hong ChenPublished in: Molecular systems biology (2022)
Cells metabolize nutrients through a complex metabolic and signaling network that governs redox homeostasis. At the core of this, redox regulatory network is a mutually inhibitory relationship between reduced glutathione and reactive oxygen species (ROS)-two opposing metabolites that are linked to upstream nutrient metabolic pathways (glucose, cysteine, and glutamine) and downstream feedback loops of signaling pathways (calcium and NADPH oxidase). We developed a nutrient-redox model of human cells to understand system-level properties of this network. Combining in silico modeling and ROS measurements in individual cells, we show that ROS dynamics follow a switch-like, all-or-none response upon glucose deprivation at a threshold that is approximately two orders of magnitude lower than its physiological concentration. We also confirm that this ROS switch can be irreversible and exhibits hysteresis, a hallmark of bistability. Our findings evidence that bistability modulates redox homeostasis in human cells and provide a general framework for quantitative investigations of redox regulation in humans.
Keyphrases
- reactive oxygen species
- induced apoptosis
- cell death
- dna damage
- cell cycle arrest
- signaling pathway
- electron transfer
- oxidative stress
- type diabetes
- blood glucose
- mass spectrometry
- endoplasmic reticulum stress
- molecular docking
- heavy metals
- blood pressure
- metabolic syndrome
- single molecule
- living cells
- molecular dynamics simulations