Multistability maintains redox homeostasis in human cells

Abstract

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.

Structure-guided engineering of a fast genetically encoded sensor for real-time H2O2monitoring

“…Superoxide and peroxide are continuously generated as byproducts through electron transfers during aerobic metabolism 51,52,53 . In this context, glucose, as one of the primary substrates of aerobic metabolic pathways, plays a crucial role in modulating cellular metabolic activity 54 .…”

Intimate intertwining of the pathogenesis of hypoxia and systemic sclerosis: A transcriptome integration analysis

“…The most important functions of PPP are converting glucose 6-phosphate into carbon dioxide ribulose 5-phosphate and NADPH production ( 31 ). NADPH is an antioxidant that can be considered as a redox equivalent in oxidative stress and reduces the production of reactive oxygen species ( 32 ). We propose that the production of reactive oxygen species ( 9 ), a notorious oxygen-derived molecule involved in SSc pathogenesis ( 33 ), is increased by decreased PPP and NADPH production.…”

Uric acid levels and risk of cognitive impairment: Dose-response meta-analysis of prospective cohort studies

“…Several studies, including observational studies and animal experiments, have illustrated that the progression of cognitive impairment is closely linked to oxidative stress and inflammatory responses [59][60][61][62][63], and that blood UA levels are associated with these mechanisms [10,[64][65][66]. Redox homeostasis is important to maintain normal cellular physiological function [67,68]. One possible interpretation is that physiological levels of blood UA plays a neuroprotective role in the development of cognitive disorders; however, when UA values are elevated to a certain range and remain high for a long time, the neuroprotective effect might be obscured by the increased vascular risk associated with high blood UA levels.…”