Redox outside the Box: Linking Extracellular Redox Remodeling with Intracellular Redox Metabolism

Ruma Banerjee

doi:10.1074/jbc.r111.287995

Abstract

Aerobic organisms generate reactive oxygen species as metabolic side products and must achieve a delicate balance between using them for signaling cellular functions and protecting against collateral damage. Small molecule (e.g. glutathione and cysteine)- and protein (e.g. thioredoxin)-based buffers regulate the ambient redox potentials in the various intracellular compartments, influence the status of redox-sensitive macromolecules, and protect against oxidative stress. Less well appreciated is the fact that the redox potential of the extracellular compartment is also carefully regulated and is dynamic. Changes in intracellular metabolism alter the redox poise in the extracellular compartment, and these are correlated with cellular processes such as proliferation, differentiation, and death. In this minireview, the mechanism of extracellular redox remodeling due to intracellular sulfur metabolism is discussed in the context of various cell-cell communication paradigms.

Highlights

In addition to small molecule repair systems, antioxidant enzymes are utilized for maintaining the integrity of functionally critical redox-active amino acids and include sulfiredoxin [6], methionine sulfoxide reductase [5], and thioredoxin [7], whereas enzymes such as superoxide dismutase, glutathione peroxidase, and catalase keep ROS levels at bay
Because many signaling pathways involved in autocrine and paracrine regulation emanate from the cell surface, the dynamics of extracellular redox buffering are likely to have a profound effect on cell-cell communication and function
We focus on thiol-based redox buffering beyond the membrane and its regulation by a metabolic circuitry within the membrane

Summary

Redox Nodes

The primary intracellular redox hubs that interface with redox-active thiol-containing macromolecular targets are oxidized/reduced thioredoxin, GSH/GSSG, and cysteine/cystine (Fig. 1). Mammalian cells in culture hold the extracellular cysteine/cystine redox potential at approximately Ϫ80 mV, which shifts in the reductive or oxidative direction depending on whether the cells are ready for proliferation or death (Fig. 1A) [14, 15]. The GSH/GSSG redox potential ranges between Ϫ260 mV (in proliferating cells) and Ϫ220 mV (in differentiated cells) and is shifted further in the oxidative direction during apoptosis or in response to sulfur amino acid starvation [8, 9]. Because the GSH/GSSG redox couple is the most dynamic of the three redox nodes, it has been suggested that it functions as a switchable node that can be either oxidizing or reducing depending on the status of cells during the aging process, during the cell cycle, or in response to environmental triggers [11]. The relative stabilities of the reduced/oxidized thioredoxin and cysteine/cystine couples lend themselves better to their predominant roles as reducing and oxidizing nodes, respectively

Intracellular Sulfur Metabolism Modulates Extracellular Redox Potential

Redox Modulation in Extracellular Compartment

Future Perspectives