Oxidative stress, redox regulation and diseases of cellular differentiation

Abstract

Background: Within cells, there is a narrow concentration threshold that governs whether reactive oxygen species (ROS) induce toxicity or act as second messengers.

Scope of review: We discuss current understanding of how ROS arise, facilitate cell signaling, cause toxicities and disease related to abnormal cell differentiation and those (primarily) sulfur based pathways that provide nucleophilicity to offset these effects.

Primary conclusions: Cellular redox homeostasis mediates a plethora of cellular pathways that determine life and death events. For example, ROS intersect with GSH based enzyme pathways to influence cell differentiation, a process integral to normal hematopoiesis, but also affecting a number of diverse cell differentiation related human diseases. Recent attempts to manage such pathologies have focused on intervening in some of these pathways, with the consequence that differentiation therapy targeting redox homeostasis has provided a platform for drug discovery and development.

General significance: The balance between electrophilic oxidative stress and protective biomolecular nucleophiles predisposes the evolution of modern life forms. Imbalances of the two can produce aberrant redox homeostasis with resultant pathologies. Understanding the pathways involved provides opportunities to consider interventional strategies. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.

Keywords: Diseases of cellular differentiation; Glutathione; Glutathione S-transferase; Reactive oxygen species; Redox; Redox active drugs.

Figure 1

Cellular ROS, consisting of radical and non-radical oxygen species, are mainly generated in three sites: mitochondrial ETC; ER and NOX complex. Cells have evolved a system to maintain a homeostatic balance between pro- and anti-oxidant processes. Cellular ROS are eliminated by constitutively expressing an arsenal of detoxifying enzymes, including those directly destroying ROS such as SOD, catalase, and GPx. NADPH and GSH are primary contributors to the maintenance of a reduced cellular redox state. In a reduced state, both TRx and GRx reduce disulfides and become oxidized. Oxidized GRx is converted back into a reduced state using GSH, which is regenerated by NADPH-GR, whereas oxidized TRx is converted back into a reduced state using NADPH-TRxR. Nitric oxide synthases are key enzymes for the production and regulation of nitric oxide.

Figure 2

Bone marrow niche microenvironments. Various gradients help to define the osteoblastic and vascular niches of the marrow compartment. Movement between one niche and another can be facilitated by microenvironment gradients of calcium, oxygen and potentially thiol/redox state. Hematopoietic stem and progenitor cells traverse this space and mature towards the variety of blood cells that present the circulating blood lineages. Two types of HSC exist. Depicted are low and high ROS populations. As ROS formation requires oxygen, ROS levels in HSC or HPC correspond with oxygen availability. For HSC, when cells are quiescent, both ROS levels and NOX enzyme expression are low. During differentiation and migration of HSC, high ROS levels occur and act as a signaling response to promote cell migration and differentiation, ultimately contributing to maintaining hematopoiesis and immune function.

Figure 3

Representative MALDI-MS images of sectioned femurs showing niche distribution in bone marrow of GSH and GSSG in WT and Gstp1/p2^−/− mice. From left to right: scanned image of matrix sprayed MALDI slide of mouse femur with bone marrow; corresponding images of: GSH ions at m/z = 306.08; GSSG ions at m/z = 611.14. Color heat map of the data points in the GSH and GSSG images represent averaged individual ion signal intensities of the spots (taken from [175]).