Clinical review: oxygen as a signaling molecule

Abstract

Molecular oxygen is obviously essential for conserving energy in a form useable for aerobic life; however, its utilization comes at a cost--the production of reactive oxygen species (ROS). ROS can be highly damaging to a range of biological macromolecules, and in the past the overproduction of these short-lived molecules in a variety of disease states was thought to be exclusively toxic to cells and tissues such as the lung. Recent basic research, however, has indicated that ROS production--in particular, the production of hydrogen peroxide--plays an important role in both intracellular and extracellular signal transduction that involves diverse functions from vascular health to host defense. The present review summarizes oxygen's capacity, acting through its reactive intermediates, to recruit the enzymatic antioxidant defenses, to stimulate cell repair processes, and to mitigate cellular damage.

Figure 1

Molecular oxygen use by enzyme systems leading to reactive oxygen species production and downstream consequences. Oxygen (O₂) not only leads to superoxide anion (·O₂^-) generation by mitochondria and monooxygenases, but is also required for the enzymatic production of the important signaling molecules nitric oxide (NO) and carbon monoxide (CO). Some oxygen-derived reactive oxygen intermediates such as hydrogen peroxide (H₂O₂) have pluripotent effects in the cell that are not only detrimental, such as protein and DNA oxidation and lipid peroxidation, but are beneficial and adaptive, for instance by enhancement of the antioxidant defenses. Ask1, apoptosis-signaling kinase 1; Fe, iron; HIF-1, hypoxia inducible factor 1; iNOS/eNOS, inducible nitric oxide synthase/endogenous nitric oxide synthase; ONOO^-, peroxynitrite anion; PI3K, phosphoinositide 3-kinase; SOD, superoxide dismutase.

Figure 2

Complete and incomplete reduction of molecular oxygen. The production of specific reactive oxygen species by single electron additions (e^-).

Figure 3

Schematic of Nrf2 response to mitochondrial hydrogen peroxide production. Hydrogen peroxide (H₂O₂)-based molecular signal transduction involving the constitutive Nrf2 transcription factor, which is normally targeted for ubiquitination and degradation (step 1). Various oxidative and electrophilic stresses can stabilize Nrf2 by the oxidation of the kelch-like ECH-associating protein-1 (Keap1) adaptor molecule, allowing free Nrf2 to translocate to the nucleus. The diagram indicates the role of oxidative damage and increased mitochondrial H₂O₂ production (step 2) in the stabilization of Nrf2 (step 3), and activation of genes that contain the antioxidant response element (ARE) consensus sequence - in this case, superoxide dismutase (SOD2) (step 4).