Regulation of reactive oxygen species generation in cell signaling

Abstract

Reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide (H(2)O(2)) are thought to be byproducts of aerobic respiration with damaging effects on DNA, protein, and lipid. A growing body of evidence indicates, however, that ROS are involved in the maintenance of redox homeostasis and various cellular signaling pathways. ROS are generated from diverse sources including mitochondrial respiratory chain, enzymatic activation of cytochrome p450, and NADPH oxidases further suggesting involvement in a complex array of cellular processes. This review summarizes the production and function of ROS. In particular, how cytosolic and membrane proteins regulate ROS generation for intracellular redox signaling will be detailed.

Fig. 1.. Mitochondrial ROS accumulation in response to various stimuli. Mitochondria sense various external signals and stresses to induce mitochondrial ROS release to the cytosol. Mitochondrial ROS are indispensible for normal cellular function. However, dysregulation of mitochondrial ROS production or release to the cytosol is implicated in many diseases, especially those involving inflammation.

Fig. 2.. TNF-α-induced ROS production through Romo1 and Bcl-X_L. In response to TNF-α, TNF-α signaling complex II is translocated into the mitochondria and interacts with the C-terminal region of Romo1. Simultaneously, Romo1 recruits Bcl-X_L and mediates the early TNF-α- induced decrease of ΔΨm, probably by binding to Bcl-X_L and preventing its function. Subsequently, TNF-α-induced decrease of ΔΨm triggers ROS production, which leads to the late decrease of ΔΨm and ROS production. Eventually, the amplified ROS generation induces prolonged JNK activation and apoptotic cell death.

Fig. 3.. The catalytic cycle of cytochrome p450 (CYP) with the main cycle that leads to substrate hydroxylation (shown in black arrows) and with the leaky branches that lead to ROS production (shown in red arrows). See text for details.

Fig. 4.. Structure and activation of NADPH oxidase (Nox) isozymes. Nox isozymes contain six transmembrane α-helical domains containing tandem heme binding sites in NH₂-terminal region and NADPH- and FAD-binding sites in long carboxyl terminal region. Nox1, Nox3, and Nox4 have similar structure with Nox2 and then categorized into prototype. Nox5 and Duox1/2 bear EF hand structure in NH₂-terminal region. Additional peroxidasge-like domain of Duox is located in extracellular NH₂-terminal region. p22^phox protein contains proline rich region (PRR) providing a binding site for p47^phox and NoxO1. See text for details.