The Yin and Yang of redox regulation

Abstract

Mammalian cells produce reactive oxygen and nitrogen species (ROS/RNOS) in response to an oxidative environment. Powerful antioxidant mechanisms have been developed in order to avoid oxidative stress by contributing to the maintenance of redox homeostasis. Traditionally, accumulation of ROS/RNOS is considered deleterious for cells as it can lead to loss of cellular function, aging, and cell death. Consequently, ROS/RNOS imbalance has been implicated in the etiology and/or progression of numerous pathologies such as cardiovascular diseases, inflammation, and cancer. An interesting concept that has emerged more recently is that not only have cells developed efficient systems to cope with ROS/RNOS accumulation but they have also learned to profit of them under certain circumstances. This notion is supported by data showing that ROS/RNOS can act as signaling molecules affecting the function and activity of a multiplicity of protein kinases and phosphatases controlling cellular homeostasis. This review does not provide an exhaustive overview of molecular mechanisms linked to ROS/RNOS generation and processing but includes relevant examples highlighting the dichotomic nature of these small molecules and the multitude of effects elicited by their accumulation. This aspect of ROS/RNOS ought to be taken into account particularly in novel therapeutic setups that aim to achieve high efficiency and minimal or no side effects.

Figure 1.

ROS production from mitochondria in the wild-type Saccharomyces cerevisiae strain BY4743 (left) and in an isogenic strain where the gene encoding the subunit Cox6p of cytochrome c oxidase has been deleted (right). The latter strain is respiratory incompetent. ROS is determined as hydrogen peroxide using an amplex red peroxidase assay.⁷² Resorufin fluorescence results from oxidation of amplex red by H₂O₂, catalyzed by peroxidase. In the BY4743 wild-type strain ROS production is very low following onset of respiration by glucose, but increases dramatically following addition of cyanide, which inhibits respiration 100%. In the cox6Δ mutant strain ROS production is always high. Both strains were starved for three hours before the experiment in order to empty the cells for endogenous substrate.

Figure 2.

Schematic representation of pro-survival and cell death mechanisms in oxidative stress, respectively. Complex regulatory signals lead to cell death or proliferation. Cell decision is taken on the base of the levels and activity of antioxidant enzymes, level of ROS/RNOS and location. R, receptor; TNF, tumor necrosis factor; ASK1, apoptosis signal-regulating kinase 1; AIF, apoptosis inducing factor; MAPK, mitogen-activated protein kinase; CAD, caspase-activated DNase; Endo-G, endonuclease G; Apaf-1, apoptotic protease activating factor 1; HIF-1, hypoxia-inducible factor 1.