Signalling apoptosis: a radical approach

Reactive oxygen species (ROS) are frequently associated with cytotoxicity, often being described as damaging, harmful or toxic. It is generally assumed that, under pathological circumstances, ROS elicit wide-spread and random acts of oxidation. This passive attack of cellular components by ROS, in conditions where oxidative stress is the initiating stimulus for apoptosis, is assumed to simply trigger cell death as a result of cumulative oxidative damage. However, accumulating evidence now suggests that ROS may act as signalling molecules for the initiation and execution of the apoptotic death programme in many, if not all, current models of apoptotic cell death. Signalling by ROS would not appear to be random, as previously assumed, but targeted at specific metabolic and signal transduction cellular components. There is also evidence that the enzymatic generation of ROS may not simply be an unwanted by-product of the primary reaction catalysed, but that ROS may be used as signalling molecules to regulate cellular processes including apoptosis. This view of ROS as signalling molecules (as opposed to toxic metabolites) has been further bolstered by the findings that cellular antioxidants such as glutathione and thioredoxin not only serve to regulate ROS levels but also act as reversible redox modifiers of enzyme function. This review will attempt to delineate the involvement of ROS in apoptosis in light of these recent discoveries and provide evidence for a crucial role for ROS in the initiation and execution of the death process.