Necrosis: Molecular mechanisms and physiological roles

Abstract

For a long time, necrosis has been considered an accidental and uncontrolled form of cell death, lacking underlying signaling events. However, accumulating evidence supports the existence of a caspase-independent cell death pathway that is also regulated and controlled. This regulated form of necrosis seems to be of relevance in both physiological and pathological conditions. For example, necrosis occurs during excitotoxicity, ischemia-reperfusion injury, neurodegenerative diseases, and infections. Research over the past decade indicates that necrosis results from an extensive interplay between several signaling events and a wide range of mediators. However, it is still not clear whether these many mediators represent various subroutines in different cell lines and what the precise relationship is between the signaling events and the activation of the mediators. The serine/threonine kinase receptor-interacting protein 1 (RIP1) apparently is a central initiator of necrotic cell death. Reactive oxygen species (ROS) and calcium are important mediators of necrosis, but several other mediators have also been described, such as phospholipases, calpains, cathepsins, ceramide, and methylglyoxal, all of which contribute to the disruption of organelles and the plasma membrane. Necrotically dying cells initiate a proinflammatory response by actively releasing immunomodulatory factors and passively releasing their contents when they lyse. Knowledge of the molecular mechanisms involved in necrosis has contributed to the development of therapeutic strategies for the treatment of pathologies associated with necrosis. This chapter focuses on the molecular events during regulated necrotic cell death and the link with several necrosis-associated pathologies.