Necrotic cell death has long been considered an accidental and uncontrolled mode of cell death. But recently it has become clear that
necrosis is a molecularly regulated event that is associated with pathologies such as
ischemia-reperfusion (IR) injury, neurodegeneration and pathogen
infection. The
serine/threonine kinase receptor-interacting
protein 1 (RIP1) plays a crucial role during the initiation of
necrosis induced by
ligand-receptor interactions. On the other hand,
ATP depletion is an initiating factor in
ischemia-induced necrotic cell death. Common players in necrotic cell death irrespective of the stimulus are
calcium and
reactive oxygen species (ROS). During
necrosis, elevated cytosolic
calcium levels typically lead to mitochondrial
calcium overload, bioenergetics effects, and activation of
proteases and
phospholipases. ROS initiates damage to
lipids,
proteins and
DNA and consequently results in
mitochondrial dysfunction, ion balance deregulation and loss of membrane integrity. Membrane destabilization during
necrosis is also mediated by other factors, such as
acid-
sphingomyelinase (ASM),
phospholipase A(2) (PLA(2)) and calpains. Furthermore, necrotic cells release immunomodulatory factors that lead to recognition and engulfment by phagocytes and the subsequent immunological response. The knowledge of the molecular mechanisms involved in
necrosis has contributed to our under-standing of
necrosis-associated pathologies. In this review we will focus on the intracellular and intercellular signaling events in
necrosis induced by different stimuli, such as oxidative stress,
cytokines and
pathogen-associated molecular patterns (
PAMPs), which can be linked to several pathologies such as
stroke,
cardiac failure,
neurodegenerative diseases, and
infections.