title: Molecular mechanisms and pathophysiology of necrotic cell death.
abstract: 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.
authors.affiliation: Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, 9052 Ghent, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Vanlangenakker
authors.forename: Tom
authors.initials: T
authors.lastname: Vanden Berghe
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Krysko
authors.forename: Nele
authors.initials: N
authors.lastname: Festjens
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D015227:Lipid Peroxidation; D008954:Models, Biological; D009336:Necrosis / Q000209:etiology / Q000378:metabolism*; D054467:Phospholipases A2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D054467:Phospholipases A2; D013108:Sphingomyelin Phosphodiesterase