title: Molecular mechanisms of regulated necrosis.
abstract: It is now clear that apoptosis does not constitute the sole genetically encoded form of cell death. Rather, cells can spontaneously undertake or exogenously be driven into a cell death subroutine that manifests with necrotic features, yet can be inhibited by pharmacological and genetic interventions. As regulated necrosis (RN) plays a major role in both physiological scenarios (e.g., embryonic development) and pathological settings (e.g., ischemic disorders), consistent efforts have been made throughout the last decade toward the characterization of the molecular mechanisms that underlie this cell death modality. Contrarily to initial beliefs, RN does not invariably result from the activation of a receptor interacting protein kinase 3 (RIPK3)-dependent signaling pathway, but may be ignited by distinct molecular networks. Nowadays, various types of RN have been characterized, including (but not limited to) necroptosis, mitochondrial permeability transition (MPT)-dependent RN and parthanatos. Of note, the inhibition of only one of these modules generally exerts limited cytoprotective effects in vivo, underscoring the degree of interconnectivity that characterizes RN. Here, we review the signaling pathways, pathophysiological relevance and therapeutic implications of the major molecular cascades that underlie RN.
authors.affiliation: Gustave Roussy, F-94805 Villejuif, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, F-75005 Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, F-75005 Paris, France.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, F-75005 Paris, France; INSERM, U848, F-94805 Villejuif, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, F-94805 Villejuif, France.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.affiliation: Division for Nephrology and Hypertension, Christian-Albrechts-University, D-24118 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krautwald
authors.affiliation: Université Paris Descartes/Paris V, Sorbonne Paris Cité, F-75005 Paris, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, F-75005 Paris, France; INSERM, U848, F-94805 Villejuif, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, F-94805 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, F-75015 Paris, France. Electronic address: kroemer@orange.fr.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Division for Nephrology and Hypertension, Christian-Albrechts-University, D-24118 Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
mesh_terms: D053181:Caspase 8 / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D008954:Models, Biological; D009336:Necrosis / Q000378:metabolism / Q000503:physiopathology*; D011494:Protein Kinases / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8
keywords: AIF; Entosis; Ferroptosis; Mitochondrial membrane permeabilization; Pyroptosis; RIPK3