Edinburgh Research Explorer Molecular mechanisms of cell death Citation for published version: Galluzzi, L, Vitale, I, Aaronson, SA, Abrams, JM, Adam, D, Agostinis, P, Alnemri, ES, Altucci, L, Amelio, I, Andrews, DW, Annicchiarico-Petruzzelli, M, Antonov, AV, Arama, E, Baehrecke, EH, Barlev, NA, Bazan, NG, Bernassola, F, Bertrand, MJM, Bianchi, K, Blagosklonny, MV, Blomgren, K, Borner, C, Boya, P, Brenner, C, Campanella, M, Candi, E, Carmona-Gutierrez, D, Cecconi, F, Chan, FK-M, Chandel, NS, Cheng, EH, Chipuk, JE, Cidlowski, JA, Ciechanover, A, Cohen, GM, Conrad, M, Cubillos-Ruiz, JR, Czabotar, PE, D'Angiolella, V, Dawson, TM, Dawson, VL, De laurenzi, V, De Maria, R, Debatin, K-M, DeBerardinis, RJ, Deshmukh, M, Di Daniele, N, Di Virgilio, F, Dixit, VM, Dixon, SJ, Duckett, CS, Dynlacht, BD, El-Deiry, WS, Elrod, JW, Fimia, GM, Fulda, S, Garcia-Saez, AJ, Garg, AD, Garrido, C, Gavathiotis, E, Golstein, P, Gottlieb, E, Green, DR, Greene, LA, Gronemeyer, H, Gross, A, Hajnoczky, G, Hardwick, JM, Harris, IS, Hengartner, MO, Hetz, C, Ichijo, H, Jaattela, M, Joseph, B, Jost, PJ, Juin, PP, Kaiser, WJ, Karin, M, Kaufmann, T, Kepp, O, Kimchi, A, Kitsis, RN, Klionsky, DJ, Knight, RA, Kumar, S, Lee, SW, Lemasters, JJ, Levine, B, Linkermann, A, Lipton, SA, Lockshin, RA, Lopez-Otin, C, Lowe, SW, Luedde, T, Lugli, E, MacFarlane, M, Madeo, F, Malewicz, M, Malorni, W, Manic, G, Marine, J-C, Martin, SJ, Martinou, J-C, Medema, JP, Mehlen, P, Meier, P, Melino, S, Miao, EA, Molkentin, JD, Moll, UM, Munoz-Pinedo, C, Nagata, S, Nunez, G, Oberst, A, Oren, M, Overholtzer, M, Pagano, M, Panaretakis, T, Pasparakis, M, Penninger, JM, Pereira, DM, Pervaiz, S, Peter, ME, Piacentini, M, Pinton, P, Prehn, JHM, Puthalakath, H, Rabinovich, GA, Rehm, M, Rizzuto, R, Rodrigues, CMP, Rubinsztein, DC, Rudel, T, Ryan, KM, Sayan, E, Scorrano, L, Shao, F, Shi, Y, Silke, J, Simon, H-U, Sistigu, A, Stockwell, BR, Strasser, A, Szabadkai, G, Tait, SWG, Tang, D, Tavernarakis, N, Thorburn, A, Tsujimoto, Y, Turk, B, Vanden Berghe, T, Vandenabeele, P, Heiden, MGV, Villunger, A, Virgin, HW, Vousden, KH, Vucic, D, Wagner, EF, Walczak, H, Wallach, D, Wang, Y, Wells, JA, Wood, W, Yuan, J, Zakeri, Z, Zhivotovsky, B, Zitvogel, L, Melino, G & Kroemer, G 2018, 'Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018', Cell Death and Differentiation, vol. 25, no. 3, pp. 486-541. https://doi.org/10.1038/s41418-017-0012-4 Digital Object Identifier (DOI): 10.1038/s41418-017-0012-4 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Cell Death and Differentiation Cell Death & Differentiation (2018) 25:486–541 https://doi.org/10.1038/s41418-017-0012-4 REVIEW Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 1,2,3 4,5 Lorenzo Galluzzi ● Ilio Vitale et al. Received: 11 October 2017 / Accepted: 13 October 2017 / Published online: 23 January 2018 © The Author(s) 2018. This article is published with open access Abstract Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell 1234567890 death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field. Introduction or accelerated) by pharmacological or genetic interventions [5, 17]. For a long time, cell death has been dismissed by biologists Although the underlying molecular mechanisms exhibit as an inevitable and, hence, spurious consequence of cel- considerable overlap (see below), RCD is involved in two lular life. A large body of experimental evidence accumu- diametrically opposed scenarios. On the one hand, RCD can lating over the past decades, however, has unveiled and occur in the absence of any exogenous environmental per- characterized in ever greater detail a set of genetically turbation, hence operating as a built-in effector of physio- encoded mechanisms for targeted elimination of super- logical programs for development or tissue turnover [6, 18]. fluous, irreversibly damaged, and/or potentially harmful These completely physiological forms of RCD are generally cells [1–4]. Intriguingly, regulated cell death (RCD) is not referred to as programmed cell death (PCD). On the other unique to multicellular life forms, a setting in which RCD hand, RCD can originate from perturbations of the intra- has an obvious advantage for organismal homeostasis in cellular or extracellular microenvironment, when such per- both physiological and pathological settings [5–9], but is turbations are too intense or prolonged for adaptative also found (in simplified variants) among unicellular responses to cope with stress and restore cellular home- eukaryotes living (at least for part of their life cycle) in ostasis [5]. Importantly, stress-driven RCD also constitutes colonies (such as several yeast species and Dictyostelium a strategy for the preservation of a biological equilibrium, discoideum)[10–15], and at least in some prokaryotes (e.g., hence resembling adaptative stress responses. However, Escherichia coli)[16]. In striking contrast with accidental while adaptative stress responses operate at the cellular level cell death (ACD)—the instantaneous and catastrophic (which—by extension—promotes the maintenance of demise of cells exposed to severe insults of physical (e.g., homeostasis at the level of organism or colony), RCD high pressures, temperatures, or osmotic forces), chemical directly operates at the level of the organism or colony in (e.g., extreme pH variations), or mechanical (e.g., shear spite of cellular homeostasis [5]. Such a homeostatic func- forces) nature—RCD relies on a dedicated molecular tion not only reflects the elimination of useless or poten- machinery, implying that it can be modulated (i.e., delayed tially dangerous cells, but also the ability of dying cells to expose or release molecules that alert the organism or col- Extended author information available on the last page of the article ony about a potential threat. Such danger signals are Signaling modules in the control of cell death 487 commonly referred to as damage-associated molecular as the process proceeds to completion, which—in vivo— patterns (DAMPs) or alarmins [19–22]. allows for the rapid clearance by macrophages or other cells Cell death manifests with macroscopic morphological with phagocytic activity (a process commonly known as alterations. Together with the mechanisms whereby dead efferocytosis) [35]. Importantly, intrinsic (and extrinsic, see cells and their fragments are disposed of, such morphotypes below) apoptosis and consequent efferocytosis are not have historically been employed to classify cell death into always immunologically silent, as previously thought (see three different forms: (1) type I cell death or apoptosis, below) [36, 37]. In vitro, end-stage apoptosis is generally exhibiting cytoplasmic shrinkage, chromatin condensation followed by complete breakdown of the plasma membrane (pyknosis), nuclear fragmentation (karyorrhexis), and and the acquisition of a necrotic morphotype (secondary plasma membrane blebbing, culminating with the formation necrosis), unless cultured cells display phagocytic activity of apparently intact small vesicles (commonly known as [38], a process that has recently been linked to the pore- apoptotic bodies) that are efficiently taken up by neigh- forming activity of gasdermin E (GSDME; best known as boring cells with phagocytic activity and degraded within DFNA5) [39]. lysosomes; (2) type II cell death or autophagy, manifesting The critical step for intrinsic apoptosis is irreversible and with extensive cytoplasmic vacuolization and similarly widespread mitochondrial outer membrane permeabilization culminating with phagocytic uptake and consequent lyso- (MOMP) [40, 41], which is controlled by pro-apoptotic and somal degradation; and (3) type III cell death or necrosis, anti-apoptotic members of the BCL2, apoptosis regulator displaying no distinctive features of type I or II cell death (BCL2) protein family, a group of proteins sharing one to and terminating with the disposal of cell corpses in the four BCL2 homology (BH) domains (i.e., BH1, BH2, BH3, absence of obvious phagocytic and lysosomal involvement and BH4) [29, 42, 43]. In response to apoptotic stimuli, [23, 24]. Of note, this morphological classification is still MOMP is mediated by BCL2 associated X, apoptosis reg- extensively employed, irrespective of multiple limitations, ulator (BAX), and/or BCL2 antagonist/killer 1 (BAK1; best and caveats. Starting from 2005, the Nomenclature Com- known