Intrinsic apoptosis. In response to multiple intracellular stress conditions (e.g., DNA damage, cytosolic Ca²⁺ overload), pro-survival and pro-death signals are generated and converge to a mitochondrion-centered control mechanism. When lethal signals prevail, mitochondrial outer membrane permeabilization (MOMP) occurs and leads to mitochondrial transmembrane potential (Δψ_m) dissipation, arrest of mitochondrial ATP synthesis and Δψ_m-dependent transport activities. Moreover, the respiratory chains gets uncoupled, leading to reactive oxygen species (ROS) overgeneration, and proteins that are normally confined within the mitochondrial intermembrane space (IMS) are released into the cytosol. Among these, cytochrome c (CYTC) drives – together with the cytoplasmic adaptor protein APAF1 and dATP – the assembly of the so-called apoptosome, a multiprotein complex that triggers the caspase-9 → caspase-3 proteolytic cascade. Direct IAP-binding protein with low pI (DIABLO, also known as second mitochondria-derived activator of caspases, SMAC) and high temperature requirement protein A2 (HTRA2) facilitate caspase activation by sequestering and/or degrading several members of the inhibitor of apoptosis protein (IAP) family. On the contrary, apoptosis-inducing factor (AIF) and endonuclease G (ENDOG) function in a caspase-independent manner by relocating to the nucleus and mediating large-scale DNA fragmentation. Of note, the serine protease HTRA2 also contributes to caspase-independent apoptosis by cleaving a wide array of cellular substrates (including cytoskeletal proteins). IM, mitochondrial inner membrane; OM, mitochondrial outer membrane; PTPC, permeability transition pore complex

Autophagic cell death. In response to stress and during development, eukaryotic cells often activate autophagy, a mechanism whereby organelles and portion of the cytoplasm are sequestered in double-membraned vesicles (autophagosomes) that are delivered to lysosomes for degradation. Stress-induced autophagy most often exerts cytoprotective functions and favors the re-establishment of homeostasis and survival (a). In this setting, pharmacological or genetic inhibition of autophagy accelerates cell death. On the contrary, these interventions frequently inhibit developmental cell death, indicating that autophagy also constitutes a lethal mechanism that mediates ‘autophagic cell death' (b)

Extrinsic apoptosis. Upon FAS ligand (FASL) binding, the cytoplasmic tails of FAS (also known as CD95, a prototypic death receptor) trimers recruit (among other proteins) FAS-associated protein with a death domain (FADD), cellular inhibitor of apoptosis proteins (cIAPs), c-FLIPs and pro-caspase-8 (or -10). This supramolecular platform, which has been dubbed ‘death-inducing signaling complex' (DISC), controls the activation of caspase-8 (-10). Within the DISC, c-FLIPs and cIAPs exert pro-survival functions. However, when lethal signals prevail, caspase-8 gets activated and can directly trigger the caspase cascade by mediating the proteolytic maturation of caspase-3 (in type I cells) or stimulate mitochondrial outer membrane permeabilization (MOMP) by cleaving the BH3-only protein BID (in type II cells). Extrinsic apoptosis can also be ignited by dependence receptors like DCC or UNC5B, which relay lethal signals in the absence of their ligand (netrin-1). In the case of DCC and UNC5B, the pro-apoptotic signaling proceeds through the assembly of a DRAL- and TUCAN- (or NLRP1-) containing caspase-9-activating platform or by the dephosphorylation-mediated activation of death-associated protein kinase 1 (DAPK1) by UNC5B-bound protein phosphatase 2A (PP2A), respectively. DAPK1 can mediate the direct activation of executioner caspases or favor MOMP. tBID, truncated BID

Regulated necrosis. Upon tumor necrosis factor α (TNFα) binding, the cytoplasmic tails of TNF receptor 1 (TNFR1, a prototypic death receptor) trimers recruit TNFR-associated death domain (TRADD), receptor-interacting protein kinase 1 (RIP1), cellular inhibitor of apoptosis 1 (cIAP1), cIAP2, TNFR-associated factor 2 (TRAF2) and TRAF5. Within the so-called complex I, RIP1 is polyubiquitinated by cIAPs, thereby providing a docking site for the recruitment of transforming growth factor β (TGFβ)-activated kinase 1 (TAK1), TAK1-binding protein 2 (TAB2) and TAB3 (which together deliver a pro-survival signal by activating the transcription factor NF-κB). In some pathophysiological and experimental settings, and in particular when caspase-8 is absent or when caspases are inhibited by pharmacological agents, cylindromatosis (CYLD)-deubiquitinated RIP1 engage in physical and functional interactions with its homolog RIP3, ultimately activating the execution of necrotic cell death. Regulated necrosis can also be induced by alkylating DNA damage (possibly by the overactivation of poly(ADP-ribose) polymerase 1, PARP1). In some (but not all) instances, regulated necrosis requires the kinase activity of RIP1, that is, it can be blocked by the RIP1-targeting compounds necrostatins. FADD, FAS-associated protein with a death domain

Mitotic catastrophe. (a) In the absence of chemical and genetic perturbations of the mitotic apparatus (including chromosomes and the molecular machinery that ensures their faithful segregation), cells progress through the different phases of the cell cycle to generate a diploid offspring. On the contrary, if chromosomal defects or problems affecting the mitotic machinery are sensed during the M phase, cells become arrested in mitosis due to the activation of mitotic catastrophe (b–d). These cells can undergo different fates: they can die without exiting mitosis (b), reach the G₁ phase of the subsequent cell cycle (through a phenomenon that is known as mitotic slippage) and then die (c), or exit mitosis and undergo senescence (d). Irrespective of this diversity of outcomes, mitotic catastrophe can be defined as an oncosuppressive mechanism that precedes and is distinct from, but operates through, cell death and senescence