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. 2023 Aug 23;55(8):1595–1619. doi: 10.1038/s12276-023-01046-5

Fig. 5. Mitochondria-associated nonapoptotic cell death.

Fig. 5

a Necroptosis is formed from necroptosis-driving factors such as TNF α binding with complementary receptors to recruit RIPK1, where the engagement renders RIPK1 and RIPK3 activated, which fuels necrosome configuration. The necrosome thereafter phosphorylates and activates MLKL, which is translocated to and permeabilizes the plasma membrane and permits DAMP release. b Ferroptosis is driven by iron-dependent lipid peroxidation and ROS overexpression. GPX4 converts excessive peroxides into lipid alcohols to mitigate this process under normal conditions; however, once stimuli occur, overexpressed superoxide from OXPHOS complexes reacts with ferrous ions to yield a slew of unstable radicals, leading to excessive ROS and, afterward, lipid peroxidation reboots to induce ferroptosis. Another route to ferroptosis is the buildup of lipid peroxide by circumstances such as cysteine deprivation, which induces the breakdown of certain iron-binding proteins, including FtMt and heme, to free iron and ROS, therefore triggering nearby MLP and hence ferroptosis. c Pyroptosis is initiated by the pathogen component-activated inflammatory caspase response, which not only converts IL‐1β and IL‐18 to mature forms but also cleaves GSDMD to facilitate pore penetration and enable IL-1β and IL-18 release, thus resulting in cell swelling and pyroptosis. Apart from these, inflammatory stimuli also lead to pyroptosome-mediated caspase-3 activation and GSDME cleavage to unleash membrane permeabilization to favor the release of ions and mtDNA to induce pyroptosis. DAMPs Damage-Associated Molecular Patterns, MLKL Mixed-Lineage Kinase Domain-Like pseudokinase, PDH pyruvate dehydrogenase, GPX4 Glutathione Peroxidase 4, TCA Tricarboxylic acid cycle, ETC Electron Transport Chain, GSH Glutathione, MLP Membrane Lipid Peroxidation, FtMt Mitochondrial Ferritin, α-KG Alpha-ketoglutarate, IDH2 Isocitrate Dehydrogenase 2, NADH Nicotinamide Adenine Dinucleotide Dehydrogenase, OXPHOS mitochondrial Oxidative Phosphorylation System, GSDMD Gasdermin D, GSDME Gasdermin E, IL-18 Interleukin-18, IL-1β Interleukin-1β.