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Review
. 2022 Nov 1;14(11):a041079.
doi: 10.1101/cshperspect.a041079.

Nonapoptotic Cell Death Pathways

Douglas R Green  1
Affiliations
Review

Nonapoptotic Cell Death Pathways

Douglas R Green. Cold Spring Harb Perspect Biol. .
No abstract available

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
A fibroblast cell dying by necrosis. (Reprinted from Edinger and Thompson 2004, ©2004 with permission from Elsevier.)
Figure 2.
Figure 2.
Apoptosis and secondary necrosis. Living cell (left), apoptotic cell (center), and secondary necrosis (right). Note that, in secondary necrosis, the nucleus is condensed, as in apoptosis. (Reprinted with permission from Springer Science+Business Media: Silva et al. 2008, ©2008.)
Figure 3.
Figure 3.
Tumor necrosis factor receptor (TNFR) signaling engages necroptosis if FADD–caspase-8–FLIP activity is blocked or overwhelmed.
Figure 4.
Figure 4.
Other pathways can activate RIPK3 and necroptosis. Some Toll-like receptors (e.g., TLR3, TLR4) engage the adapter protein TRIF when they are activated by their ligands. TRIF contains a RIP-homology interaction motif (RHIM) that interacts with the RHIM of RIPK3 directly, activating the kinase. ZBP1 (DAI) is an intracellular sensor of viral nucleic acids, and it too can directly activate RIPK3 via RHIM–RHIM interactions. The figure shows activation of necroptosis in the absence of RIPK1. When RIPK1 is present, the interactions are more complex. The function of MLKL is discussed below.
Figure 5.
Figure 5.
Structure of the mixed-lineage kinase domain-like protein MLKL. (Left) The amino-terminal bundle, brace, and pseudokinase domain are shown. (Right) MLKL is the weapon of necroptosis. (Model made by Dr. Scott Brown, St. Jude Children's Research Institute.)
Figure 6.
Figure 6.
Dimerizing the amino-terminal bundle of the mixed-lineage kinase domain-like protein MLKL. (A) Scheme of a chimeric protein that can be expressed in cells. The amino-terminal bundle of MLKL is fused to a domain (FKBP) that can be bound by a cell-permeable dimeric drug that can connect two chimeric monomers. (B) A three-dimensional electron micrograph of cells expressing the construct in A. Without the dimerizer agent, the plasma membrane remains intact (left), but, upon addition of the dimerizer (right), the plasma membrane is rapidly destroyed, although intracellular membranes appear unaffected. (3D scanning electron micrographs by Dr. Giovanni Quarato and Dr. Sharon Frase, St. Jude Children's Research Institute.)
Figure 7.
Figure 7.
The FADD–caspase-8–FLIP complex inhibits necroptosis. RIPK1 binds to FADD, which in turn is bound to caspase-8–FLIP. The catalytically active caspase-8–FLIP cleaves RIPK1 to prevent necroptosis.
Figure 8.
Figure 8.
The two faces of RIPK1. (A) The complex inhibitory “balancing act” between FADD–caspase-8–FLIP and RIPK3–MLKL interactions depends on RIPK1 to prevent both apoptosis and necroptosis, resulting in normal development. (B) When RIPK1 is removed, both apoptosis and necroptosis occur, and signals promote lethality. (C) Removal of either RIPK3 or MLKL in RIPK1-deficient animals (or cells) does not restore survival in RIPK1-deficient animals (or cells), as apoptosis still occurs. (D) Removal of either FADD or caspase-8 in RIPK1-deficient animals does not restore survival, as necroptosis still occurs. (E) Removal of either RIPK3 or MLKL plus either caspase-8 or FADD allows RIPK1-deficient animals to survive.
Figure 9.
Figure 9.
RIPK3 and pancreatic injury. Wild-type (left) or RIPK3-deficient (right) mice were treated with an agent that induces necrotic injury in the pancreas. Animals without RIPK3 were protected. This protection has also been described in animals lacking the mixed-lineage kinase-like protein MLKL. (Reprinted from He et al. 2009, ©2009 with permission from Elsevier.)
Figure 10.
Figure 10.
One view of excitotoxicity. Calcium influx triggers NADPH oxidase, which produces reactive oxygen species (damaging DNA and inducing the poly(ADP-ribose) polymerase PARP) and hydrogen ions (creating plasma membrane charge). Necrosis occurs as a consequence of energy depletion.
Figure 11.
Figure 11.
One view of ischemia–reperfusion injury. Reperfusion induces an opening in potassium channels, and, in turn, the change in potassium opens calcium channels. The influx of calcium triggers NADPH oxidase, and its consequences, and activates calpain, a protease. Death can be a consequence of energy depletion, calpain action, or both. Other forms of cell death contribute to this form of injury, including apoptosis and probably necroptosis and ferroptosis (see below).
Figure 12.
Figure 12.
The mitochondrial permeability transition (MPT) in ischemia–reperfusion injury. Elevated calcium induces the MPT, which disrupts energy generation and curtails scavenging of reactive oxygen species (ROS). Mice lacking the MPT are resistant to ischemia–reperfusion injury.
Figure 13.
Figure 13.
Ferroptosis. Iron (Fe2+) is transported into cells by transferrin, where it can catalyze the oxidation of lipids by hydrogen peroxide (H2O2) in the cell to form toxic lipid peroxides. System Xc− imports cystine (exporting glutamate), which is converted to cysteine and used in the generation of glutathione. The enzyme GPX4 reduces lipid peroxides but requires glutathione to regenerate its reducing potential. Disruption of System Xc−, glutathione synthesis, or GPX4 function can therefore result in ferroptosis.
Figure 14.
Figure 14.
Autophagosomes. Shown are early autophagosomes (AVi) and autophagolysosomes (AVd). (Reprinted from Eskelinen 2008, ©2008 with permission from Elsevier.)
Figure 15.
Figure 15.
Simplified, hierarchical autophagy pathway. (Left) At the cytosolic face of the endoplasmic reticulum (ER), the serine kinase complex, activated, for example, by conditions of nutrient restriction, recruits and activates the phosphoinositide 3-kinase complex, which, in turn, promotes the assembly of the ligase complex. The latter directly conjugates the small molecules of the LC3 family to lipid in the ER membrane. (Center) The membrane is then extruded to form the phagophore. (Right) The phagophore seals to form a double-membrane structure, the autophagosome, trapping cytosolic material.
Figure 16.
Figure 16.
The initial steps in autophagy.
Figure 17.
Figure 17.
LC3 and the phagophore. The interaction of motor proteins with lipidated LC3 in the membrane to promote membrane extrusion is speculative. LC3 proteins also function at a later step in the fusion of the phagophore to form the autophagosome.
Figure 18.
Figure 18.
mTOR and autophagy.
Figure 19.
Figure 19.
An autophagic survivor. Arrows indicate autophagosomes. (Reprinted from Lum et al. 2005, ©2005 with permission from Elsevier.)
Figure 20.
Figure 20.
Mitophagy mediated by PINK1–PARKIN.
Figure 21.
Figure 21.
Mitophagy in action. Immunoelectron microscopy showing double-membrane autophagosome with associated LC3 (black dots), enclosing a damaged mitochondrion. (Courtesy of Ynjie Wei and Beth Levine.)
Figure 22.
Figure 22.
Hypothetical connection between autophagy and necrosis. Abundant ATG5–ATG12 on the phagophore can bind FADD. This might recruit RIPK1 and RIPK3 to signal for necroptosis.
Figure 23.
Figure 23.
γ-Irradiation causes nonapoptotic cell death in intestines lacking BAX and BAK. Mice with (left) or without (right) intestinal BAX and BAK were irradiated. Although apoptosis (green stars) was decreased, cell death nevertheless occurred in the deficient cells. This was associated with abnormal mitosis. (Reprinted from Kirsch et al. 2010, ©2010 with permission from AAAS.)
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References

    1. Green DR. 2022a. The death receptor pathway of apoptosis. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041053 - DOI - PMC - PubMed
    1. Green DR. 2022b. The burial: clearance and consequences. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041087 - DOI - PMC - PubMed
    1. Green DR. 2022c. Inflammasomes and other caspase-activation platforms. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041061 - DOI - PMC - PubMed
    1. Green DR. 2022d. A matter of life and death. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041004 - DOI - PMC - PubMed
    1. Green DR. 2022e. The future of death. Cold Spring Harb Perspect Biol 10.1101/cshperspect.a041111 - DOI - PMC - PubMed

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