Diversity and complexity of cell death: a historical review

Abstract

Death is the inevitable fate of all living organisms, whether at the individual or cellular level. For a long time, cell death was believed to be an undesirable but unavoidable final outcome of nonfunctioning cells, as inflammation was inevitably triggered in response to damage. However, experimental evidence accumulated over the past few decades has revealed different types of cell death that are genetically programmed to eliminate unnecessary or severely damaged cells that may damage surrounding tissues. Several types of cell death, including apoptosis, necrosis, autophagic cell death, and lysosomal cell death, which are classified as programmed cell death, and pyroptosis, necroptosis, and NETosis, which are classified as inflammatory cell death, have been described over the years. Recently, several novel forms of cell death, namely, mitoptosis, paraptosis, immunogenic cell death, entosis, methuosis, parthanatos, ferroptosis, autosis, alkaliptosis, oxeiptosis, cuproptosis, and erebosis, have been discovered and advanced our understanding of cell death and its complexity. In this review, we provide a historical overview of the discovery and characterization of different forms of cell death and highlight their diversity and complexity. We also briefly discuss the regulatory mechanisms underlying each type of cell death and the implications of cell death in various physiological and pathological contexts. This review provides a comprehensive understanding of different mechanisms of cell death that can be leveraged to develop novel therapeutic strategies for various diseases.

Fig. 1. Timeline of the discovery of cell death.

This timeline depicts the important discoveries and advancements in cell death research, including the recognition of multiple forms of cell death.

Fig. 2. Necrosis and apoptosis: morphological features and signaling pathways.

A Hallmarks of necrosis and apoptosis are illustrated. Necrosis is an uncontrolled and pathological form of cell death, marked by cell swelling, membrane rupture, and intracellular content release, leading to inflammation and tissue damage. In contrast, apoptosis is a tightly controlled form of cell death that involves characteristic morphological features, such as cell shrinkage, chromatin condensation, membrane blebbing, nuclear fragmentation, and apoptotic body formation. B The two signaling pathways that lead to apoptosis are described. The extrinsic pathway is initiated by the binding of death ligands, such as tumor necrosis factor (TNF)-α or Fas ligand (FasL), to death receptors, which activates caspase 8. The intrinsic pathway, regulated by the Bcl-2 family, is triggered by intracellular stressors, such as DNA damage and oxidative stress, resulting in the release of cytochrome c from mitochondria and activation of caspase 9. The two pathways ultimately converge on caspase 3, which mediates the execution of apoptosis.

Fig. 3. Progression and morphological features of autophagy-mediated cell death.

A The figure shows three types of autophagy, namely, macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy involves the formation of double-membrane vesicles that engulf cytoplasmic components and organelles and then fuse with lysosomes to form autolysosomes. Microautophagy involves engulfing cytoplasmic components and organelles directly into lysosomes. Chaperone-mediated autophagy degrades specific proteins via chaperone proteins that transport them to lysosomes. B The figure highlights the contrast between autophagy and autosis, two processes involving autophagy. While autophagic cell death is a result of excessive autophagy, autosis is characterized by three distinct phases characterized by cells with unique morphological features and is triggered by various signals, such as Na⁺/K⁺-ATPase, Tat-Beclin 1, and hypoxia–ischemia.

Fig. 4. Mechanism of lysosomal cell death.

This figure illustrates lysosomal cell death caused by lysosomal membrane permeabilization and the release of lysosomal enzymes into the cytoplasm, leading to the activation of apoptotic cell death pathways. Lysosomal cell death can be induced by stimuli, such as changes in lysosomal pH, oxidative stress, and lysosomotropic agents. The release of lysosomal proteases, such as cathepsins, activates the lysosomal apoptotic pathway by cleaving Bid and degrading antiapoptotic Bcl-2 homologs.

Fig. 5. Comparison of mitoptosis and mitophagy.

This figure illustrates the crucial processes of mitoptosis and mitophagy that maintain mitochondrial quality and prevent cell pathology. A Mitoptosis is characterized by several events, including mitochondrial fission, the clustering of spherical mitochondria in the perinuclear area, enwrapping of these clusters by a membrane to form a “mitoptotic body,” decomposition of mitochondria into small vesicles, protrusion of the body from the cell, and disruption of the boundary membrane. This process is driven by mitochondrial dysfunction and reactive oxygen species (ROS) production. B Mitophagy is a selective autophagic mechanism for the degradation of damaged or unnecessary mitochondria. This procedure requires activation of general autophagy and priming of injured mitochondria via the Pink1/Parkin signaling pathway. Autophagosomes engulf targeted mitochondria, which are then digested and degraded in lysosomes.

Fig. 6. Mechanism underlying immunogenic cell death (ICD).

This figure illustrates the mechanism of ICD and its potential as a cancer therapeutic strategy. During ICD, dying cells release damage-associated molecular patterns (DAMPs), such as ATP, high-mobility group box 1 (HMGB1), and heat shock proteins (HSPs), which activate dendritic cells (DCs) and other immune cells, promoting antigen presentation and immune activation. Effector T cells release interferon (IFN)-γ and TNFα, which activate other immune cells, such as natural killer cells and macrophages that detect and eliminate cancer cells.

Fig. 7. Mechanisms of pyroptosis, NETosis, and necroptosis.

A Pyroptosis is characterized by cell swelling, plasma membrane rupture, and the release of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18. Pyroptosis is triggered by the activation of inflammasomes, cytoplasmic complexes that sense danger signals, and initiate a caspase-1-dependent cascade that ultimately leads to cell death. B NETosis is a process in which neutrophils release DNA fibers coated with antimicrobial peptides to trap and kill pathogens. During NETosis, neutrophils undergo marked morphological changes, including chromatin decondensation, nuclear envelope rupture, and granule mixing, leading to the formation of neutrophil extracellular traps (NETs). The release of NETs is triggered by various stimuli, such as pathogens, cytokines, and immune complexes. C Necroptosis is mediated by death receptors. Upon activation of death receptors, such as TNFR1, receptor-interacting protein kinase 1 (RIPK1) binds to RIPK3 to form a necrosome. The necrosome complex promotes the oligomerization and phosphorylation of the mixed lineage kinase domain-like protein (MLKL). The oligomeric form of MLKL is translocated from the cytosol to the plasma membrane, leading to the formation of membrane pores and subsequent plasma membrane rupture. This results in the release of damage-associated molecular patterns (DAMPs), which trigger inflammation.

Fig. 8. Copper and iron-driven cell death: cuproptosis and ferroptosis.

A Cuproptosis is triggered by the accumulation of copper. It results in mitochondrial stress due to the aggregation of lipoylated mitochondrial enzymes and the loss of Fe–S cluster proteins, which can be mediated by ferredoxin 1 (FDX1). B Ferroptosis is characterized by the depletion of intracellular glutathione and decreased activity of glutathione peroxidase 4 (GPX4), which leads to the accumulation of unmetabolized lipid peroxides and increased ROS production. Membrane damage is also a result of lipid peroxidation.

Fig. 9. Mechanism underlying paraptosis.

Paraptosis is characterized by the development of large vacuoles in the endoplasmic reticulum (ER) and mitochondria, ultimately leading to the formation of large cytoplasmic vacuoles. Impaired proteostasis, altered ion homeostasis, and ER stress cause paraptosis, resulting in the discharge of Ca²⁺ from the ER and accumulation of Ca²⁺ in mitochondria. Paraptosis can be facilitated by the activation of mitogen-activated protein kinase (MAPK) signaling pathways via IGF-IR and inhibited by AIP-1/Alix.

Fig. 10. Molecular basis of methuosis.

This image depicts the working model of methuosis. Methuosis is initiated by prolonged high-level expression of RAS (G12V) and chronic activation of Rac1, which leads to enhanced macropinocytic activity. Moreover, this mechanism hampers macropinosome recycling by lowering the active Arf6 pool. Nascent macropinosomes, which are created from lamellipodial membrane projections, penetrate the cell and merge to form large fluid-filled vacuoles that, in contrast to typical macropinosomes, cannot be recycled. These vacuoles grow rapidly, resulting in a stable population with certain late endosomal features (Rab7 and LAMP1).

Fig. 11. Cell-in-cell structures: a hallmark of entosis.

Entosis is a biological process characterized by the internalization of one living cell into the cytoplasm of another. It is caused by adherent cell matrix separation, which results in the establishment of E-cadherin-mediated cell connections (shown in red) between the engulfing cell and the entotic cell. RhoA activity within the entotic cell causes actomyosin buildup at the cell cortex, resulting in the creation of cell-in-cell structures that mimic an active invasion-like process. Most internalized cells die as a result of entotic cell death, which is followed by lysosome fusion or apoptosis, especially when macroautophagy has been inhibited. However, certain entotic cells may divide within their hosts or even escape death.

Fig. 12. Mechanism underlying parthanatos.

This diagram depicts the molecular processes underlying parthanatos. ROS, ischemia, alkylating chemicals, and radiation activate PARP-1 by activating NOS, resulting in the creation of excess NO and subsequent synthesis of peroxynitrite (ONOO⁻). Peroxynitrite activates PARP-1, resulting in the formation of copious amounts of PAR polymer in the nucleus. Certain poly(ADP)-ribosylated carrier proteins escape from the nucleus, prompting the outer mitochondrial membrane to release apoptosis-inducing factor (AIF). AIF then enters the cytoplasm and attaches to macrophage migration inhibitory factor (MIF). AIF and MIF enter the nucleus and cause widespread DNA degradation, ultimately resulting in cell death.

Fig. 13. Molecular pathways in alkaliptosis.

This figure illustrates the activation mechanism of alkaliptosis, which is characterized by intracellular alkalinization and subsequent cell death. JTC801 activates the IKK protein complex, which includes CHUK (IKKα), IKBKB (IKKβ), and IKBKG (IKKγ). Then, the IKK protein complex phosphorylates and degrades NFKBIA (IκBα), leading to the nuclear translocation of NFKB1 (p50) or RELA (p65), which regulate gene expression. Furthermore, NF-κB negatively regulates the expression of CA9, a member of the carbonic anhydrase family, to inhibit alkaliptosis.

Fig. 14. Mechanism underlying oxeiptosis.

This figure illustrates the key features of oxeiptosis. Oxeiptosis is activated in response to oxidative stress induced by ROS or ROS-generating agents, such as viral pathogens. The KEAP1/PGAM5/AIFM1 signaling pathway plays a central role in oxeiptosis, in which AIFM1 is dephosphorylated under oxidative stress conditions via the regulatory action of PGAM5. Dephosphorylated AIFM1 is translocated from mitochondria to the nucleus, leading to chromatin condensation and DNA fragmentation, ultimately resulting in cell death.

Fig. 15. Structural characteristics of erebosis.

This figure depicts the process of erebosis, a novel form of cell death observed during the natural turnover of enterocytes that constitute the gut epithelium. Nuclear expansion and accumulation of angiotensin-converting enzyme (ACE) are observed in the early stages of erebosis. Subsequently, cell shrinkage and nuclear fragmentation are observed. Late erebotic cells are surrounded by stem cells that eventually undergo division to generate new epithelial cells, contributing to the replenishment of the gut epithelium.

Fig. 16. Classification of cell death.

This figure illustrates the classification of the different forms of cell death and nonlethal processes based on their underlying mechanisms and morphological features. This figure was generated according to the 2018 guidelines for the classification of cell death issued by the Nomenclature Committee on Cell Death (NCCD).

Fig. 17. Complexity of cell death.

This figure illustrates the complex and interconnected nature of cell death pathways. The figure shows the mechanisms by which different types of cell death pathways interact and influence each other and the ways in which they can be regulated by various signaling pathways and environmental factors.

Fig. 18. Overview of PANoptosis.

PANoptosis is triggered by the formation of a protein complex called the PANoptosome, which includes several protein domains, namely, RIPK1, RIPK3, caspase-8, NLRP3, and ASC. This complex activates multiple types of cell death, including pyroptosis, apoptosis, and necroptosis, resulting in an inflammatory cell death response. During influenza A virus (IAV) infection, Z-DNA-binding protein (ZBP1) recognizes viral ribonucleoproteins and induces the formation of the ZBP1-dependent PANoptosome. TGF-β-activated kinase 1 (TAK1) is a crucial regulator of PANoptosis that negatively controls this process; however, bacterial infections can interrupt its suppression. Inhibition of TAK1 and activation of signaling through TLRs or death receptors promotes the formation of RIPK1-dependent PANoptosomes. During PANoptosis, the activation of caspase-1 or caspase-8 leads to the cleavage and activation of downstream effector proteins, such as gasdermin D and RIPK3, which drive pyroptosis and necroptosis, respectively. Activated caspase-8 subsequently cleaves and activates caspase-3, resulting in cell apoptosis.