Types of cell death

Classification: Accident or Program

Pathogenic factors can lead to two main outcomes: necrosis followed by lysis (necropolysis) or apoptosis followed by phagocytosis. Globally, all types of cell death are divided into two large groups.

The first is accidental necrosis. It represents an unregulated process that occurs in response to severe external injury. The cell swells, and its membrane ruptures. This releases DAMPs (Damage-Associated Molecular Patterns), which serve as danger signals.

The second group comprises regulated types of cell death. These are genetically programmed processes, which include apoptosis, necroptosis, ferroptosis, and pyroptosis.

Apoptosis: "Silent" Death

Apoptosis is a classic example of programmed cell death that does not cause inflammation.

• Key enzymes: the process is executed with the participation of caspase-8 and caspase-3.
• Morphology: the cell does not rupture, but neatly breaks down into fragments—apoptotic bodies—which are then phagocytosed by other cells.
• Secretion: anti-inflammatory molecules are released, and the cell contents do not enter the external environment.

Regulated Death with Inflammation

Unlike apoptosis, other types of programmed cell death are accompanied by the release of DAMPs and an inflammatory response.

• Necroptosis. Triggered in the absence or inactivation of caspase-8. Outwardly resembles accidental necrosis (membrane rupture occurs), but is strictly genetically controlled. Accompanied by the release of cytokines (e.g., IL-6) and chemokines.
• Ferroptosis. The mechanism is centered on lipid peroxidation of cell membranes. The process depends on iron and glutathione. A key factor is the impaired function of the enzyme glutathione peroxidase 4 (GPX4), which leads to the accumulation of reactive oxygen species (ROS).
• Pyroptosis. Cell death accompanied by pronounced inflammation. It involves specific human enzymes: h-caspase-1, h-caspase-4, and h-caspase-5. The cell releases pro-inflammatory cytokines, specifically IL-1$\beta$ and IL-18.

Disposal of Cellular Debris: Lysis and Autophagy

Following the death of a cell or its organelles, their destruction takes place. Lysis (destruction of the dead cell) proceeds via two pathways:

1. Autolysis (self-destruction) is executed by lysosomal enzymes activated within the cell itself. Excess ROS and free radicals are involved in the process.
2. Heterolysis—destruction occurs with the participation of other cells (phagocytes) or microorganisms.

A distinct variant of lysis is immunogenic cell death. Its goal is the elimination of foreign (e.g., viral) or endogenous antigens by activating adaptive immune response mechanisms.

To destroy damaged or obsolete organelles within the cell, autophagy exists:

• Microautophagy: lysosomes fuse with denatured macromolecules or membrane fragments for hydrolysis.
• Macroautophagy: a large vacuole forms—the autophagosome (derived from fragments of the cytolemma, cytoplasm, and altered organelles). It fuses with a lysosome to form an autolysosome, where hydrolysis takes place.
• Chaperone-mediated autophagy: transport of denatured proteins to the lysosome. hsc-70 pool chaperones bind to the protein, and the lysosome-associated membrane protein LAMP-2 acts as a receptor for this complex.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of autophagosome and autolysosome formation during macroautophagy.
• The role of hsc-70 chaperones and LAMP-2 receptors in targeted protein transport.
• Differences between autolysis and heterolysis during the destruction of a dead cell.
• Immunogenic cell death: mechanisms of adaptive immune response activation.
• Specific caspase cascades: the role of caspase-8 in apoptosis and h-caspases 1, 4, 5 in pyroptosis.

Other topics in "Chapter 4: Cell Injury as the Basis for the Development of Various Forms of Human Pathology"

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