The process by which a cell can kill itself is called programmed cell death (ZGK). This mechanism has several varieties and plays a crucial role in the physiology of various organisms, especially multicellular ones. The most common and well-studied form of ZGK is apoptosis.
What is apoptosis?
Apoptosis is a controlled physiological process of cell self-destruction, characterized by phased destruction and fragmentation of its contents with the formation of membrane vesicles (apoptotic bodies), subsequently absorbed by phagocytes. This genetically engineered mechanism is activated by certain internal or external factors.
With this variant of death, the cellular content does not extend beyond the membrane and does not cause inflammation. Violations in the regulation of apoptosis lead to serious pathologies, such as uncontrolled cell divisions or tissue degeneration.
Apoptosis is only one of several forms of programmed cell death (ZGK), so it is a mistake to identify these concepts. Mitotic catastrophe, autophagy and programmed necrosis are also known types of cellular self-destruction. Other mechanisms of ZGK are not studied yet.
Causes of Cell Apoptosis
The reason for triggering the programmed cell death mechanism can be both natural physiological processes and pathological changes caused by internal defects or external adverse factors.
Normally, apoptosis balances the process of cell division, regulating their number and promoting tissue renewal. In this case, the cause of ZGK are certain signals that are part of the homeostasis control system. With the help of apoptosis, disposable or fulfilled cells function cells are destroyed. So, the increased content of leukocytes, neutrophils and other elements of cellular immunity at the end of the fight against infection is eliminated precisely due to apoptosis.
Programmed death is part of the physiological cycle of reproductive systems. Apoptosis is involved in the process of oogenesis, and also contributes to the death of the egg in the absence of fertilization.
A classic example of the participation of cell apoptosis in the life cycle of autonomic systems is autumn leaf fall. The term itself comes from the Greek word apoptosis, which literally translates as “falling off”.
Apoptosis plays a crucial role in embryogenesis and ontogenesis, when tissues in the body change and certain organs atrophy. An example is the disappearance of membranes between the fingers of the limbs of some mammals or the death of the tail during the metamorphosis of a frog.
Apoptosis can be triggered by the accumulation of defective changes in the cell resulting from mutations, aging, or mitosis errors. The reason for triggering HGC can be an unfavorable environment (lack of nutrients, oxygen deficiency) and pathological external influences mediated by viruses, bacteria, toxins, etc. Moreover, if the damaging effect is too intense, the cell does not have time to implement the apoptosis mechanism and dies as a result development of the pathological process - necrosis.
Morphological and structural-biochemical changes in the cell during apoptosis
The apoptosis process is characterized by a certain set of morphological changes that can be observed using microscopy in an in vitro tissue preparation.
The main features characteristic of cell apoptosis include:
- rearrangement of the cytoskeleton;
- compaction of cellular contents;
- chromatin condensation;
- core fragmentation;
- decrease in cell volume;
- wrinkling of the contour of the membrane;
- the formation of bubbles on the cell surface,
- destruction of organelles.
In animals, these processes are completed by the formation of apoptocytes, which can be absorbed by both macrophages and neighboring tissue cells. In plants, the formation of apoptotic bodies does not occur, and after protoplast degradation the skeleton in the form of a cell wall is preserved.
In addition to morphological changes, apoptosis is accompanied by a number of rearrangements at the molecular level. There is an increase in lipase and nuclease activities, which entail the fragmentation of chromatin and many proteins. The content of cAMP sharply increases, the structure of the cell membrane changes. The formation of giant vacuoles is observed in plant cells.
How is apoptosis different from necrosis?
The main difference between apoptosis and necrosis is the cause of cellular degradation. In the first case, the source of destruction is the molecular tools of the cell itself, which operate under strict control and require ATP energy expenditure. With necrosis, a passive cessation of vital activity occurs due to external damaging effects.
Apoptosis is a natural physiological process designed in such a way as not to harm the surrounding cells. Necrosis is an uncontrolled pathological phenomenon that occurs as a result of critical injuries. Therefore, it is not surprising that the mechanism, morphology, and consequences of apoptosis and necrosis are largely opposite. However, there are common features.
| Process characteristic | Apoptosis | Necrosis |
| cell volume | decreases | is increasing |
| membrane integrity | saved | broken |
| inflammatory process | is absent | is developing |
| ATP energy | expended | not used |
| chromatin fragmentation | is available | is present |
| sharp drop in ATP concentration | there is | there is |
| process summary | phagocytosis | discharge of contents into the intercellular space |
In case of damage, the cells trigger the programmed death mechanism, in order to prevent necrotic development. However, recent studies have shown that there is another non-pathological form of necrosis, which is also attributed to ZGK.
The biological significance of apoptosis
Despite the fact that apoptosis leads to cell death, its role in maintaining the normal functioning of the whole organism is very large. Thanks to the ZGK mechanism, the following physiological functions are carried out:
- maintaining a balance between proliferation and cell death;
- renewal of tissues and organs;
- elimination of defective and "old" cells;
- protection against the development of pathogenic necrosis;
- tissue and organ change during embryo and ontogenesis;
- removal of unnecessary elements that have completed their function;
- elimination of cells that are undesirable or dangerous for the body (mutant, tumor, infected with the virus);
- prevention of infection.
Thus, apoptosis is one way of maintaining cell-tissue homeostasis.
In plants, apoptosis is often triggered to block the spread of parasitic agrobacteria that infect the tissue.
Stages of Cell Death
What happens to the cell during apoptosis is the result of a complex chain of molecular interactions between different enzymes. Reactions proceed as a cascade, when some proteins activate others, contributing to the gradual development of a death scenario. This process can be divided into several stages:
- Induction.
- Activation of proapoptotic proteins.
- Caspase activation.
- Destruction and rearrangement of cellular organelles.
- The formation of apoptocytes.
- Preparation of cell fragments for phagocytosis.
The synthesis of all the components necessary for the launch, implementation and control of each stage is laid genetically, which is why apoptosis is called programmed cell death. The activation of this process is under the strict control of regulatory systems, including including various ZGK inhibitors.
Molecular mechanisms of cell apoptosis
The development of apoptosis is determined by the combined action of two molecular systems: induction and effector. The first block is responsible for the controlled launch of the ZGK. It includes the so-called death receptors, Cys-Asp proteases (caspases), a number of mitochondrial components and pro-apoptotic proteins. All elements of the induction phase can be divided into triggers (involved in induction) and modulators that provide transduction of the death signal.
The effector system is composed of molecular tools that ensure the degradation and rearrangement of cellular components. The transition between the first and second phases is carried out at the stage of the proteolytic caspase cascade. It is due to the components of the effector block that cell death occurs during apoptosis.
Apoptosis Factors
Structural-morphological and biochemical changes during apoptosis are carried out by a certain set of specialized cellular tools, among which the most important are caspases, nucleases and membrane modifiers.
Caspases are a group of enzymes that cut peptide bonds into asparagine residues, fragmenting proteins into large peptides. Prior to the onset of apoptosis, they are present in the cell in an inactive state due to inhibitors. The main target of caspases are nuclear proteins.
Nucleases are responsible for cutting DNA molecules. Of particular importance in the development of apoptosis is the active CAD endonuclease, which breaks chromatin in the regions of linker sequences. As a result, fragments of 120-180 nucleotide pairs long are formed. The complex effect of proteolytic caspases and nucleases leads to deformation and fragmentation of the nucleus.
Cell membrane modifiers - violate the asymmetry of the bilipid layer, turning it into a target for phagocytic cells.
A key role in the development of apoptosis belongs to caspases, which gradually activate all subsequent mechanisms of degradation and morphological rearrangement.
The role of caspases in cell death
The caspase family includes 14 proteins. Some of them are not involved in apoptosis, while the rest are divided into 2 groups: initiator (2, 8, 9, 10, 12) and effector (3, 6 and 7), which are otherwise called second-tier caspases. All these proteins are synthesized in the form of precursors - pro-caspases activated by proteolytic cleavage, the essence of which is the detachment of the N-terminal domain and the separation of the remaining molecule into two parts, subsequently associated in dimers and tetramers.
Initiative caspases are necessary to activate the effector group, which exhibits proteolytic activity against various vital cellular proteins. The caspases of the second tier include:
- DNA repair enzymes;
- protein inhibitor p-53;
- poly (ADP-ribose) polymerase;
- DNAase DFF inhibitor (the destruction of this protein leads to the activation of CAD endonuclease), etc.
The total number of targets of effector caspases totals more than 60 proteins.
Inhibition of cell apoptosis is still possible at the stage of activation of initiating procaspases. When effector caspases take effect, the process becomes irreversible.
Ways to activate apoptosis
Signal transmission for triggering cell apoptosis can be accomplished in two ways: receptor (or external) and mitochondrial. In the first case, the process is activated through specific death receptors that perceive external signals, which serve as proteins of the TNF family (tumor necrosis factor) or Fas ligands located on the surface of T-killers.
The receptor contains 2 functional domains: a transmembrane (designed to bind to a ligand) and an "death domain" that induces apoptosis oriented inside the cell. The mechanism of the receptor pathway is based on the formation of a DISC complex that activates initiator caspases 8 or 10.
Assembly begins with the interaction of the death domain with intracellular adapter proteins, which, in turn, bind initiator procaspases. As part of the complex, the latter turn into functionally active caspases and trigger a further apoptotic cascade.
The mechanism of the internal pathway is based on the activation of the proteolytic cascade by special mitochondrial proteins, the release of which is controlled by intracellular signals. The output of the organoid components is through the formation of huge pores.
A special role in the launch belongs to cytochrome c. Once in the cytoplasm, this component of the electrotransport chain binds to the Apaf1 protein (apoptotic protease activation factor), which leads to the activation of the latter. Then, Apaf1 bind initiator procaspases 9, which initiate apoptosis by the cascade mechanism.
Control of the internal pathway is carried out by a special group of proteins of the Bcl12 family, which regulate the exit of the intermembrane components of mitochondria into the cytoplasm. The family includes both pro-apoptotic and anti-apoptotic proteins, the balance between which determines whether the process will be launched.
One of the powerful factors triggering apoptosis by the mitochondrial mechanism is reactive oxygen species. Another significant inducer is the p53 protein, which activates the mitochondrial pathway in the presence of DNA damage.
Sometimes the launch of cell apoptosis combines two paths at once: both external and internal. The latter usually serves to enhance receptor activation.