The process by which a cell can kill itself is called programmed cell death (PCD). This mechanism has several varieties and plays an important role in the physiology of various organisms, especially multicellular ones. The most common and well-studied form of CHF is apoptosis.
What is apoptosis
Apoptosis is a controlled physiological process of cell self-destruction, characterized by the gradual destruction and fragmentation of its contents with the formation of membrane vesicles (apoptotic bodies), which are subsequently absorbed by phagocytes. This genetic mechanism is activated under the influence of certain internal or external factors.
With this variant of death, the cell content does not go beyond the membrane and does not cause inflammation. Dysregulation of apoptosis leads to serious pathologies such as uncontrolled cell division or tissue degeneration.
Apoptosis is only one of several forms of programmed cell death (PCD), so it is a mistake to identify these concepts. To the famoustypes of cellular self-destruction also include mitotic catastrophe, autophagy, and programmed necrosis. Other mechanisms of PCG have not yet been studied.
Causes of cell apoptosis
The reason for triggering the mechanism of programmed cell death can be both natural physiological processes and pathological changes caused by internal defects or exposure to external adverse factors.
Normally, apoptosis balances the process of cell division, regulating their number and promoting tissue renewal. In this case, the cause of HGC is certain signals that are part of the homeostasis control system. With the help of apoptosis, disposable cells or cells that have fulfilled their function are destroyed. Thus, the increased content of leukocytes, neutrophils and other elements of cellular immunity after the end of the fight against infection is eliminated precisely due to apoptosis.
Programmed death is part of the physiological cycle of the 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 involvement of cell apoptosis in the life cycle of vegetative systems is autumn leaf fall. The term itself comes from the Greek word apoptosis, which literally translates as "falling".
Apoptosis plays an important role in embryogenesis and ontogenesis, when tissues change in the body and certain organs atrophy. An example is the disappearance of the membranes between the fingers of the limbs of some mammals or the death of the tail during metamorphosis.frogs.
Apoptosis can be triggered by the accumulation of defective changes in the cell resulting from mutations, aging, or mitotic errors. An unfavorable environment (lack of nutrients, oxygen deficiency) and pathological external influences mediated by viruses, bacteria, toxins, etc. can be the reason for the launch of CHC. Moreover, if the damaging effect is too intense, then the cell does not have time to carry out 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 process of apoptosis is characterized by a certain set of morphological changes, which can be observed by microscopy in a tissue preparation in vitro.
The main features characteristic of cell apoptosis include:
- rebuilding the cytoskeleton;
- seal cell content;
- chromatin condensation;
- core fragmentation;
- cell volume reduction;
- wrinkling of the membrane contour;
- bubble formation on the cell surface,
- destruction of organelles.
In animals, these processes culminate in the formation of apoptocytes, which can be engulfed by both macrophages and neighboring tissue cells. In plants, the formation of apoptotic bodies does not occur, and after the degradation of the protoplast, the skeleton remains incell wall.
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. In plant cells, the formation of giant vacuoles is observed.
How does apoptosis differ from necrosis
The main difference between apoptosis and necrosis lies in the cause of cell degradation. In the first case, the source of destruction is the molecular tools of the cell itself, which operate under strict control and require the expenditure of ATP energy. With necrosis, passive cessation of life occurs due to an external damaging effect.
Apoptosis is a natural physiological process designed in such a way as not to harm 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 in many respects opposite. However, there are also commonalities.
| Process characteristic | Apoptosis | Necrosis |
| cell volume | decreases | increasing |
| membrane integrity | maintained | violated |
| inflammatory process | missing | developing |
| ATP energy | expending | not used |
| chromatin fragmentation | available | present |
| a sharp drop in ATP concentration | is | is |
| result of the process | phagocytosis | release of contents into the intercellular space |
In case of damage, the cells trigger the mechanism of programmed death, including in order to prevent necrotic development. However, recent studies have shown that there is another non-pathological form of necrosis, which is also referred to as PCD.
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 great. The following physiological functions are carried out due to the mechanism of PCG:
- maintaining a balance between cell proliferation and death;
- updating tissues and organs;
- elimination of defective and "old" cells;
- protection against the development of pathogenic necrosis;
- change of tissues and organs during embryogenesis and ontogenesis;
- removing unnecessary elements that have fulfilled their function;
- elimination of cells that are unwanted or dangerous to the body (mutant, tumor, infected with a virus);
- prevention of infection.
Thus, apoptosis is one of the ways to maintain cell-tissue homeostasis.
In plantsapoptosis is often triggered to block the spread of tissue-infecting parasitic Agrobacteria.
Stages of cell death
What happens to a 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 the death scenario. This process can be divided into several stages:
- Induction.
- Activation of proapoptotic proteins.
- Activation of caspase.
- Destruction and restructuring of cell organelles.
- Formation of apoptocytes.
- Preparation of cell fragments for phagocytosis.
The synthesis of all the components necessary to launch, implement and control each stage is genetically based, which is why apoptosis is called programmed cell death. The activation of this process is under the strict control of regulatory systems, including various inhibitors of CHG.
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 (participate in induction) and modulators that provide transduction of the death signal.
The effector system consists of molecular tools that ensure the degradation and restructuring of cellular components. The transition between the first and second phases occurs 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 at asparagine residues, fragmenting proteins into large peptides. Before the onset of apoptosis, they are present in the cell in an inactive state due to inhibitors. The main targets of caspases are nuclear proteins.
Nucleases are responsible for cutting DNA molecules. Especially important in the development of apoptosis is the active endonuclease CAD, which breaks chromatin regions in the regions of linker sequences. As a result, fragments with a length of 120-180 nucleotide pairs are formed. The complex effect of proteolytic caspases and nucleases leads to deformation and fragmentation of the nucleus.
Cell membrane modifiers - break the asymmetry of the bilipid layer, turning it into a target for phagocytic cells.
The key role in the development of apoptosis belongs to caspases, which gradually activate all subsequent mechanisms of degradation and morphological rearrangement.
The role of caspase in cellulardeath
The caspase family includes 14 proteins. Some of them are not involved in apoptosis, while the rest are divided into 2 groups: initiatory (2, 8, 9, 10, 12) and effector (3, 6, and 7), which are otherwise called second-tier caspases. All these proteins are synthesized as precursors - procaspases, activated by proteolytic cleavage, the essence of which is the detachment of the N-terminal domain and the division of the remaining molecule into two parts, subsequently associated into dimers and tetramers.
Initiator caspases are required to activate an effector group that exhibits proteolytic activity against various vital cellular proteins. Second-tier caspase substrates include:
- DNA repair enzymes;
- p-53 protein inhibitor;
- poly-(ADP-ribose)-polymerase;
- inhibitor of DNase DFF (destruction of this protein leads to activation of CAD endonuclease), etc.
The total number of targets for effector caspases is more than 60 proteins.
Inhibition of cell apoptosis is still possible at the stage of activation of initiator procaspases. Once effector caspases are activated, the process becomes irreversible.
Apoptosis activation pathways
Signal transmission to start cell apoptosis can be carried out 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 are proteins of the TNF (tumor necrosis factor) family or Fas ligands located on the surfaceT-killers.
The receptor includes 2 functional domains: a transmembrane one (designed to bind to the ligand) and a "death domain" oriented inside the cell that induces apoptosis. 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 are converted 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 specific mitochondrial proteins, the release of which is controlled by intracellular signals. The release of organelle components is carried out through the formation of huge pores.
Cytochrome c plays a special role in the launch. Once in the cytoplasm, this component of the electrotransport chain binds to the Apaf1 protein (apoptotic protease activating factor), which leads to the activation of the latter. Apaf1 is then bound by initiator procaspases 9, which trigger apoptosis by a cascade mechanism.
Control of the internal pathway is carried out by a special group of proteins of the Bcl12 family, which regulate the release of intermembrane components of mitochondria into the cytoplasm. The family contains both pro-apoptotic and anti-apoptotic proteins, the balance between which determines whether the process will be launched.
One of the powerful factors that trigger apoptosis by the mitochondrial mechanism are reactiveforms of oxygen. Another significant inducer is the p53 protein, which activates the mitochondrial pathway in the presence of DNA damage.
Sometimes the start of cell apoptosis combines two ways at once: both external and internal. The latter usually serves to enhance receptor activation.
