Cellular tragedies, part 1

On the verge of suicide

Polina Loseva, "The Attic"

The life of a cell is eventful no less than that of a human. It is full of passions, dangers and, like any life, ends sooner or later. Polina Loseva decided to find out what stories are found in the fate of cells and how their development affects you and me. And we decided to start this story with the most common thing for all living things – death.

In general, the life path of a cell, like any living being, is quite simple. There are few options for the development of events: rest, reproduction or death. Only a few cells can actively divide in our body, the rest are either not capable of this at all, or are waiting for a signal from outside. In the latter case, the cells usually contain proteins that stimulate division, but in small quantities, which can increase dramatically if a signal comes. At the same time, all cells constantly contain proteins that trigger cell death. Fortunately, it is also usually in small quantities. That is, the key to a quiet cell life is a balance between proteins that trigger division and "death proteins". It's just like people: good health occurs when there are at least as many good thoughts as bad ones.

But let's say something went wrong. How to determine if a cell is dying or already dead? Unlike a person, here it is enough to look at her appearance. If you notice that the cell has acquired an irregular shape and has lost its outer membrane, then it seems to be in trouble. And if the cell has disintegrated into pieces that are already being eaten by its neighbors, then we can safely state its death. But let's try to rewind time and figure out what could have caused such an inglorious end.

Accident

Alas, no one is immune from it. Even a small cage can be accidentally crushed or pierced. In addition, it can be suddenly deprived of food. And if the cell has no reserves for a rainy day, then the energy runs out instantly. Usually, a significant part of the cell's energy is spent on controlling the transport of substances through the outer membrane. And if there is no energy, then the transport is disrupted and substances can actually pass through it uncontrollably and damage it, and this is the same as if the membrane was pierced.

Then the situation develops according to the standard scenario: a hole forms in the membrane, water flows through it into the cell, the cell swells and is about to burst. Different intracellular substances come out of the hole, they are slowly absorbed by neighboring cells. But the neighbors do not have time to eat some of the substances, and they spread out over the tissue, often causing inflammation. This type of death is called necrosis (not to be confused with tissue necrosis – blackening and decay, which occurs, for example, with gangrene).

Interestingly, sometimes a cell can sacrifice itself for the good of the motherland, this was called necroptosis (by analogy with apoptosis, which will be discussed later). For example, it happens that a macrophage cell selflessly ate a bacterium, but could not digest it. You can accept that the bacterium will live inside, or you can show tragic heroism. Such a hero cell creates a complex of proteins that pierces its own membrane from the inside. At the same time, neighbors get the opportunity to finish off the bacterium and call for help from other immune cells.

Such cell deaths become more frequent when a person is ill, for example, with a neurodegenerative disease such as Parkinson's or Alzheimer's disease. Scientists believe that by blocking necroptosis, they will be able to stop them. At the same time, necroptosis can be used for peaceful purposes and accidents can be organized, for example, for cancer cells resistant to other mechanisms of death.

Professional burnout

Stories about deliberate death are best started with a description of the long and gradual death of a cell, which even the tongue does not turn to call suicide. It's more like death in the line of duty. It is known that some types of activity require an excessive investment of effort from a person, as a result of which they do not remain for everyday life. Cells also have such a profession – to protect the body from external aggressors.

This, for example, is done by the cells of the epidermis, the upper layer of the skin. They form in the depth of the epidermis and gradually move upward as their predecessors exfoliate. In order for the skin to be strong, the cells have to strengthen themselves from the inside, accumulating solid proteins and holding tightly to each other with cellular contacts. In such a structure there is no place for either the nucleus or other organelles, so they gradually disappear while the cell rises outwards. 

Ultimately, a fat pouch filled with proteins remains from the cell. This is how the process of keratinization occurs – the slowest and most inevitable cell death.

True suicide

However, the most well–studied mechanism remains the real suicide of the cell - apoptosis. It occurs when a cell, for one reason or another, "decides" that its continued existence is unsafe for the body. These reasons can be very different.

External causes

"They say I'm not like everyone else." If immune cells, such as T-lymphocytes, detect a cell with the wrong proteins on the surface, it is sent a death signal through receptors on the membrane. Usually after that, the cell obediently dies. And if not, then perhaps we are facing a rebel and a delinquent – a future tumor.

"Let's make room for others." There are many periods in the development of the body when organs or tissues are replaced by others or die completely. In such cases, suicide is absolutely normal, the cell can be persuaded by neighbors from other tissues. If for some reason it did not happen, then rudiments remain: for example, a person is born with fused fingers.

"Nobody loves me." Cells in the body exchange support signals, that is, signaling molecules. They are often distinguished by nerve endings. If the nerve ending is damaged, then the surrounding cells do not feel supported and conclude that they are no longer in the body. And there is no life outside the body.

"The earth is falling out from under my feet." In addition to communicating with neighbors, it is important for the cell to gain a foothold on the intercellular substance (with the exception of blood cells). Sometimes it helps her to perform her functions, such as crawling, and sometimes survival signals come from this substance. If the cell is not attached to anything, it considers itself inoperable and dies.

Internal reasons

"Disintegration of personality". The center of the cell, as is known, is the nucleus with DNA. If errors accumulate in the DNA, the chance of tumor transformation increases. Therefore, repair systems that fix errors in DNA simultaneously stimulate apoptosis. When there are a lot of such signals, it's useless to fix something, it's easier to die.

"I'm unstable." Sometimes a cell fails to divide its chromosomes into two parts, then a so-called mitotic catastrophe occurs. Again, an imbalance of genetic material leads to the formation of tumors, so such unbalanced cells should die.

"I can't breathe." The second key organelle of the cell after the nucleus is the mitochondria. There is cellular respiration with the formation of energy. If the mitochondria is damaged, then molecules that trigger apoptosis come out of its inner space into the cytoplasm of the cell.

"I'm too excited." This happens to nerve cells with an excess of excitatory signals. Many ion channels open on the cell membrane, including for calcium, its concentration in the cell increases greatly, this causes the mitochondrial membrane to collapse – and now there is nothing to breathe.

Whatever triggers apoptosis, the result is always the same. Proteins that stimulate cell death trigger caspase enzymes, which activate each other and begin to break down all cellular molecules in a row. As a result, bulges first form on the cell, and then it all breaks up into membrane vesicles – apoptotic bodies that can absorb macrophages.

(A) Healthy cells. (C) Cells that break down into apoptotic bodies. The image is adapted. Photo: Edelweiss et al., Barnase as a New Therapeutic Agent Triggering Apoptosis in Human Cancer Cells // PLoS One, 2008.

The beauty of cell death by apoptosis is that at the same time they practically do not harm the surrounding tissues. Very few substances that cause inflammation and pollute the intercellular space are released from such cells – the rest is absorbed by macrophages. However, in order to leave so neatly, the cell needs energy. Apoptosis is an energy–dependent death, unlike necrosis. In many of the above cases, the cell can die and necrosis, that is, simply burst if it lacks energy.

Another useful property of apoptosis is that we know exactly how it works. And, unfortunately, we know that its violation is the cause of most oncological diseases. Therefore, now many studies are aimed at selectively blocking or activating it in certain cells.

A little death for salvation

Not all disorders in the work of the cell necessarily lead to death. The most advantageous option for the cell is to recognize the damage at an early stage and try to repair them in advance. To do this, there is autophagy – the process of gradual self-eating, digesting its own contents. It is almost impossible to die in this way – among the cells, this type of death was detected in isolated cases. But digesting your own spoiled proteins or whole organelles allows you to get rid of mistakes. This is rather a reboot for the cell, similar to the cleansing from unnecessary thoughts experienced by a person who has jumped with a parachute and actually been on the verge of death.

Types of cell death (Jhayes21, Wikimedia).

Therefore, autophagy is extremely useful for most cells of the body. It allows stem cells to remain stem cells longer, slows down cell aging and helps to resist external damage, for example, in atherosclerosis. And in brain cells, for example, mitophagy is especially important – the digestion of mitochondria. If it is disrupted, neurodegenerative diseases such as Parkinson's disease can develop. Mitophagy also prevents tumor growth in the early stages (although, unfortunately, it contributes to the late stages). In some cases, autophagy also helps to digest intracellular pathogens (for example, viral particles). But some viruses, such as HIV, have learned to suppress autophagy or multiply directly in the digestive vacuoles.

The study of autophagy mechanisms is now at the forefront of cell biology. It is not for nothing that in 2016 they were awarded for work in this direction The Nobel Prize. Among the immediate prospects is the fight against infections and neurodegenerative diseases and prolonging life. In any case, it has already become clear that not in all situations the cage should immediately jump off the bridge. Maybe sometimes it's enough just to jump with a parachute and life will get better.

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