Cellular tragedies, part 2

Living under stress

Polina Loseva, "The Attic"

The inner life of the cell is eventful no less than the human one. It is full of passions, dangers and, like any life, ends sooner or later. Polina Loseva understands what plots occur in the fate of cells and how their development affects you and me.

This time we will talk about stress and how cells cope with it (and we have something to learn from them).

"Cellular tragedies" is a large series of articles about cells, which continues to be replenished. And his text opened about deaths and suicides that occur at the cellular level of life.

Stress is an integral feature of our daily life. If you listen to the conversations of others, it is found everywhere: friends complain to each other about a hard life and eternal stress, doctors ask when and what kind of stress the patient experienced, employers are looking for stress-resistant employees. Cells also cannot avoid the effects of stress factors, but in some cases it even benefits them.

Slave Revolt

The most well–known of the stressful states of the cell - oxidative stress – is associated with the need to obtain energy. In general, the process of energy extraction can be represented as follows: we take a large organic molecule, split it into smaller and even smaller molecules until we can collect enough hydrogen atoms. Then we concentrate them inside the mitochondria and there we divide each atom into a proton and an electron. We accelerate protons, and due to the energy of their movement we get ATP – the main energy currency of the cell. Everything would be fine, but the problem is the remaining electrons. To disperse new protons, you need to put the old electrons somewhere. And for this, you need an active substance ready to take them, in our case, oxygen.

This system has been worked out by many generations of living organisms, there is only one problem. Oxygen is not just an active substance, but a very active substance. One can imagine a cage as a slave-owning state. It extracts the energy necessary to maintain its existence in the mine (mitochondria). But during the extraction of a valuable resource, garbage bags (electrons) arise that need to be taken out so that the work does not stop. For this purpose, slaves (oxygen molecules) are used, each of which is handed two bags. Slaves, for obvious reasons, are angry and aggressive, so if they are not loaded with bags in time, they begin to fight and attack others.

Illustration by OpenStax College, Wikimedia commons

From time to time, oxygen in the mitochondria does not get enough electrons, and it begins to take them away from other molecules, that is, to oxidize them. Molecules containing an aggressive oxygen atom are called reactive oxygen species, or free radicals. The most famous of them are superoxide (an oxygen molecule with one unpaired electron) and hydrogen peroxide (which easily decays into two OH radicals with unpaired electrons). Angry slaves (reactive oxygen species) attack everyone in their path. Some attacked molecules disintegrate at the same time, others lose their efficiency, and some themselves become radicals and join the rebellion. The number of rebellious molecules with unpaired electrons is growing, a chain reaction is developing.

Suppression of the rebels

As long as the rebellion does not go beyond the mitochondrial mine, the cell is relatively safe. Strictly speaking, individual disturbances are the norm for her, because with a large number of slaves there will always be someone underloaded and dissatisfied. It becomes possible to talk about oxidative stress when reactive oxygen species exit the mitochondria and enter the cytoplasm. There is a situation of state instability: radicals attack civilians, preventing them from performing their socially useful functions.

But the scarier thing is that the rioters are beginning to pose a threat to the state system. The cellular constitution – the DNA molecule, like many other substances, is subject to oxidation. In this case, individual nitrogenous bases may change or the bonds between the nucleotides in the chain may collapse. Some of these errors will be corrected by the proteins of the repair system – a kind of The Constitutional Assembly. But if, for example, both DNA chains have broken (a double-strand break), then it will be more difficult to restore the information. Thus, when the rebellious slaves get to the constitution, they can make random changes to it. This can lead to a cancerous transformation of the cell: it will declare its independence from the rest of the body and begin to divide and grow uncontrollably.

To protect its DNA, the cell activates an antioxidant response, that is, it begins to produce protective substances. The rebels can be dealt with by re–education - with the help of enzymes that neutralize radicals (for example, catalase destroys peroxide to harmless molecules). The second option is to plug their mouths with missing electrons: this is how antioxidant substances act. There are a lot of them in the cell, from the well-known vitamins A, C and E and coenzyme Q. But if the antioxidant response is insufficient and the DNA is seriously damaged, a program of cell death – apoptosis - is launched. A state that has failed to cope with the uprising is waiting for mass killings (destruction of molecules), fragmentation (the cell falls apart into membrane bubbles) and division between neighboring states (cells absorbing these bubbles).

Eggs stained with markers of oxidative stress. Blue – antioxidants, green – reactive oxygen species, red – mitochondria.
Vertically, from left to right:
1) control cells;
2) cells under the action of salubrinal (a drug that stimulates a stress response);
3) cells that have absorbed a lot of fat;
4) cells under the action of salubrinal and fats.
Photo CNBP CC BY 2.0

Carrots vs broccoli

Processes in individual cells cannot but affect the body. In many cases, oxidative stress leads not only to the formation of tumors, but also to deterioration and cell death, which underlies a variety of degenerative diseases. For example, cells can die in diabetes, Alzheimer's and Parkinson's diseases. In addition, it has been noticed (in worms, flies and mice) that organisms that have fewer reactive oxygen species in their cells during their lifetime live longer. Therefore, it seems that oxidative stress inevitably leads to cell death and is harmful in all its manifestations.

In this regard, some time ago there was a fashion for antioxidants. The argument in their favor looked like this: our body is not perfect and cannot cope with the radicals produced, so we need to help it by supplying antioxidants from the outside. Not only medicines, but also vegetables and fruits, rich in vitamins (carrots, currants, etc.), appeared as saving candidates. However, there is more and more evidence that the active use of antioxidants brings almost more harm than good. Let's make a reservation right away: it does not follow from this that carrots shorten our lives. But numerous clinical studies have not found a positive effect of antioxidants on the development of cancer and other diseases. Moreover, some researchers even note a negative effect from their reception. So, an error has crept into the original logic somewhere.

One of the circumstances that is easily overlooked is the role of reactive oxygen species in the immune system. Cells of innate immunity often intentionally produce them and use them against bacteria. Antioxidants entering the blood neutralize radicals and weaken our antibacterial protection. Another important factor is the training role of stress, the preparation of the cell for difficult times. Let's go back to our example with rebellious oxygen. Imagine that aggressive slaves stopped appearing in the mines. There are no uprisings, the police are inactive, they march back and forth on the parade ground and embroider a cross out of boredom. It is clear that in a critical situation that may arise unexpectedly, for example as a result of damage to the mine (mitochondria), such police will not be able to cope.

A constant low level of stress keeps the cell in a state of alert. This phenomenon was called hormesis. With its help, scientists explain the positive effect of a variety of stress factors in small doses: exercise, alcohol, diet and temperature changes. The list also includes oxidant products: tea extracts, dark chocolate, spinach and broccoli. The main thing is not to overdo it with hardening, since the line between soft and hard stress is thin. For example, soft stress is activated in fibroblasts at 41°C and hard stress at 43°C.

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A close look at the biology of the cell involuntarily makes you think: do we really suffer so much from a hard life and nervous work? In the endless battle with stressful factors, do not forget about life-saving workouts. At least now we know how to cultivate stress resistance in our own cells. And any struggle begins with a small one.

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