Stressed Cells: What Is Cellular Stress?

Cellular stress is any condition that disturbs a cell’s homeostasis and threatens to damage its proteins, DNA and lipids. Common types include oxidative, heat, osmotic and ER stress, DNA damage, hypoxia and nutrient shortage. Cells fight back with heat shock proteins, antioxidants and autophagy, and self-destruct through apoptosis if the damage is too severe.

Our cells get stressed too. But for a cell, stress doesn’t mean a fast-approaching deadline. It means something in its environment has shifted far enough to threaten the delicate chemistry that keeps it alive.

This article will examine what stresses a cell, the different forms that stress takes, and how cells manage to deal with the pressure. Understanding this process reveals a great deal about how our body responds as a whole to the environment. 

What Is Cellular Stress And What Are The Different Kinds Of Stress?

Cells, whether prokaryotic (Bacteria and Archaea) or eukaryotic (everything else that has a nucleus), have a small comfort zone in which they thrive. Pulling them out of that comfort zone is stressful. Just like you’d find it stressful to move to another city or country and adapt to life there, cells get stressed when they leave their own comfort zone. 

Any unusual or unsuitable external condition can act as a stress trigger. 

The Encyclopedia of Neuroscience (2009) defines cellular stress as “the cell’s reaction to any adverse environmental conditions that perturb cellular homeostasis, with potential macromolecular damage, that is, damage to proteins, DNA, RNA, and lipids.”

This change in the environment could mean conditions are too salty, too hot, or too acidic or basic (a change in pH).

These changes are harmful to the cell because they can hamper its proper functioning. For example, certain enzymes (the molecular machines in cells) only perform their functions in a small pH range. If conditions become too acidic or too basic, the enzymes stop working, which can shut down a whole assembly line within the cell.

Free radicals can cause mutations in DNA, protein denaturing and lipid oxidation, all of which can stress the cell as well.

Biologists tend to sort cellular stress into a handful of recurring types, depending on what is being threatened:

• Oxidative stress: a buildup of reactive oxygen species (ROS), the same kind of free radicals mentioned above, that outpaces the cell’s antioxidant defenses and oxidizes proteins, lipids and DNA.
• Heat (thermal) stress: temperatures high enough to unfold and tangle proteins. This is the classic stress that first revealed heat shock proteins.
• Endoplasmic reticulum (ER) stress: misfolded proteins piling up in the ER, the cell’s protein-folding factory, which sets off a rescue program called the unfolded protein response.
• Osmotic stress: water rushing in or out because the surroundings are too salty or too dilute, leaving the cell swollen or shrunken.
• DNA damage: breaks and chemical lesions in the genetic code, caused by radiation, UV light or reactive chemicals.
• Hypoxia: a shortage of oxygen, which starves the cell of energy and (somewhat paradoxically) ramps up ROS production.
• Nutrient deprivation: running low on glucose, amino acids or other raw materials the cell needs to keep its machinery running.

Whatever the trigger, the common thread is the same: something has knocked the cell out of homeostasis, and it now has to respond.

How Does Stress Change A Cell?

In order to cope with the new environment, cells change their own internal environment.

The cell has various known (and as yet unknown) mechanisms to detect stress, all of which ultimately send this information to the DNA through a signaling cascade. A signaling cascade is like passing a note to various people in class till it reaches who you want it to (like your crush). In a cell, proteins pass a message from one to the next until it is finally delivered to the DNA.

These cascades are elaborate and often interconnected with each other, meaning that a single stressor can make changes to many different areas of the cell. The signal from the environment activates protective regimens within the cell to defend against the stress.

How Do Cells Protect Themselves Against Cellular Stress?

A cell has many tricks up its sleeve (encoded in the DNA) that allow it to protect itself against stress. This defensive line of cellular firefighters tries to help the cell regain balance (homeostasis), while also limiting the damage that the stress can cause. A big part of that job is keeping its proteins healthy, a balancing act biologists call proteostasis (protein homeostasis).

These defenders against the dangers of the external environment are diverse, each protecting the cell in their own unique way. 

Heat Shock Proteins

The first and most frequently discussed defenders are Heat Shock Proteins or Hsp.

One of the biggest impacts of cellular stress is protein misfolding or denaturation. Denaturation is when the shape of a protein changes because the bonds maintaining that shape begin to break, or because certain chemical groups have been added to the protein. The function of a protein depends on it maintaining its specific shape.

Denatured proteins have the capacity to become cytotoxic (toxic to the cell) by clumping together and killing the cell. 

The Hsp are a family of proteins that respond to protein misfolding. They were discovered when scientists exposed cells to high temperatures. Although they were discovered by exposing cells to heat stress, they are also present in cells during normal conditions.

When the cell encounters some source of stress, it generates more Hsps (this is called upregulation). If that stress (heat stress, for example) denatures the proteins, the Hsps come to the rescue.

The Hsps bind to these denatured proteins, refolding them back into their functional shape. Hsps are present in all organisms, microscopic or macroscopic, although the names of the specific proteins differ. Some of the most important Hsps are Hsp70, Hsp40, and Hsp90.

A closely related rescue program runs inside the endoplasmic reticulum. When misfolded proteins build up there, the cell triggers the unfolded protein response (UPR), which slows down new protein production, recruits more chaperones to fix the backlog, and clears out proteins that cannot be saved.

Destroying The Faulty Proteins

Another tactic that cells use is to simply destroy what cannot be saved.

Proteins that are too denatured to be saved are sent off to be disassembled and destroyed. This clean-up mechanism (performed by a protein complex called the proteasome) prevents the unsalvageable proteins from wreaking havoc inside the cell. The proteins destined for the proteasome shredder are first tagged with a small marker protein called ubiquitin, which acts like a label reading "destroy me," and are then fed into the shredder.

The lysosome is an organelle within the cell where cells digest their own waste. Lysosomes are important when immune cells kill bacteria and viruses. Under stress, the cell can also bundle up damaged components and deliver them to the lysosome to be broken down and recycled, a self-eating process called autophagy.

Cell Death

If all else fails, and the cell just cannot protect itself, it will initiate the self-destruct function.

Apoptosis or programmed cell death is a mechanism by which a cell sacrifices itself. When the cell has incurred too much damage (or has simply become too old), certain mechanisms are activated that dismantle the cell from within.

Why Should You Care About Cellular Stress?

There are countless more ways in which cells protect themselves from the different environmental stressors they come across.

This article only highlighted those mechanisms that have been elucidated through years of research. Scientists know that these mechanisms play a role in cellular stress management, and they will surely remain popular subjects of research.

Cellular stress and the inability of cells to deal with it is a major cause (primary or secondary) of many diseases.

Neurodegenerative diseases like Alzheimer’s and other dementias are partly driven by high oxidative stress that disrupts normal neuronal function. Cancer arises when a cell’s built-in protective features malfunction over time, often under the pressure of many stressors.

These features are also highly conserved across species, meaning that the genes controlling these proteins and processes have changed very little over the course of evolution. This makes sense, as these processes are essential for survival, regardless of your species. Without these tireless defenders taking on everyday assaults, such as walking in the sun and not getting enough sleep, your life would be far less pleasant, and far more brief!