What is stress to a cell?
Cells, whether prokaryotic (Bacteria and Archaea) or eukaryotic (everything else), have a small comfort zone in which they thrive, although there are exceptions, especially in the prokaryotic world.
Pulling them out of that comfort zone is stressful, often making it impossible for the cell to survive. Unusual and unsuitable external conditions for a cell is 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 environmental stress can come in the form of too many oxygen radicals (oxidative stress), excessive heat (heat stress), and changes in the pH or salt concentrations (osmotic stress) outside, just to name a few.
These changes are harmful to the cell because they can hamper its proper functioning. Mutations in DNA, protein denaturing and lipid oxidation are a few of the consequences of cellular stress.
Changing the environment
Cellular stress changes the environment within the cell. 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 comes in the form of proteins passing on a message until it reaches 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.
The line of defense
A cell has many tricks up its sleeve (or encoded in the DNA) that allow it to protect itself against stress. This defensive line of cellular Avengers try to help the cell regain balance (homeostasis), while also mitigating the damage that the stress can cause.
These defenders against the dangers of the external environment are diverse, each protecting the cell in their own unique way.
Facing the fire: 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.
During normal conditions, Hsps serve as chaperone proteins, which make sure that newly formed proteins don’t misfold.
Newly synthesized proteins form as a long string of amino acids. If left to their own devices, this long string will fold into any shape at random, so to prevent that, chaperone proteins help the protein fold correctly.
They also make sure that new proteins end up where they’re meant to be, whether in the cell membrane, mitochondria or cytosol.
When the cell encounters some source of stress, it generates more Hsps (upregulates). If this stress—heat stress, for example—denatures the proteins, the Hsps will come to the rescue. The Hsps bind to these denatured proteins, refolding them back to their functional shape.
Hsps are present in all organisms, microscopic or macroscopic, although the name of the specific proteins are different. Some of the most important Hsps are Hsp70, Hsp40, and Hsp90.
Too much Oxygen?
Reactive Oxygen Species are highly unstable chemicals that contain oxygen, such as superoxide anion, hydrogen peroxide, hydroxyl radical, and oxygen singlet.
ROS are formed through various metabolic processes, including the main energy-giving pathways that occur within each and every cell. They are generated when electrons escape through the electron transport chain and attach to oxygen, thus forming an ROS.
ROS can oxidize lipids, denature proteins, and break down DNA. All of this damage is unacceptable, and potentially serious for any cell. The damage control for this event is an arsenal of antioxidants that can quickly neutralize the ROS.
Superoxide Dismutase (SOD), peroxidases (glutathione peroxidase), and catalase are all prominent members of the ROS destruction team that work together to neutralize the free radical threat.
Superoxide dismutase works by reducing the superoxide radicals, but this produces a hydrogen peroxide molecule, which can still pose a threat.
This is where the peroxidases come into play, as they convert the hydrogen peroxide molecule into water.
An important molecule that one cannot skip when talking about ROS is NADP+/NADPH. The full form of NADP is Nicotinamide adenine dinucleotide phosphate.
NADP in its reduced form, NADPH, is a great reducing agent. It doesn’t directly reduce ROS, but is a key part of the pathways involved in neutralizing any ROS threat.
Certain other chemicals, called antioxidants, also help the body prevent oxidative damage.
Vitamin E is an important antioxidant, as it prevents lipids from generating free radicals that could damage the cell membrane. Other antioxidants, like those found in tea, coffee, and fruit, work by a host of different mechanisms that scientists are still investigating!
Another tactic that cells use is to simply destroy what cannot be saved. Proteins that are too denatured to be saved are sent to the proteasome or funneled to the chaperone-mediated autophagy.
These two mechanisms are the clean-up systems of the cell. Any proteins that have become damaged through normal processing get tagged to be destroyed.
The proteasome pathway is a recent discovery in the world of cellular garbage clean-up methods. The proteasome is a large barrel that breaks proteins into smaller pieces of polypeptides.
Proteins destined to be broken down are tagged with a small protein molecule called ubiquitin. Ubiquitin is like a badge that the cell puts on a protein so the proteasome knows to break down the molecule.
This tagging system makes proteasomal degradation a very specific process.
The other route, chaperone-mediated autophagy, is also a selective pathway in which proteins are degraded in the lysosome. The lysosome is an organelle within the cell where cells digest their own waste. Lysosomes are important when immune cells kill bacteria and viruses.
Chaperone mediated-autophagy is a different and more specific version of the less selective autophagy process that occurs in the lysosome.
The chaperone function of Hsps is also involved in this pathway, along with various others. These chaperones recognize patterns on the protein that signal to the chaperones there is something wrong with the protein, so it needs to be sent to the bin.
These chaperones then send this faulty protein to the lysosome to be broken down. Scientists have noticed that this pathway is especially active during periods of oxidative stress.
If all else fails, the cell will initiate its own death. 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. Proteins called caspases slowly break down all the proteins in the cell, reducing the cell to a blob. This blob is then eaten or phagocytosed by an immune cell, usually the macrophage.
Before undergoing apoptosis, the cell probably incurred a great deal of damage to its DNA. If the DNA repair mechanisms failed to repair all the damage, it can be one major factor for apoptosis or senescence to occur.
The proteins denatured by stress could also wreak havoc on their neighboring cells. Dismantling the cellular machinery from within and then being phagocytosed is a clean job, and won’t affect other healthy cells nearby.
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 clearly and comprehensively 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 dementia and Alzheimer’s are shown to be driven by high oxidative stress that affects normal neuronal function.
Cancer happens when a cell’s inbuilt protective features malfunction (over time and due to 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!
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