by Omegan Wright
What is Oxidative Stress
The human body, by design, is a highly complex, highly regulated system that maintains a tremulous balance between radical plasticity and conformity to already established functions and structures. To maintain this balance the body is compartmentalized on the cellular level, which creates trillions of microenvironments where the conditions that optimize macromolecular functions are kept stabilized. When byproducts of these processes conducted in one cellular environment invade another, significant shifts in the metabolism and eventual functionality of the cell can develop. Oxidative stress is a term used to describe the imbalance between reactive oxygen and nitrogen species and the body's ability to remove these elements or repair the damage caused by their overabundance (Koju et al., 2019). The major consequences of oxidative stress is experienced when free radicals or free radical-causing compounds are introduced from non-native sources into a cellular environment that is less protected from their effects.
In chemically based systems like the human body, reactions between molecules occur via exchanging or sharing electrons; or, more simply, an exchange of chemical energy. Molecules are composed of atoms linked together through the sharing or exchange of electrons. In stable atoms and molecules, electrons are paired together and one bond utilizes the energy of two electrons. Having all of one's electrons paired reduces the need for an atom to go looking for an electron to pair with to create a stabilizing bond. Free radicals have only one electron that isn't paired with another electron in the outer orbital of the molecule where bonding activity occurs (Wilson, Muñoz-Palma, & González-Billault, 2018). The two types of radicals commonly involved in the dysfunctions that lead to oxidative stress are Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS).
Reactive Oxygen Species (ROS) are introduced into critical cellular environments via exogenous and endogenous sources. Exogenous sources are sources from outside the body, such as: how certain foods are prepared, environmental pollutants, heavy metals, specific drugs, chemical solvents, cigarette smoke, alcohol, and radiation (Pizzino et al., 2017). When introduced into the body, these chemicals create situations where the ROS can be produced as a byproduct or introduces ROS directly into the body. Endogenous sources of ROS come from processes within the body; these include immune cell activation, inflammation, ischemia, infection, cancer, excessive exercise, mental stress, and aging (Pizzino et al., 2017). What makes ROS production in the body so dangerous is that it can occur non-enzymatically or without the help of a molecular machine, the enzyme, to bridge the energy gap between reactants and products in the reaction. Enzymes are often highly regulated by various processes in the body that cause their activation and deactivation. ROS, RNS, and free radicals provide the body a method to bridge that reactionary gap without the help of a heavily regulated mechanism. The fact that it bypasses systemic oversight by nature leaves the body prone to allow further toxic species to be produced in the area. Common ROS, RNS, and free radical precursors implicated in oxidative stress damage are hydroxyl radicals, superoxide radicals, hydrogen peroxide, and nitrous oxide.
ROS in the body (pt. I): One Organelle's Trash is Another Organelle's Treasure
ROS are valuable tools in the arsenal of human metabolism. ROS allow for reactions to occur that otherwise require an excessive amount of energy to conduct on a situational or semi-regular basis. The properties of ROS allow for multiple mechanisms of usage within the human system such as, second messengers in signaling cascades, use in immune response, and use in autophagy. Autophagy is the recycling of damaged/old intracellular structures for nutrient synthesis; the ROS act as regulators in the autophagy process (Petersen, 2017). Within the immune system, ROS are weaponized by the body's immune cells to destroy pathogens (Pizzino et al., 2017). ROS are critical in mitogen response or mitogen-initiated proliferation of key cells; cells used by the body to combat disease (Pizzino et al., 2017). As signaling molecules, ROS act as go-betweens for metabolic processes that trigger subsequent reactions for desired metabolic outcomes. ROS have many traits that make them good second messengers for the cell: their short life span, malleability that allows low energy interconversions of the chemical, the superoxide radicals that are already highly regulated, and they are also prolific helpers when the body needs to adapt to stressful conditions (Wilson, Muñoz-Palma, & González-Billault, 2018).
Regulation of second messenger molecules is particularly important because they are the chemicals that trigger enzymes to start and stop/delay their functioning. The balance that the body strikes is delicate and precise, with a very small margin of error for excess activity or inactivity. Unregulated messengers can cause deficiencies and harmful build-ups of the cellular products that cause dysfunctions in organelles, which eventually leads to some of the consequences of oxidative stress.
ROS in the body (pt. II): When it All Goes Wrong
The regulation of ROS in the body is critical due to its use in many essential processes. These essential processes include neuronal development in the womb. Through studies of mouse gestation, it has been determined that in utero, specific ROS act as triggers for particular differentiation of neuronal stem cells that determine the number of differentiated stem cells that usually develop and will develop in growing brains (Wilson, Muñoz-Palma, & González-Billault, 2018). It was found that having a ROS-rich environment, had long term effects on the development of specific parts of the mice's brains with hypothesized developmental impairment of neurons (Wilson, Muñoz-Palma, & González-Billault, 2018). In humans, this phenomenon is observed in individuals with Chronic Granulomatous Disease, a disease that causes a drastic change in functionality to the family of proteins utilized to sustain hippocampal neuronal hydrogen peroxide levels; children with this disease often demonstrate cognitive issues in childhood (Wilson, Muñoz-Palma, & González-Billault, 2018).
Outside of gestational development, ROS can cause oxidative damage to many of the major macromolecules: lipids, proteins, and nucleic acids. Lipids have many uses in cellular makeup and metabolism, but the major function affected by free radicals is the fluidity (permeability and movement) of the lipids used to create the cell’s plasma membrane. The cell's membrane is essential in its job of maintaining the structural integrity of the cell and the filtration of components allowed to cross into and out of the cell. The fluidity of this membrane is determined by many factors, which includes the types of lipids used in its makeup, the number of proteins embedded in the cell membrane, and more. A change in fluidity could mean a change in the permeability of the cell. Peroxidation of the lipids in the cell membrane occurs through the cross-linking of lipids with carbon double bonds. Lipids with carbon double bonds are referred to as unsaturated lipids because the double bond between two carbon atoms prevents the formation of a carbon-hydrogen bond on those carbon atoms. These double bonds involve four electrons to hold the carbon atoms together; one or two electrons can be removed without breaking the link between the carbon atoms completely. Free radicals are unstable molecules that want to find a single electron to pair with to help stabilize themselves. The breaking of one bond between the lipids' double carbon bonds then will donate a single electron to a free radical, the radicalized or oxidized lipid and the now stable free radical create an overall more stable end product than the previous formation of the molecules (Petersen, 2017). The reaction’s end product leaves the previously stable unsaturated lipid as an unstable free radical molecule ready to react with other unsaturated molecules and so on, a phenomenon known as chain-growth polymerization. The polymerization makes the membrane more rigid, making it harder to get specific molecules across the membrane (Petersen, 2017).
Proteins are also prone to free radicals, the loss of a single electron on the protein causing destabilization leading to a change in protein conformation. A change in the conformation of a protein is similar or parallel to a machine with a component warped out of place, causing the machine to malfunction; this occurs more disastrously in enzymes (Pizzino et al., 2017).
DNA is the key nucleic acid that encodes all information that’s needed for the cell to function; changes to this code can lead to changes in the product conveyed. Free radicals, ROS, and RNS all can cause damage to DNA altering the information it encodes directly and indirectly. The consequences of the damage could be a change in the conformation of a protein, leading to the aforementioned issues or changes in access to this code prohibiting the creation of certain proteins.
Certain organelles are prone to becoming the sources of these endogenous reactive oxygen species within the human body. These organelles primarily handle reactions that involve free radical intermediates; when the processes that produce these intermediates exceed/surpass the mechanisms implemented by the cell to reduce ROS concentrations, oxidative stress can occur. The mitochondria is one of these organelles. As is well known by most high school sophomores, the mitochondria is the powerhouse of the cell; the process used to make the most commonly used power source of the cell (ATP) is oxidative phosphorylation. Oxidative phosphorylation is a multi-step operation that uses free radical intermediates when chemical energy is being transferred between enzymatic processing centers, and a superoxide radical is created during this process (Wilson, Muñoz-Palma, & González-Billault, 2018). ATP (adenosine triphosphate) or a derivative is required for many higher order metabolic functions making the fact that it produces such a hazardous and prolific by-product so unfortunate. Mitochondrial dysfunction can lead to oxidative stress, a consequence of which is the continuation of axon degeneration seen in many neurological diseases. The peroxisome is another organelle that commonly causes the introduction of ROS into the cellular environment. For this specific organelle, many electron transfer reactions occur. The peroxisome produces many free radicals, including H2O2, O2- OH•, and NO• (Phaniendra, Jestadi, & Periyasamy, 2015). The endoplasmic reticulum also has enzymes contributing to ROS formation (Phaniendra, Jestadi, & Periyasamy, 2015). Organelle dysfunction is a major component of endogenous ROS proliferated oxidative stress, and it has disastrous consequences for cells that function longer than others and are sensitive to changes in the extracellular environment; like neurons.
ROS in the Brain
The brain and nervous system are particularly susceptible to oxidative stress, which is a factor in many disease outcomes, such as chronic and degenerative diseases, which speeds up the body's aging process, and also acute pathologies; such as trauma and strokes (Pizzino et al., 2017). Examples of specific diseases and illnesses involved with oxidative stress are: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, depression, dementia, and memory loss (Pizzino et al., 2017).
In Alzheimer's disease, the Nrf2 pathway, which is used to repair the damage caused by ROS species to organelles and macromolecules, when it’s disrupted; it leads to the build-up of β-Amyloid plaques. This is suspected to cause neuron loss and eventual progression to dementia, which is typical for diseases like Alzheimer’s (Ashrafizadeh et al., 2020).
Parkinson's disease is the loss of dopaminergic neurons facilitated by the deposition of Lewy bodies or protein plaque deposits of 𝛼-synuclein on the neurons, disrupting the ability of the neuron to produce dopamine (Phaniendra, Jestadi, & Periyasamy, 2015). The dopaminergic neurons most affected by Parkinson's are the neurons located in the substantia nigra, an area of the midbrain that is connected to learning, memory, and motor control (Phaniendra, Jestadi, & Periyasamy, 2015). When the neurons experience oxidative damage, the damage proliferates due to the further imbalance of the pathway, which affects the synthesis of dopamine and damages the neuron itself (Phaniendra, Jestadi, & Periyasamy, 2015). The damage to the neuron causes a dopamine deficit; the symptoms of a dopamine deficit include: jerky movements, trembling of the hands and lips, and tremors (Phaniendra, Jestadi, & Periyasamy, 2015).
Multiple sclerosis is a disorder caused by demyelination of the central nervous system, which impairs the nerves’ ability to conduct signals due to the immune system attacking itself (Phaniendra, Jestadi, & Periyasamy, 2015). Nerve conduction issues are caused by the nerve's demyelination because the nerve's insulation is worn out. The overpopulation of ROS by microglia phage and macrophage cells of the immune system causes lipid peroxidation and the eventual demyelination and damage of neurons (Phaniendra, Jestadi, & Periyasamy, 2015).
How the Body Repairs Oxidative Damage
The body repairs and mitigates oxidative damage via the antioxidant defense system. The antioxidant defense system is a set of mechanisms the cell uses to compensate for the damage caused to the macromolecules and organelles affected by reactive oxygen species (ROS). One of the major processes used to reduce damage to macromolecules is the Nrf2 pathway; this pathway triggers the expression of antioxidant enzymes which activates the expressions of: the heme oxygenase-1 (HO-1), NADPH quinone reductase-1 (NQO1), superoxide dismutase (SOD), glutathione-s-transferase (GST) genes (Ashrafizadeh et al., 2020). The Nrf2 pathway is considered the command center of the antioxidant defense system because it plays one of the most critical roles in maintaining the balance of the cell (Ashrafizadeh et al., 2020).
The molecule Hydrogen sulfide (H2S) is primarily produced by the mitochondria. It has cytoprotective functions that mitigate the effects of protein persulfidation caused by ROS (Zhou & Wang, 2023). In neural systems, H2S has antioxidant activity; in animals, it acts as a neuroprotective factor in neurodegenerative diseases perpetuated by mitochondrial dysfunction (Zhou & Wang, 2023).
The NOX family of proteins is also a part of the antioxidant defense system. It’s a part of the defense system because it regulates the levels of hydrogen peroxide in hippocampal neurons (Wilson, Muñoz-Palma, & González-Billault, 2018). In Chronic Granulomatous Disease the NOX family of proteins are inactivated and the buildup of hydrogen peroxide in the brain damages the surrounding neurons (Wilson, Muñoz-Palma, & González-Billault, 2018).
Potential Treatments
The most commonly recommended treatment doctors prescribe for oxidative stress is antioxidants, as they are widely regarded as a way to mitigate the effects of oxidative stress. Antioxidants can complete this function because they act to neutralize free radicals by donating an electron to the molecule and stabilizing it (Lobo, Patil, Phatak, & Chandra, 2010). Antioxidants are also easy to prescribe because they exist in many common food items that contain oils and fats that protect the food against oxidation (Lobo, Patil, Phatak, & Chandra, 2010). Antioxidants are naturally produced by the body, but in some cases, supplementation is prudent for preventative or minor corrective action combating oxidative stress (Pizzino et al., 2017).
A newer treatment for oxidative stress is microRNA-based therapies. MicroRNAs are nucleic acids that do not code for proteins but are hypothesized to be involved in apoptosis, cell proliferation and differentiation, the cell cycle, and the cell's survival (Ashrafizadeh et al., 2020). In therapies, the microRNA is used to modulate oxidative pathways, specifically the over-expression of miR-371-5p and other macromolecules like to suppress oxidative stress and stimulate neuronal repair in spinal cord injuries and more (Ashrafizadeh et al., 2020). MicroRNA-based therapy is a cutting-edge approach to a new and prolific problem that affects many systems and plays a role in the worst symptoms of many diseases.
Oxidative stress has a hand in many disease pathways but is not generally discussed within general circles. People are told about antioxidants but not why the antioxidants work or what they do. Understanding the complex science isn’t too far outside the reach of the average adult, and better understanding of what supplement they’re taking or the dietary changes the physician is recommending, will only cause a more informed and dedicated patient. Further research into how widespread an impact oxidative stress has on metabolic dysfunctions and potential novel treatments need to be explored in the future.
References
Ashrafizadeh, M., Ahmadi, Z., Samarghandian, S., Mohammadinejad, R., Yaribeygi, H., Sathyapalan, T., & Sahebkar, A. (2020). MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress. Life sciences, 244, 117329. https://doi.org/10.1016/j.lfs.2020.117329
Koju, N., Taleb, A., Zhou, J., Lv, G., Yang, J., Cao, X., Lei, H., & Ding, Q. (2019). Pharmacological strategies to lower crosstalk between nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 111, 1478–1498. https://doi.org/10.1016/j.biopha.2018.11.128
Lobo, V., Patil, A., Phatak, A., & Chandra, N. (2010). Free radicals, antioxidants and functional foods: Impact on human health. Pharmacognosy reviews, 4(8), 118–126. https://doi.org/10.4103/0973-7847.70902
Phaniendra, A., Jestadi, D. B., & Periyasamy, L. (2015). Free radicals: properties, sources, targets, and their implication in various diseases. Indian journal of clinical biochemistry : IJCB, 30(1), 11–26. https://doi.org/10.1007/s12291-014-0446-0
Pizzino, G., Irrera, N., Cucinotta, M., Pallio, G., Mannino, F., Arcoraci, V., Squadrito, F., Altavilla, D., & Bitto, A. (2017). Oxidative Stress: Harms and Benefits for Human Health. Oxidative medicine and cellular longevity, 2017, 8416763. https://doi.org/10.1155/2017/8416763
Petersen R. C. (2017). Free-radicals and advanced chemistries involved in cell membrane organization influence oxygen diffusion and pathology treatment. AIMS biophysics, 4(2), 240–283. https://doi.org/10.3934/biophy.2017.2.240
Wilson, C., Muñoz-Palma, E., & González-Billault, C. (2018). From birth to death: A role for reactive oxygen species in neuronal development. Seminars in cell & developmental biology, 80, 43–49. https://doi.org/10.1016/j.semcdb.2017.09.012
Zhou, L., & Wang, Q. (2023). Advances of H₂S in regulating neurodegenerative diseases by preserving mitochondria function. Antioxidants, 12(3), 652. https://doi.org/10.3390/antiox12030652
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