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Abstract: The main cause of cell death leading to aging and other dysfunctions is characterized by the overproduction of reactive oxygen species (ROS), which influences mitochondrial mutation, altering the mitochondrial respiratory chain and altering membrane permeability. The free radical theory explains that the aging of cells is the conducive effect of oxidative damage to the cells and tissues of the body by damaging the mitochondrial DNA and through oxidative stress. This oxidative damage affects different organs in different ways.
In this article, we focus on three systems mainly: The lymphatic system, digestive system, and neurological effects on the brain leading to various diseases and outcomes. These systems are crucial for human survival and are mainly affected by oxidative stress.
Oxidative stress is a condition that is caused by the imbalance between the production of antioxidants and the reacting free species or the radicals on the side of our body due to various processes happening in our cells. Most importantly, the reacting oxygen species (ROS) is meant to cause mitochondrial oxidative stress that has shown to cause cell apoptosis, aging, various other neurological diseases, and other severe damage to the cell. In addition, it has severely damaging effects on various organ systems.
Lymphatic system and oxidative stress
The lymphatic system plays an essential role in tissue blood homeostasis, immune cell trafficking, and lipid absorption metabolism. The lymphatic system consists of lymph nodes, lymph vessels, and lymphoid organs. The flow of lymph through the lymphatic system is affected by many factors, but mainly oxidative stress (Mukohda et al., 2020). According to the free radical theory of aging, there is a subsequent reduction in NO production and a simultaneous increase in free radical production, which thereby leads to endothelial dysfunction. The endothelial dysfunction caused by aging may involve mechanisms such as alterations in the antioxidant defense systems and increased oxidative injury. Inactivation of nitric oxide by superoxide contributes to impaired vascular function where NO reacts with superoxide radical (O2-) to form peroxynitrite (ONOO-), which may further induce protein modification and DNA damage in the capillary system. Thus, less NO bioavailability because of excess O2- formation becomes a significant cause of endothelial dysfunction in aging.
Aging-associated elevations in oxidative stress may be related to alterations in antioxidant defense enzymes such as the superoxide dismutase (SOD) isoforms. The endothelial cell membrane damage is assumed to be an early incident leading to microvascular dysfunction and may be started by several factors, including lipid peroxidation. ROS such as superoxide, hydrogen peroxide, and hydroxyl radicals damage bio-membranes and induce peroxidation of lipids, accelerating cell permeability and resulting in loss of endothelial integrity. The oxidative stress created inside by the ROS leads to lipoperoxidative damage in the mesenteric lymphatic network observed, and the impairment of the mesenteric lymph transport function in aged vessels reported earlier may predispose the elderly to excessive mesenteric fat deposition, thereby potentially contributing to the lipid deregulation commonly seen in aging-associated diseases. Thereby we can say that aging-related oxidative stress has a prominent effect on mitochondrial dysfunction of the lymphatic system leading to the poor contractility of lymphatic vessels (Thangaswamy et al., 2012).
Effect on GI tract
Mitochondria undergo various ROS-induced damage to epithelial cells and are also the primary source of intracellular ROS produced by oxidative phosphorylation (Ramachandran et al., 2001). Exposure of organelles to modest amounts of ROS will activate critical cytoprotective processes such as the autophagy pathway, which is designed to maintain cellular homeostasis during stress by clearing or recycling damaged organelles. However, excessive ROS generation overwhelms the protective function of the autophagy pathway leading to activation of apoptotic cell death and eventually causing loss of mucosal barrier. In addition, cells undergo alteration in mitochondrial fission/fusion dynamics during microbial stress, potentially contributing to mitochondrial damage.
Oxidative stress-induced damage to intestinal epithelial cells is a significant event in the initiation and progression of pathologies associated with multiple intestinal inflammatory disorders, including ulcerative colitis, colon cancer, and enteritis. The intestinal epithelial layer is uniquely tasked with maintaining tolerance to commensal bacteria while recognizing and initiating immune responses to pathogenic infectious agents. Once tolerance is breached, immune and epithelial cells respond to commensal and pathogenic bacteria in an exaggerated manner and produce inflammatory mediators and reactive oxygen species (ROS) that can not only damage DNA, proteins, and lipids but also eventually lead to the activation of an apoptotic pathway that destroys the epithelial cell layer (Packiriswamy et al., 2017).
To test whether ROS produced during the microbial stress was responsible for the decrease in mitochondrial OMP, a mitochondrial-targeted oxidant scavenging molecule (MitoTempo) was used to inhibit ROS-induced mitochondrial damage. Cells were stained with MitoTracker to assess the antioxidant impact on the OMP to evaluate mitochondrial integrity. Corrected total cell fluorescence was measured using ImageJ software. These demonstrate that scavenging mitochondrial ROS prevented mitochondrial damage and dysfunction, suggesting that most of the ROS produced were of mitochondrial origin. During inflammatory responses, increased mitochondrial oxidative phosphorylation is required to meet increasing cellular demand, and this may result in oxidative stress. Excessive accumulation of ROS that leads to oxidative stress can elicit cellular damage through the oxidation of various macromolecules and thus alter their biological functions and potentiate cell death. For example, previous studies highlighted the contribution of mitochondrial dysfunction to the loss of epithelial cell integrity, leading to increased epithelial permeability and promoting microbial translocation. One mechanism that promotes mitochondrial damage and dysfunction is the excessive production of ROS. Mitochondrial ROS generation is considered to be a continuous physiological process under aerobic conditions. During times of microbial stress, however, mitochondrial oxidative phosphorylation increases, leading to the generation of additional ROS. Increased ROS production must be neutralized by antioxidant systems to prevent oxidative damage to mitochondria and other cellular organs.
Neuro-degenerative disease and oxidative stress
Neurodegenerative diseases are characterized by progressive loss of neurons (Cenini et al., 2019). Though the correct source of these diseases is unknown, oxidative stress leads to mitochondrial dysfunction and lipid absorption dysfunction, making it a critical factor in the most common pathophysiology of neurodegenerative diseases (Guo et al., 2013). The effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to the oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the cause of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer's disease, Huntington's disease, Multiple sclerosis, Amyotrophic lateral sclerosis, and Parkinson's diseases. In addition, oxidative stress causing the protein to misfold may turn to other NDDs, including Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. The source of the ROS can be both endogenous and exogenous, as endogenously it is mainly formed in mitochondria and exogenously by Ultraviolet light and several environmental factors also.
As the brain is always in high demand of oxygen, the presence of highly polyunsaturated fats around it and the presence of heavy metals make it very susceptible to oxidative stress causing several neurodegenerative diseases.
Alzheimer's disease: the significant presence of ROS and the oxidative imbalance leads to the initiation and progression of this disease.
Parkinson's disease: Parkinson's disease is a neurodegenerative disorder caused by selective neuronal loss of dopaminergic neurons in the brain's DA pathway (Dopamine pathway). Oxidative stress has been considered one of the primary pathophysiological mechanisms underlying Parkinson's disease.
References
Cenini, G., Lloret, A., & Cascella, R. (2019). Review Article Oxidative Stress in Neurodegenerative Diseases : From a Mitochondrial Point of View. 2019.
Guo, C. Y., Sun, L., Chen, X. P., & Zhang, D. S. (2013). Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regeneration Research, 8(21), 2003. https://doi.org/10.3969/J.ISSN.1673-5374.2013.21.009
Mukohda, M., Mizuno, R., & Ozaki, H. (2020). Increased Blood Pressure Causes Lymphatic Endothelial Dysfunction via Oxidative Stress in Spontaneously Hypertensive Rats. Hypertension, 598–606. https://doi.org/10.1161/HYPERTENSIONAHA.119.14636
Packiriswamy, N., Coulson, K. F., Holcombe, S. J., & Sordillo, L. M. (2017). Oxidative stress-induced mitochondrial dysfunction in a normal colon epithelial cell line. World Journal of Gastroenterology, 23(19), 3427–3439. https://doi.org/10.3748/WJG.V23.I19.3427
Ramachandran, A., Patra, S., & Balasubramanian, K. A. (2001). Intestinal mitochondrial dysfunction in surgical stress. Journal of Surgical Research, 99(1), 120–128. https://doi.org/10.1006/jsre.2001.6104
Thangaswamy, S., Bridenbaugh, E. A., & Gashev, A. A. (2012). Evidence of Increased Oxidative Stress in Aged Mesenteric Lymphatic Vessels. Lymphatic Research and Biology, 10(2), 53. https://doi.org/10.1089/LRB.2011.0022
About the Author
About the Author
Author: Arunaa NG
Bio: A biotech enthusiast, a passionate reader, and writer, ever ready to take up challenges and interested in neuroscience, behavioral science, genetics, and molecular biology, and an aspiring researcher in the field of medicine and science.
Editor: Himanshi Yadav
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