Written by Joseph Suh ‘25
Edited by Josue Navarro ‘25
Oxygen, or O2 in its gas form, is undoubtedly an important molecule for many biological species. Without it, you would not be able to read this article right now! Comprising about 21% of the Earth’s atmosphere, nearly all known living organisms require oxygen to survive—unless you happen to be a Henneguya salminicola, a white parasite infecting the flesh of salmon that is also the first known animal that does not breathe oxygen (2). While many know it to be the very air we breathe to survive, it is present in other helpful molecules, like water—H2O! However, it is also important to consider what can happen when oxygen becomes not-so-helpful.
Oxidative stress is defined as the imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify them. Examples of reactive oxygen species include superoxide radicals (O2•-), hydrogen peroxide (H2O2), and hydroxyl radicals (•OH) (3). In living organisms, they are naturally generated as byproducts of metabolism. Specifically, ROS are mainly produced in the mitochondria, which are commonly referred to as the “powerhouse of the cell” and are thought to have originated from an ancient symbiotic relationship between an aerobic prokaryote and a eukaryote that engulfed it.
Mitochondria are responsible for a process known as oxidative phosphorylation, which is the final step in cellular respiration to generate adenosine triphosphate (ATP), the primary source of energy at the cellular level. Oxidative phosphorylation takes place in the inner mitochondrial membrane, which surrounds the mitochondrial matrix, the inside of the mitochondria. There are two electron-carrying molecules that begin the process—NADH and FADH2. Specifically, they deliver electrons to what is called the electron transport chain, where electrons are passed down a series of protein complexes embedded in the inner mitochondrial membrane. At several of these complexes, protons (H+) are pumped across the mitochondrial membrane, which creates a proton gradient due to the difference in concentration of protons. At the end of this chain, oxygen (O2) “accepts” the electrons as the terminal electron acceptor, and the flow of protons—which move naturally due to the gradient—through a protein called ATP synthase is used to drive the addition of a phosphate group to adenosine diphosphate, creating adenosine triphosphate (4).
In the context of oxidative phosphorylation, the one electron reduction, or the gain of one electron, by oxygen results in the formation of superoxide, O2•-. There are two primary modes of mitochondrial operation that increase ROS production. The first is a high ratio of NADH to its oxidized form, NAD+, which leads to increased O2•- formation at Complex I, the protein complex appearing first in the electron transport chain (5). The second is the absence of ATP production, which results in a high proton motive force, meaning there is a large electrochemical gradient of protons across the mitochondrial membrane, and reduced coenzyme Q, a cofactor functioning as another electron carrier. The result is reverse electron transport through Complex I, generating large amounts of superoxide as electrons instead move backwards through the electron transport chain (5). In both cases, ATP production and cellular respiration are reduced.
If these reactive oxygen species are so harmful to the body, it is natural to wonder how we can possibly hope to survive if we are continuously generating them? Fear not, for there exists a number of countermeasures! The regulation of reactive oxygen species by the body is complex and involves enzymes tailored to breakdown specific ROS in addition to other defense mechanisms. The major enzymes acting as antioxidants are superoxide dismutases, catalase, glutathione peroxidase, glutathione-reductase, and superoxide reductases, of which the first two provide primary defenses against ROS (6). Both enzymes are scavengers that neutralize their respective substrates; superoxide dismutases converts superoxide into the more stable hydrogen peroxide, while catalase breaks down hydrogen peroxide into oxygen and water.
On the other hand, other proteins such as mitochondrial uncoupling proteins (UCPs) play important roles in superoxide protection. Superoxide and other reactive oxygen species can lead to lipid peroxidation, the oxidation of fatty organic compounds, which can then produce reactive aldehyde species that activate UCPs, triggering mild uncoupling (7). The electrochemical proton gradient is then dissipated to some extent by bypassing the typical flow of protons through ATP synthase. Overall, this uncoupling increases oxygen consumption and causes a decrease in local oxygen concentration, attenuating the production of mitochondrial reactive oxygen species (7).
Previous studies suggest that mitochondrial damage and oxidative stress are involved in a number of neurodegenerative diseases, which are often characterized by the progressive loss of neurons. For example, Alzheimer’s Disease, the most common neurodegenerative disease in the world, results in oxidative stress from mitochondrial dysfunction that can damage lipids, DNA, and proteins (8). Mitochondrial damage has also been implicated in other prominent diseases such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS) (8).
It is almost frightening to think that the very air we breathe can become something dangerous with as little as the addition of one tiny electron! However, combined with our body’s defense mechanisms and ongoing research in the field, we can rest assured that we will remain equipped to combat and prevent oxidative stress now and into the future.
References
Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000 Nov 9;408(6809):239–47.
This is the only known animal that doesn’t need oxygen to survive [Internet]. [cited 2025 Feb 24]. Available from: https://www.science.org/content/article/only-known-animal-doesn-t-need-oxygen-survive
Collin F. Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases. Int J Mol Sci. 2019 May 15;20(10):2407.
Cooper GM. The Mechanism of Oxidative Phosphorylation. In: The Cell: A Molecular Approach 2nd edition [Internet]. Sinauer Associates; 2000 [cited 2025 Feb 24]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9885/
Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009 Jan 1;417(Pt 1):1–13.
Bhattacharyya A, Chattopadhyay R, Mitra S, Crowe SE. Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases. Physiol Rev. 2014 Apr;94(2):329–54.
Brand MD, Affourtit C, Esteves TC, Green K, Lambert AJ, Miwa S, et al. Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins. Free Radical Biology and Medicine. 2004 Sep 15;37(6):755–67.
Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013 Jul 25;8(21):2003–14.