Mitochondria, Reactive Oxygen Species (ROS), and Their Effect on the Body

Reactive oxygen species (ROS) are highly reactive molecules and free radicals formed as a natural byproduct of oxygen metabolism. These molecules, which are present at low levels in normal cells, play a vital role in maintaining healthy redox processes and ensuring proper function in the cells. However, an overproduction of ROS may cause oxidative stress, cellular damage, and DNA damage, which may lead to several physiological and pathological conditions.

Reactive Oxygen Species: An Overview

Basically, ROS is produced in the mitochondria, peroxisomes, and chloroplasts during the process of respiration and photosynthesis. It can be produced in several ways:

• During the respiration process as the mitochondria converts energy into ATP. When the hydrogen ions (protons) are transported across the inner mitochondrial membrane, the electrons pass through a series of acceptor proteins, each having a greater reduction potential than the one before it. Ideally, the remaining electron is passed to an oxygen molecule at the end of the chain to produce water. However, this is not always the case. Sometimes, the premature and incomplete reduction of oxygen produce superoxide radicals instead.
• During electron transfer reactions catalyzed by P450 systems. Superoxide radicals can also be produced when electrons leak and react with oxygen as electrons are passed from NADPH to P450 systems in steroidogenic tissues.
• In the NOX pathway. ROS can also be produced upon the stimulation of phagocytic cells (e.g. neutrophils, eosinophils, mononuclear phagocytes).
• External factors. ROS production can be affected by several exogenous factors, which may include ionizing radiation, pollutants, drugs, xenobiotics, tobacco, smoke, and heavy metals. In plants, ROS is produced in the presence of abiotic stress (e.g. UVB radiation, drought, significant rise or drop in temperature, salinity, nutrient deficiency, metal toxicity, etc.).

Some of the most notable examples of ROS include superoxide radical (^•O^-₂), hydrogen peroxide (H₂O₂), hydroxyl radical (^•OH), peroxynitrite (ONOO^-), singlet oxygen (¹O₂), and alpha-oxygen (α-O).

Understanding the Dual Nature of ROS

ROS are largely misunderstood. They are more widely known for the role they play in various pathologies rather than their beneficial effects in pathogen response, homeostasis, and cell signal cascades. Recent studies also indicate that ROS play a crucial role in memory formation.

Generally, everything has a good side and a bad side, and ROS are not an exception. Under normal conditions, these highly reactive chemical molecules are vital in inducing host defense (platelets release ROS to recruit additional platelets to the site of injury) and in activating the adaptive immune system (through the recruitment of leukocytes).

Interestingly, ROS is shown to be capable of inducing both antimicrobial and antiviral defense. Studies show that it is powerful enough to damage bacterial DNA, RNA, and proteins while increased ROS levels activate the nuclear factor kappa B and interferon regulatory factor (IRF-3 and IRF-7) to induce an antiviral state and inhibit the replication of many viruses.

Besides its role in pathogen response, the body needs a balanced ROS level (referred to as redox window) to maintain redox homeostasis which is necessary for ensuring proper signaling processes. In addition, ROS is also responsible for regulating cell proliferation and apoptotic pathways, coronary collateral growth, and endothelial cell migration and proliferation.

Problems occur when the balance tips and the ROS levels move farther away from the redox window. Exceedingly high levels of ROS bring about oxidative stress and may lead to mitochondrial and cell apoptosis while extremely low levels result in reductive stress.

Both conditions can lead to the development of certain pathologies which may include premature aging, inflammatory diseases such as rheumatoid arthritis and multiple sclerosis, degenerative diseases such as Alzheimer’s disease, male infertility, cardiovascular diseases, stroke, heart attack, and cancer.