Trait: Protection against reactive oxygen species (UCP2)
Dr Haran Sivapalan
March 1, 2021
What are reactive oxygen species (ROS)?
Reactive Oxygen Species (ROS) are highly reactive biological substances that are derived from oxygen.
Many ROS are examples of what we call “free radicals” – atoms or molecules with unpaired electrons that makes them highly reactive. For example we previously encountered the superoxide anion (O2-) in your SOD2 and oxidative stress trait.
Other ROS, including hydrogen peroxide (H2O2) are not, technically speaking, free radicals, but are nevertheless highly reactive.
As they are highly reactive, ROS can react with and damage important molecules, such as DNA, lipids (such as those in cell membranes) and proteins (including key enzymes and structural proteins). This type of damage is known as “oxidative damage.”
ROS can be generated by exogenous factors, such as exposure to pollutants, cigarette smoke, or UV radiation. However, our body also produces ROS during normal processes. In this respect, one of the major sources of ROS is cell respiration – the process by which cells derive chemical energy. In particular, aerobic respiration by mitochondria (the “powerhouses of the cell”) leads to the production of ROS as oxygen is gradually converted into water.
- Reactive Oxygen Species (ROS) are highly reactive substances derived from oxygen that are capable of damaging DNA, lipids and proteins.
- ROS are produced during aerobic respiration in mitochondria.
What are antioxidants?
Antioxidants are biological substances that act to neutralise and get rid of harmful ROS (Reactive Oxygen Species) and other free radicals. By doing so, antioxidants protect our cells against oxidative damage caused by ROS.
Our body has evolved several different antioxidant defences to guard against oxidative damage. Some antioxidants, such as glutathione, Vitamin E (alpha-tocopherol) and Vitamin C (ascorbic acid), work by binding to and immobilising (or ‘scavenging’) ROS. We can obtain some of these antioxidants from our diet, with fruits and vegetables being particularly rich sources.
Other antioxidant defences involve enzymes that convert ROS into other less harmful molecules. An example of an antioxidant enzyme is superoxide dismutase, which we encountered in your Oxidative Stress (SOD2) trait.
Our mitochondria also have specialised uncoupling proteins (e.g. UCP2) that prevent the build-up of ROS during cell respiration. These proteins may also be considered to be an antioxidant system.
- Antioxidants are substances that neutralise reactive oxygen species (ROS) and free radicals.
- Antioxidants protect us from oxidative damage caused by ROS and free radicals.
- Some antioxidants (e.g. Vitamin E) bind to and immobilise ROS.
- Other antioxidants are antioxidant enzymes that convert ROS into less harmful substances.
- Our mitochondria have antioxdant systems to prevent the build-up of ROS during respiration.
What is oxidative stress?
Our antioxidant defences (explained above) generally do a good job of preventing the accumulation of ROS and preventing cell damage.
Sometimes, however, the production of ROS can exceed and overwhelm our antioxidant defences. This is known as oxidative stress –an imbalance between the production of ROS and their neutralisation by antioxidants.
Due to this imbalance, ROS start to accumulate and cause damage to important cellular molecules (e.g. DNA, lipids, proteins) and cell components (e.g. cell membranes, mitochondria).
Cell damage from oxidative stress has been linked to several negative health consequences, including: chronic inflammation, ageing, diabetes, cardiovascular disease, neurodegeneration, and cancer.
- Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and their clearance by antioxidants.
- Oxidative stress damages cells.
- Oxidative stress is linked to inflammation, ageing, cardiovascular disease and cancer.
How are ROS produced during respiration?
Aerobic respiration is the process by which we use oxygen to convert fuel (e.g. glucose) into ATP (adenosine tri phosphate) - the chemical energy currency of our cells. ATP generated by aerobic respiration can then be used to power muscle contraction, transport of molecules, nerve function, and all the other various processes that keep us alive.
Our mitochondria are the major site of aerobic respiration. In the last stage of aerobic respiration, known as the electron transport chain, our mitochondria gradually convert oxygen into water and simultaneously pump out H+ ions across their inner membrane to create a voltage gradient.
Eventually, the H+ ions are allowed to pass back down the voltage gradient, but are funnelled through a specially designed enzyme known as ATP synthase, which produces ATP. You can read more about this in the Metabolic Efficiency (UCP1) trait article.
As oxygen gets converted into water and H+ ions are pumped out to create a voltage gradient, however, oxygen is temporarily converted into intermediate ROS molecules. As shown in the diagram below, oxygen forms superoxide anions (O2-), hydrogen peroxide (H2O2), and hydroxyl radicals (OH) as it converted into water.
Normally, the intermediate ROS are eventually converted into water as H+ ions are allowed to travel back across the inner mitochondrial membrane down their voltage gradient.
If H+ ions are pumped out excessively, however, causing the voltage gradient to become too high, then the process of converting oxygen into water starts to get backed up. Consequently, intermediate ROS molecules start to accumulate and cause oxidative damage to proteins, lipids, DNA and other key cell components.
- Reactive oxygen species are produced by mitochondria during aerobic respiration as oxygen is converted into water.
- The pumping of H+ ions across the inner mitochondria to create a voltage difference leads to the build up of ROS.
What is UCP2?
UCP2 stands for uncoupling protein 2.
It is a protein produced by mitochondria. It belongs to a class of proteins called 'uncoupling proteins' that serve to 'uncouple' or divert cell respiration from the production of ATP.
One of the major roles of UCP2 is to prevent the build-up of ROS during cell respiration. In this respect, UCP2 helps to protect against oxidative stress and cell damage caused by the accumulation of ROS
- UCP2 (uncoupling protein 2) is a mitochondrial protein that helps to prevent the build-up of ROS.
- UCP2 helps to protect against oxidative stress.
How does UCP2 protect against ROS?
UCP2 (uncoupling protein 2) acts to prevent the build-up of reactive oxygen species (ROS) during cell respiration.
It does this by simply acting as a conduit for H+ ions to pass through the inner mitochondrial membrane. In doing so, it dissipates the voltage gradient across the inner membrane, which allows oxygen to be converted into water more easily. This then prevents the generation of intermediate ROS molecules.
As stage C in the above diagram shows, UCP2 allows H+ ions to pass back down through the inner mitochondrial membrane. This is known as uncoupling or proton leak, which dissipates the voltage gradient (or reduces the proton motive force), as shown in stage D.
Uncoupling relieves the congestion on the electron transport chain, allowing oxygen to be converted into water more freely. This prevents the build up of intermediate ROS molecules, such as the superoxide anion (O2-), as shown in stages B and E in the diagram above.
It’s worth noting that UCP2 likely acts as a “mild uncoupler” – it only allows some H+ ions through, meaning the majority of H+ ions can continue to flow through the ATP synthase enzyme. This permits mitochondria to continue producing ATP, while simultaneously reducing the build up of ROS.
- UCP2 acts a conduit for H+ ions to pass through the inner mitochondrial membrane.
- UCP2 dissipates the voltage gradient across the inner mitochondrial membrane, which reduces the production of reactive oxygen species.
How do UCP2 gene variants affect protection against ROS?
The UCP2 protein is coded for by your UCP2 gene.
Variants of the UCP2 gene can affect the expression of the UCP2 protein i.e. how much UCP2 protein is produced by mitochondria and is present on the inner mitochondrial membrane.
Your Protection against reactive oxygen species (UCP2) trait looks at a SNP (Single Nucleotide Polymorphism) within the UCP2 gene designated rs659366 (-866G>A). This creates a change in the DNA code, thereby giving rise to two UCP2 gene variants or alleles: ‘G’ and ‘A’.
The ‘A’ allele is associated with greater UCP2 expression and therefore higher levels of UCP2 protein.
It is thought that higher levels of UCP2 protein in mitochondria affords greater protection against the build-up of ROS and oxidative stress during cell respiration.
The ‘A’ allele is also proposed to have an additive effect on UCP2 protein levels. This means that someone inheriting two copies of the ‘A’ allele (i.e. AA genotype) would have higher UCP2 levels (and greater protection against ROS) than someone with one copy of the ‘A’ allele (AG genotype).
By contrast, inheriting two copies of the ‘G’ allele (i.e. GG genotype) is linked to lower UCP2 expression and poorer protection against ROS (relative to those with the ‘G’ allele).
- Variants of the UCP2 gene can affect production of the UCP2 protein.
- Higher UCP2 protein levels may confer greater protection against ROS and oxidative stress.
- The ‘A’ allele of the UCP2 gene (rs659366) is linked to higher UCP2 levels and greater protection against the build-up of ROS.
- The ‘G’ allele is, relatively speaking, linked to lower UCP2 levels and poorer protection against ROS.
How do UCP2 gene variants affect health outcomes?
UCP2 gene variants and cardiometabolic disease
Oxidative stress, caused by the accumulation of ROS, can cause damage to various cells and tissues, including liver cells, blood vessels, nerves, and adipose tissue.
This oxidative cell damage has been implicated in the development of various health conditions, including cardiometabolic diseases such as Type II diabetes, heart disease, and non-alcoholic fatty liver disease (NAFLD).
It follows that UCP2 gene variants associated with lower UCP2 protein levels, and therefore less protection against ROS and oxidative stress, could also be linked to these cardiometabolic diseases.
On this note, some studies have shown an association between the ‘G’ allele (rs659366) of the UCP2 gene and an increased risk of Type II diabetes, diabetic retinopathy and poorer insulin sensitivity.
It is important to note, however, that other studies have suggested the opposite (i.e. reduced risk) or no association between the ‘G’ allele and Type II diabetes. Overall, the relationship between UCP2 gene variants and risk of metabolic diseases such as Type II diabetes is complicated. This is partly because, in addition to protecting against ROS and oxidative stress, the UCP2 protein may function to suppress insulin secretion, thereby playing opposing roles in the development of diabetes.
- UCP2 gene variants and ageing
Oxidative stress is thought to contribute to biological ageing. On this note, UCP2 gene variants linked to higher protein levels and greater protection against ROS and oxidative stress have been associated with slower biological ageing.
As discussed in your Telomere-linked ageing (TERC) trait, one marker of ageing is shortening of telomeres: stretches of DNA at the end of chromosomes. For a given chronological age, shorter than average telomeres are indicative of faster rates of biological ageing.
In a study of 950 people without diabetes or pre-diabetes, researchers found that subjects carrying the ‘A’ allele (rs659366) of the UCP2 gene was linked to significantly longer telomeres.
As shown in the graph below, those with the AA and GA genotypes had longer leukocyte telomere lengths (LTL) compared to those with the GG genotype.
Source: Zhou, Y., Simmons, D., Hambly, B. D., & McLachlan, C. S. (2016). Interactions between UCP2 SNPs and telomere length exist in the absence of diabetes or pre-diabetes. Scientific reports, 6(1), 1-7.
Although it cannot be concluded from the study in question, it’s possible that higher UCP2 protein levels conferred by the ‘A’ allele act to slow biological ageing by protecting against the accumulation of ROS.
- UCP2 gene variants and smoking
Smoking is a well-established cause of oxidative stress. Tobacco smoke contains free radicals and ROS, while other components of cigarette tar can generate further ROS.
One study that diabetic people with AA genotype have higher plasma markers of oxidative stress when smoking. While smoking causes oxidative stress regardless of genotype, those with the AA genotype may be particularly susceptible to the damaging effects of smoking.
The exact mechanism behind this relationship is unclear. It may be the case that the smoking is less likely to induce further expression of the UCP2 protein in carriers of the ‘A’ allele.
- Some studies have found the ‘G’ allele of the UCP2 gene linked to an increased risk of cardiometabolic disease (although findings are mixed).
- The ‘A’ allele is linked to slower rates of biological ageing.
- People with two ‘A’ alleles (AA) may experience more severe oxidative stress when smoking.
Your Protection against ROS (UCP2) trait
Your Protection against ROS (UCP2) trait analyses variants of your UCP2 gene, including rs659366, to assess how effectively mitochondria prevent the build-up of ROS. You will fall into one of three groups:
- Increased protection against ROS – Higher UCP2 expression (AA genotype).
- Moderate protection against ROS - Moderate UCP2 expression (GA genotype).
- Reduced protection against ROS – Lower UCP2 expression (GG genotype).
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