Trait#60: Oxidative Stress Risk (SOD2)

Monday, March 30, 2020. Author FitnessGenes

What is SOD2?

SOD2 stands for superoxide dismutase 2. 

It is an enzyme found within mitochondria, the “powerhouses of the cell” that are responsible for the generation of energy. 

Through a process called cell respiration, mitochondria generate a molecule called ATP – the chemical energy currency of our cells. 

Unfortunately, as we learned in the Metabolic Efficiency and UCP2 blog, this process of generating ATP also leads to the accumulation of harmful molecules called Reactive Oxidative Species (ROS).

(Readers are encouraged to read the UCP2 blog for more on how ROS are produced during respiration).

The role of SOD2 is to clear away these harmful ROS molecules, thereby preventing cell damage. 

As we’ll find out in this article, variants of the SOD2 gene, which encodes the SOD2 enzyme, influence how effectively we clear away ROS. This, in turn, affects our susceptibility to cell damage, inflammation and ageing.

KEY POINTS

• SOD2 is an enzyme found in mitochondria that helps clear away harmful reactive oxygen species (ROS) molecules.
• ROS molecules are produced during respiration and are linked to cell damage and inflammation. 

Why are reactive oxygen species (ROS) harmful?

Reactive oxygen species (ROS) are examples of substances called free radicals – atoms and molecules with unpaired electrons, which makes them highly reactive.

As ROS are highly reactive, they can react with and damage several important molecules within the nucleus and membranes of cells, including DNA, proteins and lipids. This damage can ultimately lead to cell death. 

The superoxide anion

One of the ROS molecules produced by mitochondrial respiration is called the superoxide anion (O2-). This highly reactive molecule has the potential to damage cell components and inactivate key enzymes. 

In addition to cell damage, superoxide anions also bind to and reduce the availability of another important molecule: nitric oxide (NO). Nitric oxide, which we encountered in the Nitric oxide and blood flow blog, is a vasodilator – it widens blood vessels, thereby increasing blood flow to tissues and organs. By reducing the availability of NO, the superoxide anion can promote vasoconstriction (narrowing of blood vessels) and the development of clots, thereby impairing blood flow to tissues and organs. 

KEY POINTS

• Reactive oxygen species (ROS) are examples of free radicals - highly reactive substances with unpaired electrons. 
• The superoxide anion (O2-) is a ROS produced by mitochondria during respiration. 
• The superoxide anion can react with DNA, proteins and lipids, thereby damaging cells. 
• The superoxide anion can impair blood flow to tissues and organs.

What is oxidative stress?

Our mitochondria and, more generally, our cells have evolved several defence mechanisms to protect us from damage caused by ROS (free radicals). 

For example, we have previously encountered uncoupling proteins such as UCP2, which prevent the build-up of ROS by dissipating voltage-gradients generated as mitochondria convert oxygen into water. 

We also have molecules called antioxidants, which directly bind to and neutralise ROS molecules. Examples of antioxidants include Vitamin C, Vitamin E, beta-carotene and glutathione. 

Some antioxidants, such as SOD2, the topic of this trait, are enzymes. They take part in chemical reactions to convert ROS into less harmful molecules. 

Due to these various defence mechanisms, our body is able to effectively deal with the production of ROS. 

In some circumstances, however, the rate of ROS production exceeds and overwhelms our antioxidant and other defences. We call this oxidative stress: an imbalance between the production of ROS and their neutralisation by antioxidants. 

This imbalance leads to the accumulation of ROS, which, in turn, inflict damage to our cells. 

Oxidative stress is therefore considered a damaging process and has been linked to various negative health outcomes, including inflammation, ageing, diabetes, cardiovascular disease, neurodegeneration, and cancer.

KEY POINTS 

• Oxidative stress is an imbalance between the production of damaging ROS molecules and our ability to counteract this with protective antioxidant defences. 
• Oxidative stress causes cell damage and is linked to inflammation, ageing and other negative health outcomes. 

How does SOD2 reduce / prevent oxidative stress?

SOD2 helps to reduce oxidative stress by clearing away one particular reactive oxygen species (ROS) molecule – the superoxide anion (O2-). 

As mentioned previously, the superoxide anion is produced by mitochondria during respiration. If superoxide anions are allowed to accumulate, this can lead to oxidative stress and cell damage. 

The SOD2 enzyme guards against this by converting the superoxide anion (O2-) into the less reactive hydrogen peroxide (H2O2). 

Two other enzymes, catalase and glutathione peroxidase, then subsequently convert hydrogen peroxide into water (H2O), which can be safely re-used or excreted.

To work effectively, the SOD2 enzyme requires manganese, a mineral found in foods such as nuts, seeds, and leafy green vegetables. It’s for this reason that SOD2 is also referred to as manganese superoxide dismutase (MnSOD).

KEY POINTS

• The build-up of superoxide anions (O2-) can lead to oxidative stress.
• SOD2 clears away the harmful superoxide anion into hydrogen peroxide.
• Hydrogen peroxide gets converted into water. 
• SOD2 requires manganese to work effectively - therefore manganese intake in your diet is important for limiting oxidative stress. 

Genetics

The SOD2 enzyme is coded for the SOD2 gene. 

Variants of this gene can affect the activity of the SOD2 enzyme, and therefore alter the rate at which we clear away reactive oxygen species (ROS). This, in turn, changes our susceptibility to oxidative stress and related processes such as inflammation. 

In simple terms, lower SOD2 activity will lead to less clearance of ROS and thereby increase a person’s susceptibility to oxidative stress. 

SOD2 gene variants and oxidative stress

A SNP (rs4880) in the SOD2 gene causes a change in the DNA code from the letter ‘T’ to the letter ‘C’. 

This results in a change within the amino acid sequence of the SOD2 enzyme from valine to alanine. As the activity of enzymes highly depends on their chemical structure, this amino acid change causes a significant decrease in SOD2 activity. 

The gene variant linked to reduced SOD2 enzyme activity is called the ‘C’ allele, with the ‘normal’ or ‘wildtype’ gene variant being the ‘T’ allele. *

People who inherit two copies of C allele (i.e. people who have the CC genotype) are shown to have 33% and 40% lower activity than those with CT and TT genotypes respectively. 

Due to reduced SOD2 activity, individuals with the CC genotype clear away ROS produced in mitochondria less effectively and therefore may be more susceptible to oxidative stress.

If you do have reduced SOD2 activity due to your gene variants, don't worry, there are several dietary and lifestyle measures to mitigate this. Be sure to check out your personalized actions. 

* Depending on which genotyping technology is used to generate your DNA results, the ‘C’ allele may be referred to as the ‘G’ allele, while the ‘T’ allele is referred to as the ‘A’ allele. Accordingly, the CC genotype linked to low SOD2 activity will be known as the GG genotype. 

KEY POINTS

• The SOD2 gene encodes the SOD2 enzyme. 
• A SNP of SOD2 gene creates two variants/ alleles - the 'C' (or 'G') allele and the 'T' (or 'A') allele. 
• People with two copies of the C (or G) allele (i.e. the CC or GG genotype) have reduced SOD2 activity.
• People with the CC (or GG) genotype may be more susceptible to oxidative stress.