Free Radical damage to Cells

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A lot is spoken and written about free radicals and their aging affects on cells, tissues and organisms.  This is a very public discussion, which has resulted in the popularity of antioxidants as a food supplement (something that I discuss further in other sections of this site).  Some of what has become common knowledge on the subject is simply hearsay and a lot more is guesswork.  I will attempt in this section of the site to outline exactly what a free radical is and how exactly it affects the aging and longevity of a cell and ultimately the organism to which the cell belongs.

Definition of a Radical

In chemistry, radicals (often referred to as free radicals) are atomic or molecular species with unpaired electrons on an otherwise open shell configuration. These unpaired electrons are usually highly reactive, so radicals are likely to take part in chemical reactions. Radicals play an important role in combustion, atmospheric chemistry, polymerization, plasma chemistry, biochemistry, and many other chemical processes, including human physiology. For example, superoxide and nitric oxide regulate many biological processes, such as controlling vascular tone. "Radical" and "Free Radical" are frequently used interchangeably, however a radical may be trapped within a solvent cage or be otherwise bound.  http://en.wikipedia.org/wiki/Radical_(chemistry)

Basic Free Radical Terminology

Before outlining exactly how a Free Radical goes about damaging cellular organelles, proteins and DNA, I need to first define the three distinct processes that free radical reactions tend to be grouped into.

  • Initiation Reactions.  An Initiation reaction is one in which the net number of free radicals increases.  This may involve the creation of free radicals from a stable species or it may involve the creation of free radicals by means of a reaction between a free radical and a stable species.
  • Propagation Reactions.  A Propagation reaction is one in which the overall number of free radicals stays the same as it previously was.
  • Termination Reactions.  Finally a Termination reaction is one in which there is a net decrease in the overall number of free radicals.  This commonly occurs when two free radicals combine, resulting in the formation of a more stable species.  An example would be 2Cl·→ Cl2 (note that the dot after the 2Cl is the means of denoting free radicals in a chemical reaction).

Benefits of Free radicals

Free radicals are mainly discussed in relation to the detrimental effects that they have on cells and organisms.  In biology, free radicals do however have their uses.  Without them in fact there would be all sorts of problems.  Free radicals for example are used by the cells for several important reasons:

  • In the cellular organelle known as the lysosome, free radicals are used to break down other cellular organelles that have become damaged.
  • Lysosomes also use free radicals to cause cell suicide or Apoptosis by breaking down all cellular components.
  • Lysosomes also use there free radicals to destroy bacteria, which have become engulfed by the white blood cells that are known as Neutrophils.
  • In phagocytes (cells that engulf material and bacteria) superoxide is produced in great quantities by the enzyme NADPH oxidase.  This free radical is then used to destroy the material and pathogens that the cell has injested.
  • They may also play a part in some cell signalling processes.

Drawbacks of Free Radicals

What is probably of interest to the reader here are the damaging affects of free radicals.  These are after all involved in a number of conditions, including that of aging itself.  The two most relevant oxygen-centred free radicals are the hydroxyl (OH) and superoxide (HO2) radicals.  Superoxide is produced by the enzyme NADPH oxidase and also as a by-product of mitochondrial respiration.  Hydroxyl can be produced due to the affects of superoxide. 

Basically superoxide has the ability to inactivate iron-sulphur cluster containing enzymes, which are essential in a large variety of metabolic pathways.  This results in the release of free iron into the cell.  Fe2+ iron is a reducing agent and can react with hydrogen peroxide (H2O2) to produce hydroxyl.  Together with other free radicals, their many effects on the body are:

  • To cause diseases such as cancer by damaging the DNA of certain genes.  These mutations can gradually cause a cells behaviour to change and for it to eventually become malignant.
  • Atherosclerosis (one major disease of the aged) is also thought to be attributed to free radical induced oxidation of a variety of chemicals that make up the body.
  • Parkinson’s and Alzheimer’s disease have also been linked to damage induced by free radicals.
  • Finally the multiple affects of aging, from damage to DNA, RNA, proteins, to arterial and general tissue damage, not to mention damage to cell membranes, have all been linked to free radicals.

Free radicals are produced during the cells natural process of respiration (utilisation of our cells energy).  A cell uses the energy that we gather from our food to manufacture a molecule called Adenosine Triphosphate (ATP) from Adenosine Monophosphate (AMP) and Adenosine Diphosphate (ADP). This ATP molecule is then broken back down to AMP and ADP to make its energy available for all sorts of intracellular processes.  During the process of respiration free radicals are generated.  These radicals by definition are molecules which lack a full complement of paired electrons.  They therefore are prone to stealing electrons from other molecules.  Molecules which have a weaker hold of their own paired electrons. 

This process obviously damages the donor molecule and also as a result of the oxidised molecule losing its full compliment of electrons, causes it also to become a free radical.  This process goes on and if it were left unchecked, would soon result in massive damage to the cell.

Free radicals have a particularly damaging affect on the unsaturated lipid molecules that make up the cell membranes.  Lipid peroxidation is the hardening of cellular membranes and is one consequence of free radical damage.  As you can imagine, if a cell wall becomes hardened, then it will make it difficult or sometimes impossible for that cell to be able to absorb nutrients, receive signals from the cells that surround it or to perform a variety of other functions that are dependent on the fluidity of the cell membrane.

The primary site of free radical damage is the DNA of the cellular organelle known as the mitochondria.  It is in the mitochondria that oxidative cellular respiration takes place.  These organelles are therefore exposed to a great deal of free radical activity and consequently suffer the most damage.  The main problem is that the DNA that we find in mitochondria (mitochondrial DNA or mtDNA) does not benefit from the DNA repair mechanisms that are present in the nucleus of the cell and which help to minimise the free radical damage to nuclear DNA.  Mitochondria therefore gradually become more and more damaged and therefore are less able to produce the energy that the cell needs to function.  This eventually results in a cell shutting down or dying.

To summarise. 

Free radicals are generated naturally in the body as a normal part of respiration and cellular metabolism.  They offer some benefits to the organism, however their production also causes a lot of damage and may ultimately result in the aging and eventual death of the cell.  In the section of the site on Antioxidants, I outline the mechanisms that are used to mange free radicals and to ultimately transform them into more stable species that no longer have the ability to damage the cell.

Mark S D'Arcy

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