Damage caused by free radicals

We will examine the mechanisms by which an excessive amount of free radicals can damage cells. Excessively produced free radicals damage cells because they take the electrons they need to stabilize themselves and remove them from the main cellular biomolecules: lipids, proteins and nucleic acids.

Damage to lipids by interaction with free radicals

The main target of the action of free radicals is represented by the so-called polyunsaturated fatty acids or PUFA (PolyUnsaturated Fatty Acids) that form the tails of membrane phospholipids. The radicals go to get the electron they need to stabilize, going to subtract it at the level of the double bond of polyunsaturated fatty acids. Lipid peroxidation is the phenomenon of damage to polyunsaturated fatty acids, due to interaction with free radicals.

Let's look in detail at what it consists of: the target is PUFAs, but fatty acids in the cell are essentially the components of the phospholipids that make up the membranes; this means that ultimately, the interaction of free radicals with PUFAs in the membranes will damage all cell membranes.

Let's start with the PUFA, which in this example has three double bonds. R, the free radical, is stabilized by subtracting an electron from the polyunsaturated fatty acid and becoming an RH. The consequence is that this PUFA in turn becomes a radical, thus a fatty acid radical. The fatty acid radical within a lipid bilayer of a membrane: what is its fate? The first thing that a free radical of a fatty acid can do in a membrane is to be stabilized by another fatty acid: a chain reaction occurs, in which one fatty acid stabilizes at the expense of another. In the presence of oxygen and then iron (both must be present, because the first phase is triggered by the presence of oxygen and then the subsequent phases by the presence of iron) the fatty acid radical can also meet another fate: a break down, that is a break down of oxidative type, a progressive degradation of oxidative type. The polyunsaturated fatty acid radical breaks down progressively, until it reaches the level of the products of lipid peroxidation, carbonyl-type molecules but much smaller. These products of lipid peroxidation and in particular the aldehydes, are in turn toxic. 

What is the consequence of this process? In the context of what is the structure of a membrane, phospholipids play both a structural function, and precisely because of the presence of polyunsaturated fatty acids, they also play a role as modulators of membrane fluidity. Starting from a plasma-membrane that has all the polyunsaturated fatty acids in the right place and that has a certain fluidity, at the end you get to a condition where the polyunsaturated fatty acid is no longer there, so it loses the structural function, but it also loses the function that ensures membrane fluidity.

The lipid peroxidation triggered by free radicals at the expense of PUFA of membrane phospholipids, ultimately determines a structural alteration (there is no more fatty acid) and a consequent functional alteration. 

The ROS or in general the free radicals, interacting with the membrane phospholipids, determine a structural and functional damage of the membrane itself, so the damage caused by free radicals on lipids is due to lipid peroxidation.

Damage to proteins by interaction with free radicals

Free radicals can also stabilize at the expense of proteins: the target of free radical interaction in a protein is the sulfhydryl group of the amino acid cysteine, which is present in proteins. The radicals will subtract there an electron to stabilize themselves. 

Free radicals in proteins stabilize by subtracting an electron always at the level of -SH groups. In proteins, the presence of -SH groups is important, because usually amino acids that have an -SH group, are located in the functional center of the protein itself. So if an electron is subtracted from the -SH group of a protein, the functionality is also altered.

If the radical subtracts an electron to a -SH group of a protein and to a -SH group of another protein, disulfide bridges are formed, the functionality is lost and the structure is also lost. This is logically true for both enzymatic and structural proteins.

DNA damage due to interaction with free radicals

Free radical damage to DNA involves tumors, neoplasms. Certainly free radicals damage the DNA, causing the breakage of filaments, cross-links and mutations of bases. When these damages occur, we speak of an oxidative type of damage and there is a marker of oxidative damage of free radicals to DNA: 8 hydroxy-deoxyguanosine (8-OHDG). If you expose cells to a source of free radicals, you can check for DNA damage by measuring this marker of oxidative damage.

The free radicals produced in excess create damage to proteins, lipids and DNA; in the context of the discourse of cellular damage, the effects more immediate and more penalizing for the cell, will derive from damage to lipids, proteins or DNA. Mainly to lipids and proteins, but an excess production of free radicals, can also damage DNA. The most immediate repercussions, are those due to membrane phospholipids, and damage to proteins. The cell dies first because it has an altered membrane, not because it has altered DNA. The DNA damage will become evident when the altered gene has to be transcribed and translated, if the damage was to a portion of DNA that is not transcribed and translated, that damage would not manifest itself.