oxygen free radical
Graphic credit: HonChemistry | CC SA 3.0 license

In response to my post, “Too much food and too little exercise lead to leaks in our energy pipeline,” I received an email raising a very interesting question. Rather than paraphrasing it, here it is:

“Much of what I have been reading says that ‘oxidation’ is bad and oxidation is burning; oxidation makes cells die and shortens life; ‘antioxidants are very good for you’. Would you explain these apparently contradictory statements, burning protects and oxidation is bad?

(P.S. Sounds like another good topic for TDWI.)”


Indeed, Barry, an excellent topic for TDWI. So here it goes.


Not all oxidations are created equal: First, “normal” oxidation

We get our energy from the food we eat:

  • Carbohydrates and proteins are converted, via a series of biochemical steps, into a molecule called pyruvic acid.
  • Fats are converted into fatty acids.

These two molecules, pyruvic acid, and fatty acids, next become oxidized. That means, in chemical terms, that they lose electrons. Those electrons then pass through a chain of proteins embedded in the inner wall of the mitochondria—the powerhouse of cells.  Finally, they arrive at the last protein in the chain: cytochrome oxidase.

Cytochrome oxidase, an enzyme, then transfers the electrons to molecules of oxygen, thereby causing the oxygen to be “reduced”. The reduced oxygen combines with two molecules of hydrogen that are missing their electrons. This forms water or H2O.

The net effect is that pyruvic acid and fatty acids lose electrons (they get oxidized). The electrons pass down the mitochondrial electron transport chain and, eventually, oxygen molecules receive electrons and gets reduced. One reduced oxygen molecule then combines with two molecules of hydrogen to create a molecule of water.

What is the purpose of all of this electron transfer you might ask? It turns out that the oxidation of pyruvic acid and fatty acids is not only associated with the release of electrons, it is also associated with the release of energy that is stored in those molecules. This energy is recaptured by forming a molecule of ATP from a molecule called ADP (Adenosine Tri-Phosphate and Adenosine Di-Phosphate, respectively). ATP is the energy “currency” of all organisms that depend on oxygen. ATP provides the energy for enzymes and other proteins to perform their functions.

The whole process is called “oxidative phosphorylation”. It is an absolute necessity for life. Cyanide, a deadly poison, works by inhibiting cytochrome oxidase. It stops life-sustaining oxidative phosphorylation in its tracks. The results, for the organism, are quite dire and quite fast.


What happens when the electron transport chain is backed up? Harmful oxidation

When the electron transport chain cannot keep up with the flow of electrons and energy, quite simply, the electron transport chain springs a leak. This leak occurs at the first “station” of the transport chain, at the site of a protein called Complex I.

Once the leak occurs, we end up with electrons that are “running loose” among the mitochondrial proteins, combining with them and causing damage to their structure and function. Furthermore, because of the loss of electrons that leak out, we get a lot of oxygen molecules at the end of the transport chain that don’t get “their” electron.

These electron-poor oxygen molecules are called Reactive Oxygen Species, or ROS for short. They are the infamous highly reactive “free radicals”. These free radicals react with two hydrogens just as reduced oxygen does. However, instead of forming water, H2O, they form H2O2, which is hydrogen peroxide.

Hydrogen peroxide molecule reacts with everything in sight…think about those bubbles that form when you pour hydrogen peroxide on a finger cut. Hydrogen peroxide impairs the function of mitochondrial proteins, lipids, and DNA. These pesky free radicals can also wreak havoc outside the mitochondria, as well as damage the cytoplasmic (cell body) proteins, the cell membrane proteins and lipids, and the nuclear DNA. As you can readily appreciate, these reactive free radicals wreak total mayhem inside of the cell. It is not a pretty picture.

One final question: What causes the leak of electrons from the respiratory chain in the first place? The answer is that the leak occurs when there are too many electrons trying to enter the electron transport. This occurs when we have flooded the mitochondria with too much pyruvic acid or too many fatty acids. How does that happen? Remember, ultimately, the pyruvic acid and fatty acids come from the food we eat. So, too much food causes our energy pipeline to spring a leak. Leaks can also occur when the transport chain is too sluggish in transporting the electrons, thus causing a traffic jam.


Now, what you have all been waiting for…What can we do to reduce the formation of these damaging oxygen free radicals?

  • Reduce your food intake (you knew I was going to say this, no?). How does control of food intake help? By reducing the amount of pyruvic acid and fatty acids trying to pass their electrons down the chain, we reduce the pressure of electrons on the limited capacity of the chain.
  • Exercise. How does exercise help? Exercise increases the efficiency of the transport chain. It also increases the number of mitochondria per cell and it increases the number of muscle cells.
  • Take resveratrol? Resveratrol is a substance in red wine (and grapes) that increases the efficiency of the electron transport chain. Resveratrol also increases the number of mitochondria per cell. Miracle drug, you are thinking? However, it is currently not possible to ingest enough resveratrol to achieve this effect in humans.

So, here is the bottom line: The best and currently only realistic way to reduce oxygen free radical damage is diet and exercise!

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.