Assumption about cause DNA damage debunked

Assumption about cause DNA damage debunked

Tobias Dansen en Daan van Soest

Worldwide, many supplements containing antioxidants, such as vitamins C and E, are being sold. These supplements would prevent cancer and ageing. New research from UMC Utrecht calls the rationale behind the protective role of antioxidants into question, putting the use of supplements with high doses of antioxidants in a different light.   

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Antioxidants can prevent damage to DNA, is the widespread assumption. Such damage is said to be caused by the release of free radicals during energy production in our cells. This reasoning is often even the basis for the idea that these antioxidant supplements could prevent ageing and cancer. But new research shows that the assumption that free radicals from energy production cause DNA damage is not correct.   

The idea that this assumption might be wrong has long existed, and the research group of associate professor Tobias Dansen from UMC Utrecht now provides important evidence for this in the scientific journal Nature Communications.   

"It sounds very attractive: 'If we take a pill that traps radicals we might be able to prevent cancer, stay healthy and grow very old.' Unfortunately, it just doesn't work like that," Tobias says.  

What was it again?  

When oxygen is used to burn nutrients in the body, free oxygen radicals and their derivatives are released, together also called Reactive Oxygen Species (ROS). Mitochondria, the energy factories of our cells, play an important role in this and cause the production of these ROS. As the name suggests, these substances are highly reactive. That is, they can easily enter a chemical reaction, including reactions that can damage DNA. DNA damage can lead to mutations, and mutations can cause cancer.   

Antioxidants, such as vitamins C and E, are substances that can trap ROS. The research group led by Dansen focuses on the molecular mechanisms surrounding ROS. What do they do in our cells? And what role do they play in diseases such as cancer and diseases of aging?   

No direct evidence   

It is often assumed that ROS from energy production in mitochondria are responsible for damage and mutations to DNA, thereby contributing to the development of cancer. "At first glance, that is not a strange thought: DNA can be damaged by ROS, and mitochondria are the main source of ROS in the cell. But in fact, there is no evidence for a direct link between ROS from energy production and damage to DNA further away in the cell nucleus," says Daan van Soest, PhD candidate in Tobias' research group.  

More insights thanks to new system  

With a grant from KWF Dutch Cancer Society, the Dansen Lab developed a new system. It allows very precise production of exact amounts of ROS at specific sites in the cell. Using a protein originally from yeast, the researchers devised a clever trick. This protein produces ROS as soon as the substance (D-Ala) is added to the cells. The amount of D-Ala added determines the amount of ROS produced. They attached this protein to the mitochondria. This allows them to mimic the effect of ROS produced by mitochondria without interfering with energy metabolism.  

No DNA damage from energy production 

Daan wondered whether ROS produced by the mitochondria could lead to DNA damage in the cell nucleus. Because, to do so, these ROS must first travel from the mitochondria to the DNA.   

"That intermediate step has actually never been properly investigated. We have now done that," Daan explains. And what turns out? ROS produced by our energy production (in the mitochondria) does not reach the DNA in the cell nucleus at all and therefore does not cause any damage there. "About 100 times more ROS must be produced than is normally made by the mitochondria to lead to DNA damage," says Daan.   

The billion-dollar antioxidant supplement industry is partly based on a mechanism that now seems to be debunked. "They might not like our story," notes Tobias. "Because the idea that our energy metabolism would cause DNA damage is precisely the basis for the idea that antioxidants work against cancer and ageing."   

It is one of the reasons antioxidants are popular and taken by many people. The researchers hope to make clear that there seems to be no direct evidence for this, and that supplementing high doses of antioxidants may also have negative effects.   

The downside of antioxidants  

Free radicals also have important functions in our bodies. In fact, earlier research by Tobias' team showed that they are indispensable for correct cell division. The researchers therefore question taking high doses of antioxidants because it might also take away these positive effects.   

For cancer patients, there is still much uncertainty about the effects of taking antioxidants. Tobias: "There are plenty of studies in which antioxidants actually show a negative effect. For example, mouse studies in which metastases returned faster when antioxidants were administered. We also see that some tumor cells actually need more antioxidants to survive than healthy cells, and that those tumor cells therefore benefit from extra antioxidants. It's a very complex story with all kinds of factors involved."  

According to the researchers, there are still too many question marks to formulate a concrete advice on taking extra antioxidants for cancer patients. "Stay or go in consultation with a physician about the intake of antioxidants," is their advice.   

A question the researchers still want to answer in the future is where (oxidative) DNA damage in the cell nucleus then comes from. This damage does not come from ROS originating from energy production, but perhaps other processes play a role in it. The researchers are also curious whether the molecular mechanisms around ROS can tell us more about the origin of cancer and the effectiveness of existing therapies. Perhaps this will also provide clues for new treatments.  

"We still often see that something is labelled as healthy because it contains a lot of antioxidants. There exists a too much of everything, including antioxidants. We hope that our research contributes to the idea that free radicals are not necessarily a bad thing and therefore trapping them by antioxidants is not necessarily a good thing either," Daan concludes.

Want to know more?

Read the article 'Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA' in Nature Communications.

Working at UMC Utrecht





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