Our body’s cells are like bustling cities, running on an iron-powered system that uses hydrogen peroxide (H₂O₂) not only to clean dirt but also to send critical signals. Normally, this works well, but under stress, such as inflammation or increased energy use, oxidative stress damages cells at the genetic level.
This is because iron and H₂O₂ react in what is known as the Fenton reaction, producing hydroxyl radicals, destructive molecules that attack DNA and RNA indiscriminately. But there is a problem. In the presence of carbon dioxide, that annoying gas that alters global climate systems, our cells obtain a secret weapon in the form of bicarbonate that helps keep pH levels balanced.
A team of chemists at the University of Utah has discovered that bicarbonate not only acts as a pH buffer but also alters the Fenton reaction itself in cells. Instead of producing chaotic hydroxyl radicals, the reaction produces carbonate radicals, which affect DNA in a much less harmful way, according to Cynthia Burrows, distinguished professor of chemistry and senior author of a study published this week in PNAS.
“Many diseases, many conditions have oxidative stress as a component of the disease. That would include many cancers, effectively all age-related diseases, and many neurological diseases,” Burrows said. “We’re trying to understand the fundamental chemistry of cells under oxidative stress. We’ve learned something about the protective effect of CO₂ that I think is really profound.”
Co-authors include Aaron Fleming, associate research professor, and doctoral candidate Justin Dingman, both members of the Burrows Laboratory.
Without bicarbonate or CO₂ present in the experimental DNA oxidation reactions, the chemistry is also different. The species of free radical generated, the hydroxyl radical, is extremely reactive and hits DNA like a shotgun blast, causing damage everywhere, Burrows said.
In contrast, his team’s findings show that the presence of dissolved CO₂ bicarbonate changes the reaction to produce a softer radical that attacks only guanine, the G in our four-letter genetic code.
“Like throwing a dart at a bullseye where G is the center of the target,” Burrows said. “It turns out that bicarbonate is an important buffer inside cells. Bicarbonate binds to iron and completely changes the Fenton reaction. You don’t produce these highly reactive super radicals that everyone has been studying for decades.”
What do these findings mean for science? Potentially a lot.
For starters, the team’s discovery shows that cells are much smarter than previously thought, which could change the way we understand oxidative stress and its role in diseases such as cancer or aging.
But it also raises the possibility that many scientists who study cell damage have been conducting laboratory experiments in ways that don’t reflect the real world, making their results suspect, Burrows said. Chemists and biologists around the world grow cells in tissue culture in an incubator at 37 degrees Celsius, or body temperature. In these cultures, carbon dioxide levels rise to 5%, or about 100 times more concentrated than what is found in the atmosphere.
Elevated CO₂ recreates the environment that cells normally inhabit while metabolizing nutrients; However, it is lost when researchers begin their experiments outside the incubator.
“It’s like opening a can of beer. You release CO₂ when you take the cells out of the incubator. It’s like doing experiments with a glass of day-old beer. It’s pretty flat. It’s lost the CO₂, its bicarbonate buffer,” Burrows said. . “The protection of CO₂ is no longer available to modulate the reaction of iron and hydrogen peroxide.”
She believes that it is necessary to add baking soda to ensure reliable results from such experiments.
“Most people leave out bicarbonate/CO₂ when studying DNA oxidation because it’s hard to deal with the constant CO₂ outgassing,” Burrows said. “These studies suggest that to get an accurate picture of DNA damage that occurs from normal cellular processes such as metabolism, researchers must be careful to mimic the proper conditions of the cell and add bicarbonate, that is, yeast in dust”.
Burrows anticipates that his study could generate unintended results that could one day benefit research in other areas. His lab is seeking new funding from NASA, for example, to study the effect of CO₂ on people confined in closed spaces, such as inside space capsules and submarines.
“You have astronauts in a capsule living and breathing, and exhaling CO₂. The problem is how much CO₂ can they safely handle in their atmosphere? One of the things we found is that, at least in terms of tissue culture, CO₂ has a protective effect against some of the radiation damage that these astronauts could experience. So what you might want to do is increase that CO₂ level. You certainly don’t want it to be very high, but have it a little bit higher in. “It could actually have it. a Protective effect against radiation, which generates hydroxyl radicals.”