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The Role of Bicarbonate in Cellular Chemistry: Insights from University of Utah Research

Human cells function like dynamic urban environments, powered by iron and utilizing hydrogen peroxide (H₂O₂) for both cleanup and crucial signaling. While this system is typically efficient, it can be compromised under conditions of stress, such as inflammation or increased energy demands, leading to oxidative stress that damages cellular structures at the genetic level.

This damage occurs due to a chemical reaction between iron and H₂O₂, known as the Fenton reaction, which produces hydroxyl radicals. These highly reactive molecules can indiscriminately target and harm DNA and RNA. However, the presence of carbon dioxide (CO₂)—not just a greenhouse gas contributing to climate change—offers cells a means of defense through bicarbonate, which helps regulate pH levels within the body.

A recent study led by chemists at the University of Utah reveals that bicarbonate does more than maintain pH balance; it fundamentally changes the Fenton reaction outcome within cells. Instead of creating the chaotic hydroxyl radicals, the presence of bicarbonate yields carbonate radicals, which are significantly less detrimental to DNA, as indicated by Cynthia Burrows, a distinguished chemistry professor and the lead author of the study published in the Proceedings of the National Academy of Sciences (PNAS) this week.

“Many diseases exhibit oxidative stress as an underlying component,” Burrows noted. “This ranges from various forms of cancer to nearly all age-related diseases and numerous neurological disorders. Our research aims to deepen the understanding of cellular chemistry under oxidative stress, revealing profound protective effects associated with CO₂.”

The study’s co-authors, Aaron Fleming, a research associate professor, and doctoral candidate Justin Dingman, are both key members of the research team. Their findings challenge existing assumptions about how experimental conditions can alter the understanding of DNA oxidation.

In the absence of bicarbonate or CO₂, the free radicals generated during DNA oxidation reactions become highly aggressive and cause widespread damage, likening their impact to a shotgun blast, as Burrows described. Conversely, when bicarbonate is present, the resulting reaction produces a milder radical that primarily targets guanine, one of the four nucleobases in DNA.

“It resembles throwing a dart with G as the bullseye,” Burrows elaborated. “Bicarbonate not only acts as a significant buffer in cells but also modifies the Fenton reaction, preventing the formation of the dangerous radicals that have been the focus of research for many years.”

The implications of these findings are extensive for scientific research. They suggest a reevaluation of how oxidative stress influences our understanding of diseases like cancer and aging, indicating that cells possess a sophisticated mechanism for managing oxidative threats.

This study also highlights the potential discrepancies in laboratory experiments. Researchers often cultivate cells in environments with elevated CO₂ levels—approximately 100 times higher than typical atmospheric concentrations. This mimics the natural conditions cells experience during nutrient metabolism, but this protective environment dissipates when experiments are conducted outside the incubator.

“Taking cells from an incubator is akin to opening a can of beer; it releases CO₂,” explained Burrows. “Conducting experiments with cells that lack this critical cushioning renders the results misleading, akin to experimenting with a day-old flat beer that has lost its carbonic acid and bicarbonate buffer.”

She advocates for the inclusion of bicarbonate in experimental designs to yield more accurate assessments of DNA damage from normal cellular activities.

“Many researchers omit bicarbonate and CO₂ during DNA oxidation studies due to the challenges of managing CO₂ outgassing,” Burrows noted. “Our findings imply that to accurately replicate the conditions of cellular metabolism, scientists need to incorporate bicarbonate—akin to adding baking powder in cooking!”

Looking ahead, Burrows anticipates her research could lead to novel applications beyond cellular biology. Her team is seeking funding from NASA to explore the implications of CO₂ on individuals in confined spaces, such as astronauts in space capsules or submarines.

“Astronauts naturally exhale CO₂ within a closed environment. One critical question is how much CO₂ is safe for them to breathe,” said Burrows. “Interestingly, our research indicates that CO₂ might provide a protective effect against radiation damage, which produces harmful hydroxyl radicals. Optimal CO₂ levels could enhance their protection without reaching dangerous concentrations.”

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