When environmental stress harms DNA, it can set off a cascade of failures linked to heart conditions, neurodegeneration, and chronic inflammation. A new chemical tool developed at UC Riverside interrupts that process, helping preserve DNA before the damage leads to disease.
The study, published in the German Chemical Society journal Angewandte Chemie International Edition, focused on mitochondrial DNA, which is separate from the DNA housed in a cell's nucleus. While nuclear DNA contains the vast majority of the genetic code, mitochondria carry their own smaller genomes that are essential for cellular functions, including energy production.
Mitochondrial DNA (mtDNA) exists in multiple copies per cell, but when damage occurs, these copies are often degraded rather than repaired. If left unchecked, this degradation can compromise tissue function and trigger inflammation.
The researchers developed a chemical probe that binds to damaged sites in mitochondrial DNA and blocks the enzymatic processes that lead to its degradation. This approach, rather than repairing damage, lessens the loss of mtDNA.
"There are already pathways in cells that attempt repair," said Linlin Zhao, UCR associate professor of chemistry, who led the project. "But degradation happens more frequently than repair due to the redundancy of mtDNA molecules in mitochondria. Our strategy is to stop the loss before it becomes a problem."
The new molecule includes two key components: one that recognizes and attaches to damaged DNA, and another that ensures it is delivered specifically to mitochondria, leaving nuclear DNA unaffected.
"I designed the molecule by combining my expertise in chemical synthesis and the Zhao lab's extensive experience with DNA repair and mitochondria," said Anal Jana, a postdoctoral fellow in the Zhao lab and leading author of the study.
In lab tests as well as studies using living cells, the probe significantly reduced mtDNA loss after lab-induced damage mimicking exposure to toxic chemicals such as nitrosamines, which are common environmental pollutants found in processed foods, water, and cigarette smoke. In cells treated with the probe molecule, mtDNA levels remained higher, which could be critical for maintaining energy production in vulnerable tissues such as the heart and brain.
Mitochondrial DNA loss is increasingly linked to a range of diseases, from multi-organ mitochondrial depletion syndromes to chronic inflammatory conditions such as diabetes, Alzheimer's, arthritis, and inflammatory bowel disease. When mtDNA fragments escape from mitochondria into the rest of the cell, they can act as distress signals that activate immune responses.
"If we can retain the DNA inside the mitochondria, we might be able to prevent those downstream signals that cause inflammation," Zhao said.
Importantly, the researchers found that the protected DNA remained functional, despite being chemically tagged. "We thought adding a bulky chemical might prevent the DNA from working properly," Zhao said. "But to our surprise, it was still able to support transcription, the process cells use to turn DNA into RNA, and then into proteins. That opens the door for therapeutic applications."
The project builds on more than two years of research into the cellular mechanisms that govern mtDNA processing. While additional studies are needed to explore clinical potential, the new molecule represents a paradigm shift.
"This is a chemical approach to prevention, not just repair," Zhao said. "It's a new way of thinking about how to defend the genome under stress."
