Hidden mitochondrial DNA damage may be a missing link in disease

Mitochondria carry their own genetic material, known as mitochondrial DNA (mtDNA). This genetic code is essential for generating cellular energy and for sending important signals both within the cell and beyond it. Although scientists have long known that mtDNA is easily damaged, the biological details were not fully understood. The new study identifies a specific source of harm: glutathionylated DNA (GSH-DNA) adducts.

An adduct is a bulky chemical attachment that forms when a compound, such as a carcinogen, binds directly to DNA. When the cell cannot repair this kind of damage, mutations can occur and the likelihood of disease increases.

Mitochondrial DNA Shows Extreme Vulnerability

In experiments using cultured human cells, the team found that these GSH-DNA adducts build up in mtDNA at levels up to 80 times higher than in nuclear DNA. This large difference highlights how exposed mtDNA is to this form of injury.

Linlin Zhao, the study's senior author and an associate professor of chemistry at UCR, noted that mtDNA represents only about 1-5% of a cell's total DNA. It has a circular structure, contains 37 genes, and is inherited exclusively from the mother. In contrast, nuclear DNA (nDNA) is linear and is passed down from both parents.

"mtDNA is more prone to damage than nDNA," Zhao said. "Each mitochondrion has many copies of mtDNA, which provides some backup protection. The repair systems for mtDNA are not as strong or efficient as those for nuclear DNA."

Yu Hsuan Chen, the study's first author and a doctoral student in Zhao's laboratory, compared the mitochondrion to both an engine and a communication center for the cell.

"When the engine's manual -- the mtDNA -- gets damaged, it's not always by a spelling mistake, a mutation," Chen said. "Sometimes, it's more like a sticky note that gets stuck to the pages, making it hard to read and use. That's what these GSH-DNA adducts are doing."

How Sticky DNA Lesions Affect Cell Function

The scientists observed that as these sticky lesions accumulate, they disrupt normal mitochondrial activity. Proteins needed for producing energy decline, while proteins involved in stress responses and mitochondrial repair increase, indicating that the cell attempts to counteract the damage.

The team also relied on advanced computer modeling to understand how the adducts influence the structure of mtDNA.

"We found that the sticky tags can actually make the mtDNA less flexible and more rigid," Chen said. "This might be a way the cell 'marks' damaged DNA for disposal, preventing it from being copied and passed on."

Implications for Stress, Immunity, and Disease

According to Zhao, the discovery of GSH-DNA adducts creates new opportunities to study how damaged mtDNA functions as a warning signal inside the body.

"Problems with mitochondria and inflammation linked to damaged mtDNA have been connected to diseases such as neurodegeneration and diabetes," he said. "When mtDNA is damaged, it can escape from the mitochondria and trigger immune and inflammatory responses. The new type of mtDNA modification we've discovered could open new research directions to understand how it influences immune activity and inflammation."

Zhao and Chen collaborated with scientists from UCR and the University of Texas MD Anderson Cancer Center.

The research was funded by grants from the National Institutes of Health and UCR.