New type of mitochondrial DNA damage revealed

A previously unknown type of DNA damage in the mitochondria, the tiny power plants inside our cells, could shed light on how our bodies sense and respond to stress. The findings of the UC Riverside-led study are published today in the Proceedings of the National Academy of Sciences and have potential implications for a range of mitochondrial dysfunction-associated diseases, including cancer and diabetes. 

Mitochondria have their own genetic material, known as mitochondrial DNA (mtDNA), which is essential for producing the energy that powers our bodies and sending signals within and outside cells. While it has long been known that mtDNA is prone to damage, scientists didn't fully understand the biological processes. The new research identifies a culprit: glutathionylated DNA (GSH-DNA) adducts.

An adduct is bulky chemical tag formed when a chemical, such as a carcinogen, attaches directly to DNA. If the damage isn't repaired, it can lead to DNA mutations and increase the risk of disease.

A "sticky" problem for mitochondrial DNA

The researchers found in their experiments in cultured human cells that these adducts accumulate at levels up to 80 times higher in mtDNA than in the DNA of the cell's nucleus, suggesting that mtDNA is particularly vulnerable to this type of damage.

Linlin Zhao, senior author and an associate professor of chemistry at UCR, explained that mtDNA makes up only a small fraction - about 1-5% - of all the DNA in a cell. It is circular in shape, has just 37 genes, and is passed down only from the mother. In contrast, nuclear DNA (nDNA) is linear in shape and inherited from both parents.

mtDNA is more prone to damage than nDNA. 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." 

Linlin Zhao, senior author and associate professor of chemistry at UCR

Lead researcher and first author, Yu Hsuan Chen, a doctoral student in Zhao's lab, likened the mitochondrion to the cell's engine and signaling hub.

"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."

From DNA damage to disease

The researchers linked the accumulation of the sticky lesions to significant changes in mitochondrial function. They observed a decrease in proteins needed for energy production and a simultaneous increase in proteins that help with stress response and mitochondrial repair, suggesting the cell fights back against the damage.

The researchers also used advanced computer simulations to model the effect of the adducts. 

"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."

The team's findings hold promise for understanding diseases. According to Zhao, the discovery of GSH-DNA adducts opens a new frontier for research into how damaged mtDNA can act as a stress signal.

"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 were joined in the study by researchers at UCR and the University of Texas MD Anderson Cancer Center.

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