Mitochondrial Stress Signals: A Novel Form of DNA Damage
New research from UC Riverside, published in the proceedings of the National Academy of Sciences, reveals a previously unknown type of DNA damage within mitochondria – the cell’s powerhouses – that may be key to understanding how the body responds to stress. This revelation has potential implications for a range of diseases, including cancer and diabetes, where mitochondrial dysfunction plays a role.
mitochondria possess their own distinct genetic material, mitochondrial DNA (mtDNA), crucial for energy production and cellular signaling. While scientists have long recognized mtDNA’s susceptibility to damage, the specific mechanisms remained unclear. this study identifies a important source of harm: the formation of glutathionylated DNA (GSH-DNA) adducts.
These adducts are created when molecules attach directly to DNA, potentially disrupting it’s function. If left unrepaired, such damage can lead to mutations and increase disease risk. Researchers found that GSH-DNA adducts accumulate in mtDNA at remarkably high levels – up to 80 times greater than in the cell’s primary nuclear DNA (nDNA). This stark difference underscores mtDNA’s heightened vulnerability.
“mtDNA is inherently more prone to damage than nDNA,” explains Linlin Zhao, senior author and UCR associate professor of chemistry. unlike the linear,biparentally inherited nDNA,mtDNA is circular,contains only 37 genes,and is passed down exclusively from mothers. Moreover, the cellular machinery dedicated to repairing mtDNA is less robust than that for nDNA.
Yu Hsuan Chen, the study’s first author and a doctoral student in Zhao’s lab, describes these adducts as “sticky notes” interfering with the mtDNA’s instructions. The team’s experiments with human cells demonstrated that as these adducts accumulate, normal mitochondrial function is compromised. Energy production proteins decrease, while proteins involved in stress response and mtDNA repair increase, indicating the cell is actively attempting to counteract the damage.
Advanced computer modeling revealed that these adducts also physically alter mtDNA’s structure, making it more rigid and less flexible. Chen suggests this rigidity may serve as a signal for the cell to flag the damaged DNA for removal,preventing its replication.
Zhao believes this discovery opens new avenues for investigating how damaged mtDNA acts as an internal warning system. “Damaged mtDNA and associated inflammation have been linked to conditions like neurodegeneration and diabetes,” she states. “When mtDNA is compromised, it can leak from the mitochondria, triggering immune and inflammatory responses. Understanding how these newly identified modifications influence these processes is a crucial next step.”
This research, a collaboration between UCR and the University of Texas MD Anderson Cancer Center, was supported by grants from the National Institutes of Health and UCR.
