Mitochondrial Stress Signals: A โขNovel Form ofโ DNA Damage
New research from UC Riverside, published in the proceedings of the National Academy of Sciences, reveals aโค previously unknown type ofโข DNA damage within mitochondria – the cell’s powerhousesโข – that โmay be keyโฃ to โคunderstanding how the body responds to stress. This revelation โhas potentialโฃ implications for โขa range of diseases, including โcancerโ and diabetes, where mitochondrial dysfunction plays โa role.
mitochondria possess their ownโ distinct geneticโ material, mitochondrial DNA (mtDNA),โฃ crucial for energyโ production andโ cellular signaling. While scientists have long recognized โmtDNA’s susceptibility to โdamage, the specific mechanisms remained unclear. this study identifiesโข a important source of harm: the formation of glutathionylated DNA โฃ(GSH-DNA) adducts.
These adducts are created when molecules attach directly to DNA, potentially disrupting it’s function. If left unrepaired, such โdamage canโ lead to mutations and increase disease risk. Researchersโฃ found that GSH-DNA adducts accumulate in mtDNA at remarkably high levels – up to 80 times greater โขthan in the cell’s primary nuclear DNA (nDNA). Thisโค stark โdifference underscores mtDNA’s โheightened vulnerability.
“mtDNA is inherently more prone to damage than nDNA,” explains Linlin Zhao, senior author and UCR associateโค professor of chemistry. unlike the linear,biparentally inherited nDNA,mtDNAโค is circular,contains only 37 genes,and is passed โคdown exclusively from โฃmothers. Moreover, the cellular machinery dedicated to repairing โขmtDNA is less robustโ than that for nDNA.
Yu Hsuan Chen, the study’s first author and a doctoral student โin Zhao’s lab, describes these adducts as “sticky notes” interfering with the mtDNA’s instructions. The team’sโ experiments with human cellsโ demonstrated that as these โขadducts accumulate, normal โmitochondrial functionโ is compromised. Energy โขproduction proteins decrease,โข while proteins involved in stress โคresponse and mtDNA repair โคincrease, indicating the cell is actively attempting to counteract theโข damage.
Advanced computerโ modeling revealed that these adducts also physically alter mtDNA’s โคstructure, making โit more rigid and less โคflexible. Chen suggestsโ this rigidity may serve as a signal for the cell to flag theโ damaged DNAโ for โremoval,preventing its replication.
Zhao believes this โdiscovery opens new avenues for investigating how โขdamaged 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.โข Understanding โhow these newly identified modifications influence these processes is a crucial next step.”
Thisโค research, a collaborationโข betweenโ UCR and the University of โขTexas MD Anderson Cancer Center, was supported by grants from โthe National Institutes of Health and UCR.