Chemical shielding helps mitochondria keep their DNA intact

When DNA inside mitochondria is damaged, it is usually not repaired – it is destroyed. This degradation can cause inflammation and lead to Alzheimer’s disease to heart failure. Now, researchers at the University of California have developed a targeted chemical probe that intercepts this loss before it begins, retaining mitochondrial DNA (mtDNA) and potentially preventing disease.

Strategies to protect DNA, not solve it

Posted in Angewandte Chemie International Editionthe study introduced MTAP, a molecule in mitochondrial DNA that binds specifically to damaged sites, called abasic or AP sites. These lesions are common, but as they accumulate, cells usually degrade entire DNA molecules rather than fix them.

Instead of repairing the damage, MTAP binds to the AP site and blocks the enzyme that usually shreds the DNA. This protection helps keep mitochondrial DNA intact without interfering with its function.

Even when exposed to nitroamine, common contaminants found in food and cigarette smoke, cells treated with MTAP maintained a high level of mtDNA. The researchers observed that the retained mtDNA is still able to support basic functions such as transcription and replication.

How molecules work

The success of MTAP lies in its two-part design: one part detects and reacts to form stable chemical bonds with no alkaline sites, while the other part directly passes the probe directly to the mitochondria. This target delivery avoids interference with nuclear DNA.

Anal Jana, a postdoctoral researcher and lead author of the study, designed the probe using chemical synthesis techniques dedicated to mitochondrial biology studied in Zhao Lab.

Major findings from the study

• MTAP forms stable oxygen bonds with mitochondrial AP sites, preventing DNA degradation enzymes like APE1
• No detectable reactions occurred in nuclear DNA, confirming organelle specificity
• Cells treated with MTAP show fewer signs of mitochondrial DNA damage and maintain gene expression
• Even at high concentrations, molecules do not interfere with mtDNA replication
• The existing AP response probes for MTAP in terms of speed and stability under physiological conditions are better than existing AP response probes

What this might mean for chronic diseases

Mitochondrial DNA loss is increasingly associated with diseases such as diabetes, inflammatory bowel disease and neurodegeneration. When fragments of mtDNA leak into cells, they trigger an immune response that promotes chronic inflammation.

Linlin Zhao, a chemistry professor who led the study, noted that degradation occurs more frequently than mitochondrial repair. The team’s approach is designed to stop the loss before it causes further damage.

Even with bulky chemicals attached, the retained DNA still has function. This surprised the researchers and opened the door to potential therapeutic applications involving preventing (not just repairing) DNA damage.

Chemical approaches to change conversations

The ability of probes to selectively stabilize mtDNA represents a shift in thinking. Instead of using biological tools alone to cause damage, the strategy uses chemistry to intervene before degradation occurs. This is the transition from damage response to damage prevention.

Although more research is needed before clinical application, this study lays an important foundation. As Zhao said, this represents a new way to defend the genome under pressure.

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