UC Riverside Probe Reduces DNA Loss, Preventing Cellular Inflammation

Researchers at UC Riverside have developed a chemical probe, mTAP, that selectively binds to damaged mitochondrial DNA, reducing its degradation following exposure to environmental stressors such as nitrosamines. The probe, the result of over two years of research, prevents loss of mtDNA – essential for cellular energy production – without attempting direct repair, and maintains DNA functionality, enabling continued transcription. Studies utilising living cells demonstrated the probe’s ability to lessen mtDNA loss, potentially mitigating the development of conditions linked to mitochondrial dysfunction, including heart disease, neurodegeneration, and chronic inflammation.

Mitochondrial DNA and Cellular Stress

The research demonstrates that preserving mitochondrial DNA (mtDNA) can lessen DNA loss, rather than attempting direct repair of damage, due to the redundant nature of mtDNA molecules within mitochondria. The developed chemical probe selectively binds to damaged sites in mtDNA, blocking enzymatic processes that lead to degradation, and significantly reduced mtDNA loss in both laboratory tests and studies using living cells subjected to damage mimicking exposure to environmental toxins. This approach focuses on preventing loss before it becomes problematic, offering a novel strategy for defending the genome under stress.

Maintaining functional mtDNA is critical for tissues such as the heart and brain, as higher mtDNA levels remaining after induced damage suggest continued energy production. The study found that the chemically tagged, protected DNA remained functional, still supporting transcription – the process by which cells convert DNA into RNA and proteins – which opens the door for potential therapeutic applications. This is despite initial concerns that the addition of a chemical component might impede DNA function.

Increasing links are being established between mtDNA loss and a range of diseases, including multi-organ mitochondrial depletion syndromes and chronic inflammatory conditions such as diabetes, Alzheimer’s disease, arthritis, and inflammatory bowel disease. Preventing mtDNA fragments from escaping mitochondria into the cell may prevent the activation of immune responses, as these fragments can act as distress signals. This suggests that mitochondrial DNA protection could have broader implications for managing inflammatory conditions.

A Chemical Strategy for Genome Preservation

The newly developed chemical probe comprises two key components, ensuring both recognition of damaged DNA and specific delivery to mitochondria, while leaving nuclear DNA unaffected. Following induced damage mimicking exposure to toxic chemicals – such as nitrosamines found in processed foods, water, and cigarette smoke – the probe significantly reduced mtDNA loss in both laboratory tests and studies using living cells. Maintaining higher mtDNA levels is potentially critical for sustaining energy production in vulnerable tissues, including the heart and brain.

When mtDNA fragments escape from mitochondria into the cell, they can activate immune responses by acting as distress signals; retaining DNA within the mitochondria may prevent these downstream signals and subsequent inflammation. The researchers found that the protected DNA remained functional despite being chemically tagged, still supporting transcription – the process by which cells convert DNA into RNA and proteins – suggesting potential therapeutic applications. This outcome addresses initial concerns that the addition of a chemical component might impede DNA function.

The project builds on over two years of research into the cellular mechanisms governing mtDNA processing, and represents a paradigm shift towards a chemical approach to prevention rather than repair. This preventative strategy offers a novel approach to defending the genome under stress, and may have implications for a range of diseases increasingly linked to mtDNA loss, including multi-organ mitochondrial depletion syndromes and chronic inflammatory conditions such as diabetes, Alzheimer’s disease, arthritis, and inflammatory bowel disease.

Implications for Disease and Future Research

Mitochondrial DNA loss is increasingly linked to a range of diseases, extending from multi-organ mitochondrial depletion syndromes to chronic inflammatory conditions including diabetes, Alzheimer’s disease, arthritis, and inflammatory bowel disease. When mtDNA fragments escape from mitochondria into the cell, they can act as distress signals activating immune responses; retaining DNA within the mitochondria may prevent these downstream signals causing inflammation. This suggests that mitochondrial DNA protection could have implications for managing these inflammatory conditions.

Importantly, the researchers found that the protected DNA remained functional despite being chemically tagged, still able to support transcription – the process by which cells convert DNA into RNA and proteins – opening the door for potential therapeutic applications. This outcome addresses initial concerns that the addition of a bulky chemical might impede DNA function.

The project builds on over two years of research into the cellular mechanisms governing mtDNA processing, and represents a paradigm shift – a chemical approach to prevention rather than repair. This offers a novel approach to defending the genome under stress, and may have implications for a range of diseases increasingly linked to mtDNA loss.