New molecule shields mitochondrial DNA from stress-induced degradation

When environmental stress harms DNA, it might set off a cascade of failures linked to coronary heart situations, neurodegeneration, and persistent irritation. A brand new chemical device developed at UC Riverside interrupts that course of, serving to protect DNA earlier than the injury results in illness.

The examine, revealed in Angewandte Chemie Worldwide Version, centered on mitochondrial DNA, which is separate from the DNA housed in a cell’s nucleus. Whereas nuclear DNA incorporates the overwhelming majority of the genetic code, mitochondria carry their very own smaller genomes which might be important for mobile capabilities, together with vitality manufacturing.

Mitochondrial DNA (mtDNA) exists in a number of copies per cell, however when injury happens, these copies are sometimes degraded moderately than repaired. If left unchecked, this degradation can compromise tissue operate and set off irritation.

The researchers developed a chemical probe that binds to broken websites in mitochondrial DNA and blocks the enzymatic processes that result in its degradation. This method, moderately than repairing injury, lessens the lack of mtDNA.

“There are already pathways in cells that try restore,” mentioned Linlin Zhao, UCR affiliate professor of chemistry, who led the venture.

“However degradation occurs extra often than restore because of the redundancy of mtDNA molecules in mitochondria. Our technique is to cease the loss earlier than it turns into an issue.”

The brand new molecule contains two key parts: one which acknowledges and attaches to broken DNA, and one other that ensures it’s delivered particularly to mitochondria, leaving nuclear DNA unaffected.

“I designed the molecule by combining my experience in chemical synthesis and the Zhao lab’s in depth expertise with DNA restore and mitochondria,” mentioned Anal Jana, a postdoctoral fellow within the Zhao lab and main writer of the examine.

In lab assessments in addition to research utilizing dwelling cells, the probe considerably lowered mtDNA loss after lab-induced injury, mimicking publicity to poisonous chemical substances akin to nitrosamines, that are frequent environmental pollution present in processed meals, water, and cigarette smoke.

In cells handled with the probe molecule, mtDNA ranges remained greater, which might be vital for sustaining vitality manufacturing in weak tissues akin to the guts and mind.

Mitochondrial DNA loss is more and more linked to a spread of ailments, from multi-organ mitochondrial depletion syndromes to persistent inflammatory situations akin to diabetes, Alzheimer’s, arthritis, and inflammatory bowel illness. When mtDNA fragments escape from mitochondria into the remainder of the cell, they’ll act as misery indicators that activate immune responses.

“If we are able to retain the DNA contained in the mitochondria, we would have the ability to stop these downstream indicators that trigger irritation,” Zhao mentioned.

Importantly, the researchers discovered that the protected DNA remained useful, regardless of being chemically tagged. “We thought including a cumbersome chemical may stop the DNA from working correctly,” Zhao mentioned.

“However to our shock, it was nonetheless capable of assist transcription, the method cells use to show DNA into RNA, after which into proteins. That opens the door for therapeutic purposes.”

The venture builds on greater than two years of analysis into the mobile mechanisms that govern mtDNA processing. Whereas further research are wanted to discover scientific potential, the new molecule represents a paradigm shift.

“This can be a chemical method to prevention, not simply restore,” Zhao mentioned. “It is a new mind-set about easy methods to defend the genome underneath stress.”