A study led by Dr. Zhilong Yang, a professor in the Department of Veterinary Pathobiology at the Texas A&M College of Veterinary Medicine and Biomedical Sciences (VMBS), found that excess RNA produced during poxvirus infections can impair the cell's ability to produce energy. While scientists have long known that RNA degradation helps control protein production and remove defective RNA, the research identifies a new role: helping cells maintain the energy they need to function.
The researchers made a key discovery when isolating mitochondria. "When we isolated only the mitochondria and added RNA, we still saw mitochondrial damage," said Dr. Djamal Brahim Belhaouari, the study's first author. "That was the moment we realized this could be a previously unknown cellular response to RNA." This indicates the damage is direct, not merely a side effect of an immune response triggered by the RNA.
The precise mechanism is not yet fully understood, but the team proposes that RNA, which carries a negative charge, may disturb the electrical balance needed for mitochondria to produce ATP. "We think the negatively charged RNA may accumulate around mitochondria and disrupt the electrical balance needed for energy production, although how it happens is unknown," Yang said. "This is a new concept that we are continuing to explore."
The discovery has broad potential implications. In viruses, like poxviruses, it creates a balancing act: the virus needs to generate RNA to replicate, but an excess can harm the cell it relies on. Yang noted that poxviruses appear to have mechanisms to manage this buildup. "If the cell is not healthy, the virus would not replicate well. The virus needs to keep RNA levels balanced inside the cell," he said.
Beyond infections, abnormal RNA accumulation is seen in cancers, neurodegenerative disorders like Alzheimer's and Parkinson's, and conditions linked to aging. The researchers suggest this RNA buildup could be a previously unrecognized source of mitochondrial stress in these diseases.
For medicine, the finding provides a guide for developing RNA-based therapies. "Understanding this mechanism could help researchers design and optimize future RNA-based therapeutics and vaccines by better understanding how cells respond to large amounts of RNA," Yang said. The study does not indicate that current mRNA vaccines cause this damage in people but points to considerations for future designs.