Too Much RNA Can Starve Cells Of Energy, Texas A&M Study Finds
Dr. Djamal Brahim Belhaouari (left) and Dr. Zhilong Yang examine cell cultures during research that revealed excess RNA can damage mitochondria and reduce a cell’s ability to produce energy.
A new study from researchers at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (VMBS) has uncovered a previously unknown consequence of viral infection: too much RNA inside a cell can disrupt its ability to produce energy.
Published in the journal Proceedings of the National Academy of Sciences, the study found that when excess RNA builds up inside cells during poxvirus infection, it can impair mitochondria — the structures responsible for generating most of a cell’s energy — reducing the cell’s ability to function normally.
The discovery could have broad implications for understanding viral infections, aging-related diseases, and RNA-based therapeutics, including mRNA vaccines, because excess RNA can accumulate in each of these conditions.
“Scientists have long known that RNA degradation helps control protein production and remove defective RNA,” said Dr. Zhilong Yang, professor in VMBS’ Department of Veterinary Pathobiology. “Our study reveals another important role: it helps cells maintain the energy they need to function properly.”
The findings suggest that RNA degradation serves a broader purpose than scientists once realized. In addition to controlling protein production, RNA quality control, and helping cells regulate immune responses, it also helps protect the cell’s ability to generate energy.
When RNA Builds Up Inside Cells
RNA exists in many forms. Messenger RNA (mRNA) carries the genetic instructions the cells use to make proteins, which help cells perform their normal functions. Another form, double-stranded RNA (dsRNA), is commonly produced during viral infections and alerts the immune system that something is wrong.
During viral infection, viruses can produce large amounts of RNA. If cells cannot break down the excess RNA quickly enough, the buildup can damage mitochondria and reduce the cell’s ability to generate energy.
While scientists already know that excess dsRNA can trigger immune responses and the cell’s need to control dsRNA levels, the effects of mRNA came as a surprise.
“mRNA is a normal component of our cells, but it seems like with many good things, if we get too much, that can become a problem for the cell,” Yang said. “When too much RNA builds up, including mRNA, it can damage the mitochondria and interfere with the cell’s ability to produce energy.”
Viruses, meanwhile, rely entirely on host cells for energy and protein production, but producing too much viral RNA can overwhelm the very cells viruses depend on to survive.
Yang explained that poxviruses — the family of viruses that includes smallpox and mpox — appear to use RNA cleanup systems to degrade RNAs and keep infected cells functioning long enough for the virus to continue replicating.
“If the cell is not healthy, the virus would not replicate well,” Yang said. “The virus needs to keep RNA levels balanced inside the cell.”
A Novel Effect On Mitochondria
Belhaouari and Yang examine laboratory samples during research that uncovered a previously unknown link between excess RNA and impaired cellular energy production.
The researchers initially thought the mitochondrial damage was likely caused by immune responses triggered by excess RNA, since certain forms of RNA are known to alert the body’s defenses during infection.
“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.”
The team also found that mitochondrial impairment occurred before major immune responses were activated and did not depend on the immune system’s usual response to infection, further supporting the idea that RNA itself contributes to the damage.
“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.”
Implications Beyond Viral Infection
The findings may also have implications beyond viral infections.
Researchers have observed RNA accumulation in a variety of conditions — including some cancers, neurodegenerative diseases, and aging-related disorders — suggesting that mitochondrial damage may be one way excess RNA contributes to those conditions.
“We think this has quite broad translational implications,” Brahim Belhaouari said. “Too much double-stranded RNA or mRNA that cannot be degraded effectively may contribute to disease processes in some contexts.”
The study may also provide new insight into RNA-based therapeutics and vaccines by helping scientists better understand how cells respond to large amounts of RNA and may eventually help improve future RNA-based treatments.
“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 researchers say the findings could reshape how scientists think about the relationship between RNA regulation and cellular energy production.
“Scientists already knew that too much double-stranded RNA can be harmful,” Yang said. “What surprised us was finding out that too much mRNA — something cells normally need every day — can also damage mitochondria and interfere with the cell’s ability to produce energy.”
Research reported in this study was supported, in part, by the National Institute of Allergy and Infectious Diseases (R01AI143709 to Z.Y.) and Texas A&M University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
