Researchers at the Broad Institute of MIT and Harvard, in collaboration with the University of Lausanne, have made an intriguing discovery regarding the utilization of uridine as an energy source for cells. They have found that cells can process uridine from RNA in a manner similar to how they metabolize sugar when glucose is scarce, allowing them to sustain growth. While it was previously known that a uridine-rich diet leads to obesity and pre-diabetes in mice, the mechanism by which cells convert RNA into ATP, the energy molecule, was not understood.
Published in Nature Metabolism, the study identifies a biochemical pathway that cells employ to break down uridine-derived sugar for energy. The researchers propose that targeting this pathway could have potential implications for treating cancer and metabolic disorders like diabetes, as well as modulating the immune response.
The study involved a team of scientists including co-senior authors Alexis Jourdain from the University of Lausanne and Vamsi Mootha from the Broad Institute, Harvard Medical School, and Massachusetts General Hospital. The co-first authors were Owen Skinner, a postdoctoral fellow in Mootha’s lab, and Joan Blanco-Fernández, a Ph.D. student in Jourdain’s lab.
According to Jourdain, RNA, especially in the form of ribosomes, is abundantly present in living organisms and contains uridine. This means that even on a low-carbohydrate diet, the body can convert RNA from food into sugar.
Overall, this research sheds light on the role of uridine as an energy source and opens up new avenues for understanding cellular metabolism and potentially developing therapies for various diseases.
Uridine as food
Alexis Jourdain, a researcher in Mootha’s lab, embarked on a quest to identify the genes and pathways that cells rely on to survive during nutrient limitations. Through a genetic screen, Jourdain and his team made a significant discovery: the expression of two genes, UPP1 and UPP2, led to a remarkable increase in cell growth when glucose was absent from the growth media. These genes encode enzymes that facilitate the breakdown of uridine, and cells expressing UPP1 and UPP2 were able to thrive solely on uridine as their source of nourishment.
Intrigued by this finding, Jourdain explored whether cells could derive uridine from RNA. To test this, he introduced RNA into a dish of cancer cells grown in a sugar-free medium. Surprisingly, the cells exhibited growth, indicating their ability to process uridine even when it was a component of RNA.
Recalling his initial skepticism, Jourdain shared his surprise with his friends, recounting the “crazy experiment” in which he attempted to feed cells with RNA. Witnessing the cells’ growth defied his expectations.
To investigate the prevalence of this pathway across various cancer types, the research team employed PRISM, a high-throughput screening technology available at the Broad Institute. Collaborating with David Fisher’s team at Harvard Medical School, they discovered that glycolysis from uridine is particularly prominent in melanoma but also occurs in other cancer types.
Moreover, the researchers demonstrated that this process occurs in immune cells, suggesting that uridine may play a role in sustaining the immune response by providing energy to cells. Previous studies examining gene expression patterns support the likelihood of this pathway being present in blood cells, lungs, brain, and kidneys.
Despite the wide occurrence of glycolysis from RNA and uridine, the process is not regulated by the cell, which holds significant implications for metabolic disorders. Cells continue to burn RNA or uridine even when energy is unnecessary, potentially explaining the link between uridine-rich diets and conditions like obesity, fatty liver disease, and pre-diabetes observed in mice.
Harnessing glycolysis from uridine
Jourdain envisions numerous therapeutic possibilities stemming from this pathway. One potential approach involves inhibiting the pathway in cancer cells, effectively depriving them of sustenance. On the other hand, in autoimmune disorders, where immune cells are excessively active, the activity of the pathway could be dialed back to modulate the immune response. Conversely, the pathway could be enhanced to bolster immune cells involved in combating pathogens.
In Jourdain’s lab, ongoing efforts are focused on identifying inhibitors of the pathway and examining their effects in animal models. Additionally, they aspire to investigate the impact of consuming RNA-rich foods on obesity in humans.
The realization that nucleotides can yield significant energy through this pathway highlights a previously underestimated factor in the realms of metabolism and nutrition, according to Jourdain. The discovery of this novel player opens up exciting possibilities in these fields.