Nucleotide synthesis, the production of the basic components of DNA and RNA, is crucial for cell growth and division. In most animal cells, this process is closely linked to properly functioning mitochondria, the organelles responsible for respiration and energy production. When mitochondrial respiration fails—a common feature of mitochondrial diseases and several forms of cancer—cells lose their ability to proliferate normally. However, a new study published in Nature Metabolism reveals that this dependence is not irreversible.
An international team led by José Antonio Enríquez from the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and the Spanish network for research into frailty and healthy aging (CIBERFES) has successfully decoupled nucleotide synthesis from mitochondrial activity. This breakthrough was achieved using ScURA, a yeast-derived genetic tool now available to the research community, opening new avenues for exploring cellular metabolism.
Uncoupling Nucleotide Synthesis from Mitochondrial Activity
The study, which also involved scientists from the University of Cologne, the University of Valladolid (UVa), and the CSIC–UVa Institute of Biology and Molecular Genetics, provides new insights into the role of mitochondria in rare diseases and cancer. In complex organisms like humans, respiration is essential for generating the energy required for life, with mitochondria using oxygen to sustain vital cellular processes. In contrast, some organisms, such as the yeast Saccharomyces cerevisiae, can survive without oxygen and have evolved alternative metabolic pathways to produce the molecular building blocks required for RNA and DNA synthesis.
Building on this observation, the team identified a yeast enzyme capable of sustaining nucleotide synthesis independently of mitochondrial respiration. Instead of oxygen, this enzyme uses fumarate, a metabolite derived from nutrients. The gene encoding this enzyme, known as ScURA, was extracted from yeast and inserted into human cells.
Transformative Results in Diseased Cells
Unlike cells from healthy individuals, the patient-derived cells used in the study cannot grow in standard laboratory conditions due to their need for extra supplementation with nutrients and DNA precursors. When CNIC researchers introduced ScURA into these diseased cells, they found that the cells could grow under normal conditions, similar to cells from healthy individuals. “Thanks to the yeast gene, the cells ‘learned’ to build DNA in a new way,” the authors explained.
“Our work shows that if we provide a cell with an alternative route to make nucleotides, we can sustain cell proliferation even when mitochondrial respiration fails.” – José Antonio Enríquez
The results were striking: human cells expressing ScURA continued to produce DNA and RNA even when the mitochondrial respiratory chain was blocked. Unlike the equivalent human enzyme, which is physically linked to the mitochondria, the yeast version operates in the cytosol and uses an alternative metabolic pathway.
Implications for Mitochondrial Disorders and Cancer
The team also discovered that ScURA enhances the efficiency of nutrient use without disrupting other essential cellular functions—an important first step toward the more ambitious goal of improving the lives of people with mitochondrial disorders. One of the study’s most significant findings is that ScURA-modified cells can grow without uridine supplementation, a common laboratory strategy to compensate for mitochondrial defects.
Moreover, the new approach restores cell proliferation across different experimental models of mitochondrial diseases, including those caused by severe mutations in essential respiratory chain complexes. For first author Andrea Curtabbi (CNIC), “this tool allows us, for the first time, to clearly separate the direct effects of mitochondrial dysfunction on nucleotide synthesis from other secondary metabolic changes.”
Future Directions and Funding
The study also highlights the potential of ScURA as a valuable experimental tool for clarifying mitochondrial contributions to rare diseases and cancer. “Identifying which metabolic processes become limiting when mitochondrial respiration fails is crucial for designing precise therapeutic strategies,” concludes Enríquez.
In future work, the team plans to expand their findings to other disease models and optimize this approach for preclinical research. The project was funded by the Spanish Ministry of Science and Innovation (projects PID2021-127988OB-I00 and TED2021-131611B-100), the Human Frontier Science Program (RGP0016/2018), the Leducq Foundation (17CVD04), and the Instituto de Salud Carlos III–CIBERFES (CB16/10/00282).
About the CNIC
The CNIC is an affiliate center of the Carlos III Health Institute (ISCIII), an executive agency of the Spanish Ministry of Science, Innovation, and Universities. Directed by Dr. Valentín Fuster, the CNIC is dedicated to cardiovascular research and translating the knowledge gained into real benefits for patients. Recognized by the Spanish government as a Severo Ochoa center of excellence (award CEX2020-001041-S, funded by MICIN/AEI/10.13039/501100011033), the center is financed through a pioneering public-private partnership between the government (through the ISCIII) and the Pro CNIC Foundation, which includes 11 of the most important Spanish private companies.
