Yeast Enzyme Overcomes Mitochondrial Defects & Boosts Cell Growth | News Medical
Scientists have successfully bypassed a critical metabolic bottleneck in human cells by introducing a gene from yeast, offering a potential pathway to treat mitochondrial diseases and, potentially, certain cancers. The research, published today in Nature Metabolism, demonstrates a method for sustaining cell growth even when mitochondrial respiration – the process cells use to generate energy – is severely impaired.
The international team, led by José Antonio Enríquez of the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) in Spain, utilized a genetic tool called ScURA, derived from the yeast Saccharomyces cerevisiae. This enzyme allows cells to synthesize nucleotides – the building blocks of DNA and RNA – independently of mitochondrial activity, relying instead on the metabolite fumarate.
Mitochondrial dysfunction is a hallmark of numerous diseases, including rare genetic disorders and some cancers, where impaired respiration hinders cell proliferation. Typically, cells with compromised mitochondria require supplementation with nutrients and DNA precursors to survive in laboratory settings. However, researchers found that introducing ScURA into patient-derived cells with mitochondrial defects enabled them to grow normally, mirroring the behavior of healthy cells. “Thanks to the yeast gene, the cells ‘learned’ to build DNA in a recent way,” explained the study authors.
The key difference lies in the enzyme’s location and metabolic pathway. While the human equivalent of ScURA is physically linked to the mitochondria, the yeast version operates in the cytosol – the fluid portion of the cell – utilizing an alternative route for nucleotide synthesis. This bypass effectively decouples DNA production from the failing energy production within the mitochondria.
Notably, ScURA-modified cells no longer required uridine supplementation, a common laboratory practice used to compensate for mitochondrial deficiencies. The approach proved effective across various experimental models of mitochondrial diseases, including those caused by severe mutations in essential respiratory chain complexes. According to first author Andrea Curtabbi of CNIC, the tool “allows us, for the first time, to clearly separate the direct effects of mitochondrial dysfunction on nucleotide synthesis from other secondary metabolic changes.”
The research also indicates that ScURA enhances nutrient utilization without disrupting other vital cellular functions, a crucial step toward potential therapeutic applications. Enríquez emphasized the broader implications of the findings, stating, “Mitochondria not only produce energy; they also shape fundamental processes such as DNA synthesis. Our work shows that if we provide a cell with an alternative route to make nucleotides, One can sustain cell proliferation even when mitochondrial respiration fails.”
The study’s findings may also shed light on the complex interplay between mitochondrial function and cancer development. Researchers suggest that understanding which metabolic processes become limiting when mitochondrial respiration fails is critical for designing targeted therapies. The team plans to expand their research to other disease models and refine the approach for preclinical studies.
The project received funding from the Spanish Ministry of Science and Innovation, the Human Frontier Science Program, the Leducq Foundation, and the Instituto de Salud Carlos III–CIBERFES.