Breakthrough Uncouples Nucleotide Synthesis from Mitochondrial Function

Nucleotide synthesis, crucial for DNA and RNA production, typically relies on properly functioning mitochondria in animal cells. When mitochondrial respiration fails—a common issue in mitochondrial diseases and some cancers—cells lose their ability to proliferate.

A new study published in Nature Metabolism indicates that this dependency is not irreversible. An international team led by José Antonio Enríquez of the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and CIBERFES has successfully uncoupled nucleotide synthesis from mitochondrial activity.

The team identified a yeast enzyme capable of sustaining nucleotide synthesis independently of mitochondrial respiration, offering a new path for research into rare diseases and cancer.

The Key Discovery

The team identified ScURA, a yeast enzyme capable of sustaining nucleotide synthesis independently of mitochondrial respiration. Unlike human enzymes that are linked to mitochondria and use oxygen, ScURA operates in the cytosol and uses fumarate, a nutrient-derived metabolite.

Experimental Results

• Researchers extracted the gene for ScURA from yeast (Saccharomyces cerevisiae) and introduced it into human cells.
• Patient-derived cells with mitochondrial defects, which typically require extra nutrient and DNA precursor supplementation to grow, were able to proliferate under normal conditions after ScURA introduction.
• Human cells expressing ScURA continued to produce DNA and RNA even when the mitochondrial respiratory chain was blocked.
• ScURA helped cells use nutrients more efficiently without disrupting other essential cellular functions.

Implications for Disease

The findings offer new insights into the role of mitochondria in rare diseases and cancer.

• The new approach restored cell proliferation across various experimental models of mitochondrial diseases, including those caused by severe respiratory chain mutations.
• ScURA allows researchers to distinguish direct effects of mitochondrial dysfunction on nucleotide synthesis from other secondary metabolic changes.
• Identifying limiting metabolic processes when mitochondrial respiration fails is critical for developing targeted therapeutic strategies for mitochondrial disorders and cancer.