Nucleotide synthesis stands as a vital process within all living cells, underpinning the replication of DNA and RNA which, in turn, is fundamental for cell growth, division, and survival. Central to this biochemical feat in most animal cells is the proper function of mitochondria, the organelles widely recognized as the cell’s powerhouse. Mitochondria not only generate usable energy but directly influence the production of nucleotides through their role in respiration. When mitochondrial respiration falters—which is common in many pathological states such as mitochondrial diseases and numerous cancer types—cells typically cannot proliferate effectively. However, recent groundbreaking research challenges the long-held notion that nucleotide synthesis is irrevocably dependent on mitochondrial function, unlocking new therapeutic possibilities.
A multidisciplinary international consortium led by José Antonio Enríquez at the National Center for Cardiovascular Research Carlos III (CNIC) in Spain has revealed a strikingly innovative approach to disconnect nucleotide biosynthesis from mitochondrial electron transport. Utilizing a genetically encoded yeast enzyme, known as ScURA, the team has succeeded in enabling human cells to maintain nucleotide production and proliferation even when their mitochondrial respiratory chain is impaired. This discovery, recently reported in the prestigious journal Nature Metabolism, has profound implications for understanding metabolic resilience and could revolutionize treatment strategies for mitochondrial pathologies and potentially certain cancers.
Mitochondria typically harness oxygen to generate energy via oxidative phosphorylation, coupling the electron transport chain to adenosine triphosphate (ATP) synthesis. Nucleotide biosynthesis, particularly the de novo production of pyrimidines, relies heavily on this mitochondrial function—specifically because dihydroorotate dehydrogenase (DHODH), a key enzyme in pyrimidine synthesis, is mitochondrial membrane-associated. Disruption of mitochondrial respiration usually cripples DHODH activity, creating a bottleneck in nucleotide biosynthesis critical for DNA replication and RNA transcription. However, the yeast Saccharomyces cerevisiae, a facultative anaerobe, possesses a unique cytosolic pathway enabling it to perform nucleotide synthesis independently of oxygen-dependent mitochondrial respiration, a trait that inspired the innovative strategy employed.
The researchers identified a unique yeast cytosolic enzyme, ScURA, which catalyzes dihydroorotate oxidation utilizing fumarate, a metabolite derived from cellular nutrient metabolism, unlike the human counterpart anchored in mitochondria and dependent on oxygen. By cloning and expressing the gene encoding ScURA in human cells deficient in mitochondrial respiratory function, they established an alternative metabolic route for pyrimidine synthesis. These genetically modified cells could proliferate without external supplementation of nucleotides or uridine, typically necessary when mitochondrial function is compromised, demonstrating a remarkable metabolic bypass.
Further experimental validation showed that cells expressing ScURA circumvent the mitochondrial dependency by relocating dihydroorotate oxidation to the cytosol, effectively uncoupling nucleotide synthesis from electron transport chain activity. This independence from mitochondrial respiration allowed for sustained DNA and RNA synthesis even under conditions where mitochondrial function was chemically inhibited or genetically impaired. This represents a paradigm shift, indicating that mitochondrial failure does not uniformly arrest DNA replication if alternative metabolic pathways are made accessible.
Beyond merely restoring nucleotide biosynthesis, the expression of ScURA enhanced nutrient utilization efficiency without disrupting essential cellular processes. This metabolic rewiring hints at a broader underlying plasticity in mammalian cells, potentially opening doors to optimized metabolic interventions. The dual ability to maintain nucleotide pools and oxidative balance without relying on compromised mitochondria can mitigate cellular stress and improve survival in disease contexts characterized by mitochondrial dysfunction.
Mitochondrial diseases, often severe and currently lacking curative treatments, typically manifest with multi-organ involvement and proliferative deficiencies in affected cells. The newly developed ScURA model allows researchers to dissect the precise metabolic deficits caused by mitochondrial impairment. By selectively rescuing nucleotide synthesis via the cytosolic enzyme, researchers can isolate and analyze secondary metabolic alterations that contribute to disease pathogenesis. This could accelerate the development of targeted therapies, enabling interventions that address metabolic roadblocks in mitochondrial pathologies more precisely.
Intriguingly, the success of ScURA in human cells also bears implications for oncology. Certain cancers exhibit mitochondrial respiratory deficiencies as part of their metabolic reprogramming, which influences their proliferation and survival. Providing an alternative nucleotide synthesis route may affect tumor biology and responsiveness to therapeutics targeting mitochondrial metabolism. Thus, ScURA represents not only a tool for understanding mitochondrial disease mechanisms but also a potential vector for modifying cancer cell metabolism.
The experimental approach involved meticulous design, including the stable integration of the ScURA gene into human cells and rigorous testing across multiple models that emulate different mitochondrial dysfunction states. This versatility was crucial to demonstrate the robustness and universality of the metabolic bypass. Notably, cells harboring mutations in critical components of the respiratory chain complexes exhibited restored proliferation and growth under standard laboratory conditions, a striking outcome compared to their unmodified diseased counterparts.
The authors emphasize that this technology provides an unprecedented opportunity to decouple the direct effects of impaired mitochondrial respiration on nucleotide synthesis from indirect or compensatory metabolic changes. Such granularity in metabolic mapping is vital for elucidating the complex interplay of biochemical networks in diseased cells and for pinpointing vulnerabilities that may be exploited therapeutically.
Looking ahead, the research team plans to extend their investigations to a broader array of mitochondrial disease models, aiming to refine and optimize the therapeutic potential of cytosolic DHODH expression. If scalable and safe in vivo, this strategy could fundamentally transform the management of mitochondrial diseases, shifting the focus from symptomatic treatment toward underlying metabolic correction. This approach heralds a new frontier of metabolic engineering within human cells.
The project was supported by numerous scientific grants, including 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. These collaborations underscore the international and interdisciplinary commitment to solving pressing challenges in mitochondrial biology and cellular metabolism.
This landmark study not only challenges existing dogmas in mitochondrial biology but also represents a powerful proof-of-concept for metabolic flexibility in human cells. By exploiting evolutionary adaptations observed in yeast, scientists have devised a cutting-edge strategy to rescue critical cellular functions impaired in disease. The implications stretch far beyond basic science, offering hope for innovative treatments in mitochondrial medicine and oncology while deepening our understanding of cellular resilience.
Subject of Research: Cells
Article Title: ‘Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport’
News Publication Date: 17-Feb-2026
Web References:
DOI Link
Image Credits: CNIC
Keywords: Human health, Human biology, Clinical medicine, Biomedical engineering
