Mitochondrial diseases are severe, often untreatable, and they leave human cells unable to grow normally without outside help. A new study published in Nature Metabolism now shows that a single gene borrowed from baker’s yeast can restore a key biosynthetic pathway in mammalian cells whose mitochondria have stopped working properly. The finding adds to a growing body of evidence that simple, single-subunit enzymes from yeast can substitute for broken components of the far more complex human respiratory machinery, raising the prospect of gene therapies for disorders that currently have no cure.
How a Yeast Gene Bypasses Broken Mitochondria
Human cells depend on the mitochondrial electron transport chain (ETC) not only for energy but also for making pyrimidines, the building blocks of DNA and RNA. The enzyme dihydroorotate dehydrogenase (DHODH) sits inside the inner mitochondrial membrane and hands electrons to ubiquinone as part of that chain. When the ETC fails, DHODH stalls, pyrimidine production collapses, and cells stop dividing. Research published in two companion papers in Cell established that proliferation failure under ETC inhibition is driven largely by aspartate limitations rather than ATP shortage alone, meaning the metabolic bottleneck is biosynthetic, not purely energetic.
The yeast Saccharomyces cerevisiae solved this problem hundreds of millions of years ago. Its URA1 gene encodes a cytosolic version of DHODH that works outside mitochondria entirely, converting dihydroorotate to orotate while reducing fumarate to succinate instead of relying on ubiquinone. Expressing this gene, called ScURA, in mammalian cells enables respiration-independent de novo pyrimidine biosynthesis, according to the Nature Metabolism study. Because ScURA uses fumarate as its electron acceptor, it sidesteps the broken ETC altogether, letting cells with defective mitochondria resume nucleotide production and proliferate.
Evolutionary Origins of the Workaround
The reason yeast carries this alternative enzyme traces back to horizontal gene transfer events that gave certain yeast species the ability to grow without oxygen. Research published in Molecular Genetics and Genomics showed that anaerobic growth capacity in some yeasts is directly linked to de novo pyrimidine biosynthesis pathways that do not depend on the respiratory chain. In an oxygen-free environment, a mitochondria-linked DHODH would be useless because the ETC cannot run. The cytosolic version, by contrast, keeps pyrimidine synthesis going regardless of oxygen availability.
This evolutionary trick is what makes ScURA so appealing for human medicine. Cells with impaired mitochondrial respiration normally require supplementation with pyruvate and uridine to grow in the laboratory, and patient-derived fibroblasts with primary mitochondrial disease show the same dependence, as documented in metabolic studies. ScURA offers a genetic alternative to that chemical crutch: rather than feeding cells the end products they cannot make, it restores the enzymatic step that was blocked. The distinction matters because supplementation works in a dish but is far harder to deliver reliably inside a living body.
NDI1 and AOX Set the Precedent
ScURA is not the first yeast enzyme tested as a bypass for human mitochondrial defects, and the earlier experiments help frame both the promise and the limits of this approach. The yeast NDI1 gene encodes a single-subunit NADH dehydrogenase, a 53 kDa protein containing FAD as a cofactor, according to research in the bioenergetics literature. Mammalian complex I, by contrast, is the largest multi-subunit complex of the respiratory chain with a molecular mass of about 1 MDa. Sources disagree on the exact subunit count: one study in Yarrowia lipolytica reports 43 subunits in mammals, while separate analyses cite 45 subunits. Either way, replacing a massive multi-protein assembly with a single polypeptide is a striking simplification.
When Ndi1 was expressed in complex I-deficient mammalian CCL16-B2 cells, it catalyzed electron transfer from NADH in the matrix to ubiquinone and restored NADH oxidase activity, as shown in a classic functional reconstitution experiment. In Drosophila models of complex I deficiency, NDI1 expression corrected metabolic changes and extended lifespan phenotypes, while also preventing the unfolded protein response that contributes to neuronal damage. A parallel strategy using alternative oxidase (AOX) from the sea squirt Ciona intestinalis demonstrated that cytochrome c oxidase deficiency in human cells could likewise be compensated by an exogenous respiratory bypass enzyme. Together, these results established that cross-species gene transfer can functionally repair broken links in the human ETC, at least in cultured cells and animal models.
What ScURA Adds to the Toolkit
The ScURA result extends the bypass concept in a direction that NDI1 and AOX do not cover. NDI1 and AOX both intervene directly in the electron transport chain, restoring electron flow and membrane potential so that mitochondria can resume ATP production and support downstream processes. ScURA, by contrast, does not try to fix respiration itself; instead, it rescues a specific biosynthetic pathway that depends on respiration. By installing an alternative DHODH in the cytosol, ScURA decouples pyrimidine synthesis from mitochondrial status. That distinction is crucial for cells whose primary vulnerability is an inability to make nucleotides, rather than a global failure of energy production.
In the Nature Metabolism work, mammalian cells engineered to express ScURA regained the ability to proliferate under conditions that completely blocked their ETC, as long as other nutrients were available. The enzyme’s fumarate dependence also integrates neatly into existing metabolic networks, because fumarate and succinate are intermediates of the tricarboxylic acid cycle. This means ScURA can tap into cytosolic or mitochondrial pools of these metabolites without demanding a fully functional respiratory chain. In principle, this could be particularly valuable in tissues where mitochondrial dysfunction is patchy or partial, allowing cells to maintain DNA replication and repair even when oxidative phosphorylation is compromised.
Therapeutic Prospects and Open Questions
Together, the NDI1, AOX, and ScURA studies suggest a modular strategy for treating mitochondrial disease: instead of attempting to rebuild the entire ETC, clinicians might one day install compact, robust enzymes that bypass individual failure points. For disorders dominated by complex I defects, an NDI1-based therapy could restore NADH oxidation; for complex IV problems, AOX might provide an alternative electron sink; and for conditions where impaired nucleotide synthesis limits cell division, ScURA or similar cytosolic DHODHs could sustain pyrimidine production. The fact that these enzymes evolved in very different organisms yet function in mammalian cells underscores the deep conservation of core redox chemistry.
Translating these concepts into therapies will require solving substantial delivery and safety challenges. Viral vectors or other gene delivery systems must target affected tissues efficiently while avoiding immune reactions to foreign proteins. Long-term expression of non-native enzymes also raises questions about metabolic side effects, such as altered reactive oxygen species production or imbalances in intermediates like fumarate and succinate that can influence epigenetic regulation. Preclinical work in animal models, including those already used to test Ndi1-based interventions, will be essential to map these risks and refine dosing strategies.
Another open question is how broadly applicable a single enzyme like ScURA will be across the spectrum of mitochondrial disorders. Some diseases primarily affect high-energy organs such as the heart and brain, where ATP shortage may be more limiting than nucleotide supply; in others, such as certain myopathies and encephalopathies, both energy and biosynthetic deficits likely contribute. Combinatorial approaches that pair a respiratory bypass like NDI1 with a biosynthetic rescue like ScURA might ultimately prove most effective, but they also increase the complexity of clinical development. As researchers continue to dissect the metabolic consequences of ETC failure, the portfolio of potential bypass enzymes is likely to grow.
Even with these uncertainties, the conceptual shift is significant. Rather than viewing broken mitochondria as irreparable, the emerging picture is that key mitochondrial functions can sometimes be rerouted through simpler, evolutionarily distant proteins. The discovery that a single yeast gene can free mammalian pyrimidine synthesis from its mitochondrial leash adds a new tool to that arsenal. For patients with currently untreatable mitochondrial disease, each such tool brings the field a step closer to targeted, mechanism-based therapies that restore cellular function not by replacing entire organelles, but by intelligently patching the specific reactions that matter most.
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*This article was researched with the help of AI, with human editors creating the final content.
