Vitamin-Derived Molecule Shows First Signs of Treating Mitochondrial DNA Disease in Humans

For decades, mitochondrial DNA disorders have stood among the most stubborn challenges in medicine: a group of inherited neurometabolic diseases affecting roughly one in 8,000 people, for which no treatment has ever targeted the underlying disease mechanism. Now, a team led by researchers at the University of Cambridge reports the first human evidence that a simple vitamin-derived molecule, nicotinamide riboside, may begin to change that. In an experimental medicine study published in Genome Medicine, eight patients with heteroplasmic mitochondrial DNA disease took high-dose nicotinamide riboside for four weeks, and the results, while early, offer the first molecular proof in humans that the approach can reach its intended target inside muscle tissue.

The logic behind the trial rests on one of biology’s most fundamental cofactors: nicotinamide adenine dinucleotide, or NAD+. This molecule sits at the heart of cellular energy metabolism, shuttling electrons during the reactions that ultimately generate adenosine triphosphate, the chemical currency that powers everything from muscle contraction to neural signaling. In mitochondrial disorders, the oxidative phosphorylation system that performs this energy conversion is defective, and NAD+ availability is thought to become limiting. Boosting NAD+ has previously improved mitochondrial function in a range of animal and cellular models of impaired oxidative metabolism, but until now the strategy had never been tested in human patients.

Nicotinamide riboside is a form of vitamin B3 that acts as a precursor to NAD+. When cells take it up, enzymatic pathways convert it into NAD+, raising the intracellular pool of this critical cofactor. Among its downstream effects is the activation of SIRT1, an NAD+-dependent enzyme that in turn activates PGC-1α, the master regulator of mitochondrial biogenesis. In principle, this cascade should coax cells to build more mitochondria and to express more mitochondrial genes, compensating for the respiratory chain defects that define these diseases. The Cambridge team, led by Katherine Schon and Patrick Chinnery, set out to determine whether this theoretical chain of events actually unfolds in living human muscle.

The study was deliberately small but unusually deep in its measurements. Eight participants took part: three carried single large-scale mitochondrial DNA deletions, a common cause of chronic progressive external ophthalmoplegia, and five carried the m.3243 A>G or A>T pathogenic variants, which underlie conditions such as MELAS syndrome and a spectrum of neurological and muscular disease. Each participant received 1,250 to 2,000 milligrams of nicotinamide riboside per day for four weeks. Before and after treatment, the researchers measured clinical outcomes including the timed up and go test, the six-minute walk test, grip strength and quality of life questionnaires. They also tracked blood biomarkers GDF15 and FGF21, used phosphorus-31 magnetic resonance spectroscopy to assess mitochondrial function in vivo, and took quadriceps muscle biopsies for an exhaustive molecular workup.

The biopsies were where the study’s most striking findings emerged. Muscle histopathology revealed that in the three participants with single large-scale deletions, the percentage of cytochrome c oxidase deficient fibers and ragged-red fibers, the classic cellular signatures of mitochondrial dysfunction, decreased after treatment. Respiratory chain complex I and complex IV activities increased, and levels of the mtDNA deletions themselves fell. These changes were not observed in the five participants carrying the m.3243 variants, a divergence that turned out to be one of the most scientifically interesting aspects of the trial. It suggests that the two major classes of heteroplasmic mtDNA disease may respond differently to NAD+ boosting, and that the specific genetic diagnosis may determine who benefits.

Unbiased transcriptomic and integrated multi-omic analysis across all eight participants provided the mechanistic confirmation the researchers were seeking. The data showed a clear signature of mitochondrial biogenesis: activation of the SIRT1/PGC-1α axis, increased expression of mitochondrial genes, enhanced levels of NAD-related metabolites, and coordinated shifts in the abundance of mitochondrial proteins. In other words, the drug did exactly what the preclinical models predicted it would do in human tissue. This is a rare and valuable outcome in experimental medicine, where promising animal results frequently fail to translate. The multi-omic integration, combining transcriptomics, proteomics and metabolomics, demonstrated that the molecular response was coherent across multiple layers of biology rather than a scattered artifact.

On the clinical side, the results were more modest but still encouraging. Nicotinamide riboside proved bioavailable and well tolerated across the dose range, with no significant safety concerns reported. Overall, participants improved on the timed up and go test, a measure of mobility that captures the integrated function of muscle, balance and the nervous system. The other clinical measures, including the six-minute walk test and grip strength, did not show consistent improvement, which is unsurprising given the short four-week treatment period and the small number of participants. Mitochondrial disease progresses over years, and remodeling muscle biochemistry in a month is unlikely to translate immediately into measurable gains in endurance or strength.

The authors conclude that nicotinamide riboside has the potential to become the first small-molecule precision treatment for heteroplasmic mtDNA disorders, guided by the specific genetic diagnosis. That framing matters. Rather than a one-size-fits-all therapy, the data point toward a stratified approach in which patients with single large-scale deletions might be prioritized, while those with m.3243 variants may require different strategies or combination therapies. The finding that deletion levels themselves decreased in the deletion group is particularly provocative, because heteroplasmy level, the proportion of defective mitochondrial genomes within a cell, is a key determinant of disease severity. If NAD+ boosting can shift the balance toward healthier mitochondrial genomes, it would represent a genuinely disease-modifying mechanism rather than mere symptomatic support.

Important caveats remain. The study enrolled only eight participants, had no placebo control arm, and lasted just four weeks, so the clinical improvements cannot be definitively attributed to the drug, and the molecular findings require replication in larger, longer, randomized trials. The trial was prospectively registered on ClinicalTrials.gov as NCT03432871, and the researchers are candid that this is an experimental medicine study designed to establish mechanism and feasibility rather than to secure regulatory approval. Nevertheless, the field has waited a long time for any therapy that targets the root cause of these disorders, and the combination of human pharmacodynamics, histological improvement and multi-omic mechanistic evidence represents a genuine step forward.

For patients and families affected by mitochondrial disease, the study offers something that has been in short supply: a plausible path from bench to bedside. Nicotinamide riboside is already widely available as a dietary supplement, which raises both opportunities and risks, since self-dosing without medical supervision cannot replicate the monitored, genetically stratified approach the trial describes. The Cambridge team’s work, funded by a broad coalition including the Medical Research Council, the NIHR Cambridge Biomedical Research Centre, LifeArc’s Centre to Treat Mitochondrial Diseases and international partners, now sets the stage for properly powered efficacy trials. If those trials confirm what this first glimpse suggests, a vitamin B3 derivative could become the first approved precision medicine for a group of diseases that have, until now, been managed only with supportive care.

Subject of Research: Nicotinamide riboside treatment for heteroplasmic mitochondrial DNA disorders

Article Title: Effects of nicotinamide riboside in mitochondrial DNA disease

Article References: Schon, K. R., Sleigh, A., Golder, Z., Berghella, A., Tiet, M. Y., Lyons, C., Bozhilova, L. V., Nie, Y., Harrison, E., Seikus, C., Yu-Wai-Man, P., Quaegebeur, A., Roos, A., Hentschel, A., Biggs, H., Zeviani, M., Viscomi, C., van den Ameele, J., Horvath, R., & Chinnery, P. F. (2026). Effects of nicotinamide riboside in mitochondrial DNA disease. Genome Medicine. https://doi.org/10.1186/s13073-026-01764-1

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01764-1

Keywords: mitochondrial disease, mitochondrial DNA, nicotinamide riboside, NAD+, mitochondrial biogenesis, mtDNA deletions, m.3243A>G, SIRT1, PGC-1α, experimental medicine, Genome Medicine, precision medicine