Nicotinamide Riboside and Mitochondrial DNA Disease: Early Findings From a Human Study

Key Takeaways

• A new experimental study examined nicotinamide riboside (NR) in eight adults with genetically confirmed mitochondrial DNA disorders.
• NR was generally well tolerated, and participants improved on the Timed Up and Go mobility test. However, walking endurance, grip strength, quality of life, and two blood biomarkers of mitochondrial disease did not change significantly.
• The most consistent muscle-level changes appeared in the three participants with large-scale mitochondrial DNA deletions. Several muscle measurements moved in a direction consistent with improved mitochondrial function and a lower proportion of deleted mitochondrial DNA.
• Gene-expression and metabolite analyses showed changes consistent with an effect on NAD+ metabolism and mitochondrial pathways. However, the study was too small, short, and uncontrolled to establish NR as a treatment. Larger randomized, placebo-controlled trials are needed.

Mitochondria help cells convert nutrients into ATP, the usable energy that powers everything from muscle contraction and brain activity to cellular repair and growth. When inherited changes disrupt this system, the effects can reach far beyond low energy. Mitochondrial disorders can involve the muscles, brain, heart, vision, hearing, and other tissues, often causing progressive symptoms that significantly affect quality of life.

Population-based research suggests that clinically manifest primary mitochondrial disease affects at least 1 in 8,000 adults.¹ Developing therapies is especially difficult because the disorders can arise from hundreds of different genetic changes, including mutations and deletions in mitochondrial DNA.

Rather than trying to correct each genetic defect individually, researchers are asking whether they can support shared biological pathways that help cells compensate for impaired mitochondrial function. One promising target is NAD+ (nicotinamide adenine dinucleotide), a coenzyme that plays a central role in cellular energy metabolism and helps regulate pathways involved in building and maintaining mitochondria.

A new study led and conducted by researchers at the University of Cambridge offers the first systematic human test of whether raising NAD+ with nicotinamide riboside (NR) can influence mitochondrial biology in people with mitochondrial DNA disease.² It reveals early functional, muscle, and molecular signals, most consistently in participants with large-scale mitochondrial DNA deletions, while also underscoring how much remains to be tested.

Why the Researchers Targeted NAD+

The rationale was straightforward: could increasing NAD+ help cells better compensate for impaired energy production? NAD+ transfers electrons during the metabolic reactions that feed into oxidative phosphorylation, the mitochondrial process that produces ATP.³ Because this process is disrupted in mitochondrial disorders,⁴ NAD+ availability may become an added constraint on an already weakened system.

Earlier cell and animal studies found that increasing NAD+ improved aspects of mitochondrial function in models of impaired oxidative metabolism.⁵'⁶ This strategy had not yet been tested in people with mitochondrial disease.

NR offered a way to do so, because cells can convert it into NAD+. Higher NAD+ may also support SIRT1, an NAD+-dependent enzyme that helps activate PGC-1α, a major regulator of mitochondrial biogenesis and mitochondrial gene expression.⁷ In theory, stimulating this pathway could encourage cells to build and renew mitochondrial machinery, helping them compensate for defects in the respiratory chain. The researchers set out to determine whether this response would also occur in the skeletal muscle of people with mitochondrial DNA disorders.

Overview of the Study

The researchers conducted a four-week, open-label experimental medicine study involving eight adults between 21 and 68 years of age. Each participant received approximately 1,250 to 2,000 milligrams of NR per day. This dose was given under clinical supervision, with weekly visits for monitoring.

The participants represented two forms of mitochondrial DNA disease:

• Three participants had single large-scale mitochondrial DNA deletions, meaning a sizable section of their mitochondrial DNA was missing.
• Five participants had a pathogenic change at mitochondrial DNA position 3243: four with m.3243A>G and one with m.3243A>T.

Before and after treatment, the researchers assessed physical function and quality of life by measuring how quickly participants could stand and walk, how far they could walk in six minutes, and their grip strength. They also monitored blood biomarkers, assessed mitochondrial function, and closely examined small samples of thigh muscle.

What Four Weeks of Nicotinamide Riboside Supplementation Revealed

Muscle Changes Were Most Consistent in Participants with Large-Scale mtDNA Deletions

The muscle biopsies produced some of the study's most notable findings. In the three participants with large sections of mitochondrial DNA missing, several markers of mitochondrial dysfunction moved in a favorable direction, although the changes were not statistically significant. All three had fewer muscle fibers with reduced cytochrome c oxidase activity, a sign that part of the energy-producing system was not working normally. Ragged-red fibers, which are muscle fibers with abnormal accumulations of mitochondria, decreased substantially in one participant and remained low in the other two.

Activity also increased in respiratory-chain complexes I and IV, two key components of the mitochondrial energy-producing machinery. In addition, the proportion of mitochondrial DNA carrying the deletion declined. This does not mean NR repaired the deleted DNA. Rather, deleted mitochondrial DNA made up a smaller share of the total, while the amount of nondeleted mitochondrial DNA increased in the two participants for whom it could be calculated. Still, these findings involved only three people and did not reach statistical significance at the group level.

A noninvasive measure of mitochondrial function showed a similar pattern. The median rate at which muscle restored phosphocreatine, an energy reserve replenished after exercise, increased in the deletion group but not in participants with m.3243 variants, mirroring the biopsy and genetic findings. The publication did not report this subgroup change as statistically significant.

The same coordinated pattern was not seen in the five participants with m.3243 variants. This suggests that genetic subtype may influence the response to NR. Therefore, future trials may need to account for both genetic diagnosis and baseline disease severity when selecting participants and measuring treatment effects.

Nicotinamide Riboside Affected NAD+ and Mitochondrial Pathways in Skeletal Muscle

To check whether NR was acting on its intended target, the researchers analyzed gene expression, protein abundance, and metabolites in skeletal muscle. Across all eight participants, 62 genes changed significantly after treatment, and mitochondrial genes were strongly enriched among those that increased. The affected pathways included the mitochondrial respiratory chain, electron transport, and ATP production. Metabolomic analysis, available from four participants, also showed increases in NAD-related metabolites and greater activity in pathways involved in NAD+ production.

When the researchers analyzed these datasets together, gene-expression and protein patterns were strongly correlated, suggesting a coordinated biological response rather than a collection of unrelated changes. Taken together, the results were consistent with increased mitochondrial biogenesis and engagement of the proposed NAD+-SIRT1-PGC-1α pathway in human skeletal muscle.

The molecular evidence was not equally strong at every level, however. No individual proteins remained statistically significant after correction for multiple comparisons, and the study did not directly prove every step of the proposed pathway. The results offer early human support for the mechanism seen in preclinical models, but not complete mechanistic confirmation.

Nicotinamide Riboside Improved a Test of Mobility

The clinical findings were more limited. NR was generally well tolerated, and participants improved on the Timed Up and Go test, which measures how quickly someone can rise from a chair, walk a short distance, turn, and sit back down. The median completion time improved from 11.9 seconds to 9.96 seconds after four weeks, about 16.3% faster.

Other clinical measures did not improve significantly, including the six-minute walk test, grip strength, quality of life, and the mitochondrial disease biomarkers.

Because the study had only eight participants, lasted four weeks, and had no placebo group, the authors considered the mobility result preliminary. Overall, the study produced a clearer molecular signal than a clinical one: NR engaged NAD+-related and mitochondrial pathways in muscle, but whether those changes can lead to lasting improvements in strength, endurance, symptoms, or quality of life remains unknown.

What This Study Means for Nicotinamide Riboside and Mitochondrial DNA Disease

This study provides early human evidence that NR can engage NAD+-related metabolism and influence molecular pathways connected to mitochondrial biogenesis in people with mitochondrial DNA disease.

Across all eight participants, one measure of mobility improved, while walking endurance, grip strength, quality of life, and mitochondrial disease biomarkers did not. The clearest biological signals appeared in the three participants with large-scale mitochondrial DNA deletions, and the same pattern was not observed in those with m.3243 variants.

That difference gives the study a precision-medicine angle. Rather than pointing to a single treatment for all mitochondrial disorders, the findings suggest that future approaches may need to consider both the underlying genetic diagnosis and the amount of measurable disease present before treatment.

For now, NR remains an experimental strategy rather than an established treatment. These results provide a basis for larger, longer, randomized, placebo-controlled trials to determine whether the findings can be reproduced and whether they ultimately lead to improvements that matter to patients.

If you have mitochondrial disease, please talk with your doctor or mitochondrial disease specialist before considering NR, as the evidence is still limited and it is not yet an established treatment.

References

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