• Nicotinamide mononucleotide (NMN) increases the concentration of nucleotides in the mitochondria of human cells by increasing the activity of an enzyme called ubiquinone (coenzyme Q10).
  • NMN activates another enzyme that breaks NMN down into a precursor molecule for nucleotides. 
  • The findings provide an additional explanation for how NMN improves mitochondrial health.

NMN confers anti-aging benefits by increasing the essential molecule nicotinamide adenine dinucleotide (NAD+). NAD+ plays key roles in a multitude of reactions, including those that generate energy, repair DNA, and eliminate harmful oxygen-containing molecules called reactive oxygen species. Importantly, NAD+ is known to improve the health of mitochondria. However, our current understanding of just how NAD+ improves mitochondrial health is incomplete. 

In a recently released, not yet peer reviewed article, Kang and colleagues from Kyushu University in Japan demonstrate that NMN increases nucleotide production in the cell’s power-generating structures – mitochondria. Since mitochondria have their own DNA, increasing the availability of nucleotides may provide a way to enhance mitochondrial DNA synthesis and replication, important for mitochondrial health. Since numerous age-related cardiovascular and metabolic diseases have been linked to declining mitochondrial function, the findings improve our understanding of how NMN confers its benefits.

NMN Increases DNA Building Blocks in Mitochondria

To increase our understanding of how NMN provides anti-aging benefits via improving mitochondrial health, the Japan-based research team analyzed metabolic byproducts (metabolites) from the mitochondria of human kidney cells. They found that, aside from boosted levels of protein building blocks (amino acids) and NAD+ metabolites, DNA and RNA building blocks (nucleotides) were also elevated in mitochondria upon NMN treatment. Kang and colleagues also found that NMN increased orotic acid, a metabolite that increases in response to nucleotide production, suggesting that NMN increases the synthesis of mitochondrial nucleotides.

NMN drives nucleotide production in  mitochondria
(Setoyama et al., 2022 | Non peer reviewed article) NMN drives nucleotide production in mitochondria. Treating human kidney cells with NMN (NMN_1mM and NMN1.5mM) significantly increases orotic acid concentrations, indicative of increased nucleotide production.

A key mitochondrial enzyme known as ubiquinone (coenzyme Q10) plays essential roles in increasing nucleotide production, so the Kyushu University researchers measured how NMN affects its levels. They found that NMN increases ubiquinone levels substantially in mitochondria, further elucidating how NMN increases nucleotide production for these cell power-generating structures. 

NMN raises levels of coenzyme Q10
(Setoyama et al., 2022 | Non peer reviewed article) NMN raises levels of coenzyme Q10 in mitochondria. NMN significantly increases coenzyme Q10 (ubiquinone) levels in human kidney cell mitochondria as shown by concentrations of its forms with electrons (Q10H2) and without (Q10).

By analyzing mitochondrial metabolites that NMN increases, Kang and colleagues discovered yet another pathway by which NMN promotes nucleotide production. Their analysis indicated that NMN raises the activation of an enzyme (BST1) that breaks NMN down into a molecule called ribose 5-phosphate, which provides the substrate necessary to synthesize nucleotides. These findings illustrate yet another way NMN provides the materials needed to build new nucleotides, which in turn can be used to build new DNA in mitochondria. 

Although the study doesn’t show that NMN increases mitochondrial DNA abundance within cells, it provides evidence that short-term NMN supplementation increases the pool of nucleotides for mitochondria. This means that under circumstances where more mitochondrial DNA is necessary, such as when mitochondria become damaged, cells can utilize NMN-derived nucleotides to replenish mitochondria. Furthermore, when applied over longer periods, the possibility remains that NMN may increase mitochondria numbers and thus mitochondrial DNA copy numbers. At any rate, the study provides yet more evidence of NMN’s beneficial effects on cellular health.