β-Nicotinamide Mononucleotide Supplementation Increases the Nucleotide Pool Through Multiple Pathways, Improving Mitochondrial DNA Metabolism

Abstract

β-Nicotinamide mononucleotide (β-NMN), a precursor of NAD + , has been suggested to have beneficial effects on the mitochondria in various animal models, but the details remain unclear. Here, we identified two distinct metabolic pathways by which β-NMN increases the nucleotide pool to activate mitochondrial DNA replication. We found that β-NMN activated ubiquinone synthesis in the mitochondrial inner membrane and thereby enhanced the electron transfer capacity, resulting in the activation of dihydroorotate dehydrogenase, a rate-limiting enzyme involved in pyrimidine synthesis. Indeed, short-term administration of β-NMN to aged mice increased ubiquinone levels in the kidney and heart mitochondria. β-NMN is also metabolized to nicotinamide and ribose 5-phosphate by BST1 glycohydrolase in cells, and ribose 5-phosphate can be used as a source for the sugar necessary for nucleotide synthesis. Thus, supplemented β-NMN can enhance nucleotide synthesis through two metabolic pathways , which may contribute to maintaining mitochondrial DNA replication capacity.

Funding Information: This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JP21K07369 to D.S., JP18H00351 to T.N., and JP20H00530 to D.K.)

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: All procedures were performed in accordance with the guidelines of the Laboratory Animals Care and Use Committee (No. 20073, 21053, 22029). Efforts were made to minimize the number of animals used and to limit their suffering.

Keywords: beta-nicotinamide mononucleotide, nicotinamide adenine dinucleotide, Ubiquinone, nucleotide pool, electron transport system, Dihydroorotate dehydrogenase, BST1, pyrimidine synthesis, mitochondrial DNA replication