Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3-dependent mechanism in male mice

Nicotinamide adenine dinucleotide (NAD⁺) is a central signaling molecule and enzyme cofactor that is involved in a variety of fundamental biological processes. NAD⁺ levels decline with age, neurodegenerative conditions, acute brain injury, and in obesity or diabetes. Loss of NAD⁺ results in impaired mitochondrial and cellular functions. Administration of NAD⁺ precursor, nicotinamide mononucleotide (NMN), has shown to improve mitochondrial bioenergetics, reverse age-associated physiological decline, and inhibit postischemic NAD⁺ degradation and cellular death. In this study, we identified a novel link between NAD⁺ metabolism and mitochondrial dynamics. A single dose (62.5 mg/kg) of NMN, administered to male mice, increases hippocampal mitochondria NAD⁺ pools for up to 24 hr posttreatment and drives a sirtuin 3 (SIRT3)-mediated global decrease in mitochondrial protein acetylation. This results in a reduction of hippocampal reactive oxygen species levels via SIRT3-driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented due to lower interaction of phosphorylated fission protein, dynamin-related protein 1 (pDrp1 S616]), with mitochondria. In conclusion, manipulation of mitochondrial NAD⁺ levels by NMN results in metabolic changes that protect mitochondria against reactive oxygen species and excessive fragmentation, offering therapeutic approaches for pathophysiologic stress conditions.