In the microscopic world of cells, NAD⁺ (Nicotinamide Adenine Dinucleotide) plays an irreplaceable role as a core molecule in cellular energy metabolism, participating in critical physiological processes such as cell signaling and DNA damage repair. Below is a systematic breakdown of NAD⁺ metabolism from three core dimensions, followed by an analysis of the dynamic balance between these processes:
1. NAD⁺ Consumption: The "Expenditure" of Cellular Energy
NAD⁺ consumption primarily occurs through the following pathways:
Redox Reactions: Within mitochondria, the cell’s energy factory, NAD⁺ participates in redox reactions of the respiratory chain, where it is reduced to NADH to supply energy to cells. Additionally, NAD⁺ plays a pivotal role in glycolysis, and its redox state (NAD⁺/NADH) directly influences the direction of metabolic pathways.
Actions of NAD⁺-Dependent Enzymes: NAD⁺-dependent enzymes are the "main force" of NAD⁺ consumption, mainly including three categories:
Sirtuins: A family of deacetylases involved in regulating cellular metabolism, stress responses, and aging. They use NAD⁺ as a co-substrate to remove acetyl groups from target proteins, while breaking down NAD⁺ into nicotinamide (NAM) and ADP-ribose.
PARPs (Poly(ADP-ribose) Polymerases): PARPs play a key role in DNA damage repair. Using NAD⁺ as a substrate, they synthesize poly(ADP-ribose) and decompose NAD⁺ into NAM.
NAD⁺ Hydrolases: Such as CD38, CD157, and SARM1. These enzymes hydrolyze NAD⁺ into NAM and ADP-ribose; among them, CD38 and CD157 also have ADP-ribosyl cyclase activity, which can further generate cyclic ADP-ribose (cADPR).
2. NAD⁺ Synthesis: The "Production" of Cellular Energy (Endogenous Pathways) To maintain stable intracellular NAD⁺ levels, cells synthesize NAD⁺ through multiple pathways, mainly three core routes:
De Novo Synthesis Pathway: This pathway uses tryptophan as the raw material and generates NAD⁺ through a series of complex enzymatic reactions. It is most active in the liver, and the synthesized NAD⁺ is transported to peripheral cells via the bloodstream.
Preiss-Handler Pathway: Taking nicotinic acid (NA) as a precursor, this pathway produces nicotinic acid mononucleotide (NAMN) via nicotinic acid phosphoribosyltransferase (NAPRT), which is then converted into NAD⁺ through a series of reactions.
NAD⁺ Salvage Synthesis Pathway: This is the key pathway for maintaining intracellular NAD⁺ levels. NAM produced by NAD⁺-consuming enzymes is converted into nicotinamide mononucleotide (NMN) via nicotinamide phosphoribosyltransferase (NAMPT), and then NMN is converted into NAD⁺ under the action of nicotinamide mononucleotide adenylyltransferase (NMNAT).
3. NAD⁺ Supplementation: Exogenous "Recharging" Strategies With aging, intracellular NAD⁺ levels tend to decline, a change closely associated with the occurrence and development of various age-related diseases. Therefore, exogenous supplementation of NAD⁺ or its precursor substances has become a highly concerned strategy for anti-aging and disease intervention.
Supplementation of NAD⁺ Precursor Substances
Nicotinamide Mononucleotide (NMN): As a key intermediate in the NAD⁺ salvage synthesis pathway, studies have shown that exogenous NMN supplementation can significantly increase NAD⁺ levels in cells and tissues. For example, in animal experiments, NMN supplementation improves mitochondrial function, enhances energy metabolism, and delays age-related physiological decline.
Nicotinamide Riboside (NR): NR is also a precursor in the NAD⁺ salvage synthesis pathway; it can be converted into NMN in cells and then into NAD⁺. Similar to NMN, NR supplementation effectively boosts NAD⁺ levels and has shown potential benefits for cardiovascular health and neuroprotection in some studies.
Supplementation of NADH – The Reduced Form of NAD⁺
NADH (reduced Nicotinamide Adenine Dinucleotide), the reduced form of NAD⁺, is known as reduced coenzyme Ⅰ, commonly referred to as mitochrome. Supplementation of NADH is an efficient way to increase NAD⁺ levels in the body. After entering the body, NADH can be directly oxidized to NAD⁺, thereby rapidly raising intracellular NAD⁺ levels. In addition, NADH can be converted into NAD⁺ through NADH-ubiquinone oxidoreductase in the mitochondrial respiratory chain (requiring coenzyme Q10 participation). Thus, NADH supplementation not only directly increases NAD⁺ levels but also indirectly enhances NAD⁺ levels by promoting mitochondrial function.
The Significance of NAD⁺ Metabolic Balance In summary, NAD⁺ metabolism relies on three interrelated core processes: consumption, endogenous synthesis, and exogenous supplementation. Their dynamic balance is the foundation of normal cellular functions like energy metabolism and DNA repair. Aging disrupts this balance (decreased synthesis, increased consumption), leading to NAD⁺ decline and age-related diseases. Exogenous supplements (NMN, NR, NADH) help restore balance, offering potential for anti-aging and metabolic disease intervention, with further research promising new therapeutic avenues.
