NAD+ (nicotinamide adenine dinucleotide) is a fundamental coenzyme found within every living cell, from bacteria to humans. Derived from vitamin B3 (niacin), it exists in two forms: NAD+ (oxidized) and NADH (reduced). It is involved in hundreds of metabolic processes and is indispensable for efficient life processes. Its presence is essential for cells to convert nutrients into energy.
NAD+ as a Central Figure in Energy Metabolism
NAD+ plays a central role in cellular energy production by acting as an electron carrier, transferring electrons from one molecule to another in redox reactions. This function is fundamental to how cells convert food into adenosine triphosphate (ATP), the cell’s primary energy currency. The cyclical interconversion between NAD+ and NADH drives many energy-producing reactions.
During glycolysis, the initial stage of glucose breakdown in the cytoplasm, NAD+ accepts electrons and hydrogen ions from glucose derivatives, becoming NADH. This reduction is a crucial step, enabling glycolysis to continue and preparing these high-energy electrons for later energy generation. The NADH produced then carries these electrons to subsequent processes for ATP synthesis.
In the Krebs cycle (citric acid cycle) within the mitochondria, NAD+ continues its role as an electron acceptor. As molecules are oxidized during this cycle, NAD+ picks up more electrons and hydrogen ions, forming NADH. Multiple NADH molecules are generated during each turn, carrying substantial potential energy.
NADH molecules from glycolysis and the Krebs cycle transport their high-energy electrons to the electron transport chain in the inner mitochondrial membrane. Here, NADH donates electrons to protein complexes, initiating a series of reactions that lead to significant ATP production. This process, oxidative phosphorylation, generates the majority of cellular energy, highlighting NAD+’s indispensable contribution to cellular respiration.
Beyond Energy: NAD+’s Diverse Roles in Cellular Processes
Beyond energy metabolism, NAD+ functions in other cellular processes that maintain cell health. One such role is in DNA repair, where NAD+ is consumed by a family of enzymes called poly-ADP-ribose polymerases (PARPs). When DNA is damaged, PARPs are activated and use NAD+ to add ADP-ribose units to proteins, including themselves, a crucial step in signaling and orchestrating DNA repair. This consumption can rapidly deplete cellular NAD+ levels in response to extensive DNA damage.
NAD+ also serves as a substrate for sirtuins, a group of proteins that regulate cellular activities like metabolism, inflammation, and DNA repair. Sirtuins are NAD+-dependent enzymes, requiring NAD+ to function. By using NAD+, sirtuins remove acetyl groups from other proteins, modifying their activity and influencing gene expression. This regulatory function impacts numerous cellular pathways, contributing to cellular health and adaptation to stress.
Maintaining NAD+ Levels: Cellular Supply and Recycling
To support its many functions, cells have sophisticated mechanisms to maintain a continuous supply of NAD+. The primary way cells generate NAD+ is through the salvage pathway, which efficiently recycles breakdown products back into NAD+. This pathway utilizes precursors like nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), all forms of vitamin B3. Enzymes in the salvage pathway convert these precursors into NMN, then into NAD+, replenishing the cell’s NAD+ pool.
The salvage pathway is particularly important because NAD+ is constantly consumed by enzymes like PARPs and sirtuins, necessitating continuous regeneration. While NAD+ can also be synthesized from the amino acid tryptophan through a “de novo” pathway, the salvage pathway is the more efficient and dominant route for maintaining cellular NAD+ levels in many tissues. This constant recycling allows cells to meet the high demand for NAD+ in energy production, DNA repair, and various signaling processes.