In a study published in Nature Cell Biology in 2020, scientists dissected how cells maintain their levels of a critical molecule known as Nicotinamide adenine dinucleotide (NAD+), that is pivotal for cellular health and longevity. The research delves into the intricate biosynthetic pathways used by cells to produce NAD+ and manage its balance across different cellular compartments. This balance of synthesis, consumption, and regeneration in different subcellular compartments regulates NAD+ homeostasis. The study can be found here.
Cells have three independent biosynthetic pathways to generate NAD+ - the kynurenine pathway, the Preiss-Handler pathway, and the NAD+ salvage pathway. In the kynurenine pathway, the dietary amino acid tryptophan is converted into N-formyl kynurenine, leading to a series of transformations that yield NAD+. In contrast, the Preiss-Handler pathway uses dietary nicotinic acid (NA) to generate NAD+. Lastly, the NAD+ salvage pathway recycles the by-product nicotinamide (NAM) created by the enzymatic activities of NAD+-consuming enzymes.
Apart from synthesizing NAD+, cells also have to distribute it across various compartments – such as the cytoplasm, mitochondria, and nucleus – where it fulfills unique roles. The mechanisms by which NAD+ is transported into these organelles are still under investigation. Recently, scientists have discovered a mammalian NAD+ mitochondrial transporter which is responsible for intact NAD+ uptake into the organelle.
In the cytoplasm, a specific enzyme transforms NAM into nicotinamide mononucleotide (NMN), which is then converted to NAD+. Once generated, NAD+ is utilized during the metabolic process of glycolysis, generating a compound called NADH, which is then transferred to the mitochondrial matrix through specific transport processes.
Inside the mitochondria, NAD+ is consumed by NAD+-dependent mitochondrial enzymes, generating NAM. The exact mechanics of re-converting NAM back to NAD+ inside the mitochondrion, is currently unknown, as are the details of NAD+ production and homeostasis in the nucleus.
Overall, proper NAD+ maintenance is a balance of synthesis, consumption, and regeneration in different subcellular compartments. However, there are still many unknowns in these processes, prompting scientists to dig deeper. This understanding could lead to the development of interventions to improve NAD+ levels, potentially contributing to health and longevity.
- Scientists elucidated the mechanisms by which cells generate and maintain levels of a molecule called NAD+, critical for cellular health and longevity.
- Cells utilize three pathways to generate NAD+: the kynurenine pathway, the Preiss-Handler pathway, and the NAD+ salvage pathway.
- NAD+ is distributed across different compartments within a cell, fulfilling unique roles within the cytoplasm, mitochondria, and nucleus.
- A specific mammalian NAD+ mitochondrial transporter responsible for intact NAD+ uptake into the organelle has been discovered.
- Further investigation into these processes could lead to potential health and longevity interventions.
- There are significant unknowns about the details of these processes inside mitochondria and the nucleus, necessitating further investigation.