Pathway for Mitochondrial NAD+ Production in Human Cells Revealed: Preclinical Findings

Synopsis

NAD⁺ is an essential molecule for cellular energy and signaling, but how it is made and distributed inside human cells is not fully understood. In particular, the source of mitochondrial NAD+, the largest cellular pool, has remained unclear. To investigate this, researchers developed a new system that detects NAD+ levels within mitochondria by tracking the activity of an introduced enzyme. Using this tool, along with enzyme mapping and chemical inhibitors, they traced how NAD+ precursors enter and move through the cell. The study found that only specific nucleosides, not nucleotides, can enter cells directly; larger molecules like NAD+ and NMN are broken down outside the cell into smaller precursors that can pass through the membrane. Inside the cytosol, these precursors are rebuilt into NMN, which then enters mitochondria and is converted into NAD+ by the enzyme NMNAT3—located within the mitochondrial matrix. These findings reveal the complete pathway for mitochondrial NAD+ production and provide new insight into how NAD⁺ metabolism supports cell function and overall health.

Journal

Journal of Biological Chemistry