Mitochondrial NAD+ import gates neuronal resilience to active SARM1

SARM1 is a protein that induces the destruction of axons, but the specific way in which NAD+ loss leads to neuronal failure has been uncertain. Researchers have long assumed that the loss of cytosolic NAD+ is the main factor causing neuronal death. However, new findings suggest that SARM1 activation rapidly depletes both cytosolic and mitochondrial NAD+, leading to a collapse in ATP production in both compartments. This indicates that the two compartments are experiencing metabolic failure at the same time.

A key discovery is that enhancing the import of mitochondrial NAD+ through a specific transport protein called SLC25A51 can help preserve mitochondrial NAD+ levels, keep mitochondrial function healthy, and delay both axon degeneration and neuronal death, even when SARM1 activity continues. Surprisingly, SLC25A51 also restores cytosolic NAD+-dependent metabolism. It does this by fixing a glycolytic block and increasing the production of NAD+ during stressful conditions.

The researchers found that the ability of SLC25A51 to protect neurons is dependent on its ability to improve cytosolic metabolism. Inhibiting glycolysis actually reduces the protective effect of SLC25A51, highlighting the importance of restoring cytosolic metabolic function. When researchers used an adeno-associated viral (AAV) vector to deliver SLC25A51, it improved the function of a mouse model of a chronic SARM1-dependent neuropathy.

These results suggest that targeting mitochondrial NAD+ import through SLC25A51 could be a valuable downstream intervention point for preserving axons and preventing axon degeneration.