NAD+ Depletion Triggers SARM1 Activation and Cell Death, Prevented by PARP Inhibitors: Preclinical Findings

Synopsis

Sarm1 is a protein that drives programmed axon degeneration by breaking down NAD⁺, but its activity is controlled by NAD+ levels. This study found that in cells treated with the mitochondrial inhibitor rotenone, early NAD+ loss caused by overactive PARP1 triggers Sarm1 activation, leading to cell damage. Blocking PARP1 with the inhibitor PJ34 restored NAD+ levels, improved mitochondrial function, and prevented Sarm1 activation. These results were confirmed in fruit flies, where PARP inhibition reduced movement problems and lowered Sarm1 expression. The findings suggest that maintaining NAD+ levels can control Sarm1 activity and that PARP inhibitors may be repurposed to treat mitochondrial complex I deficiency disorders.

Journal

The FEBS Journal