NR and Inosine Restore Metabolic Activity in NAXD-Deficient Cells: Preclinical Findings

Synopsis

Mutations in the metabolite-repair enzyme NAXD, which normally converts damaged NADHX/NADPHX back into functional cofactors, cause the severe neurometabolic disorder PEBEL2. In human NAXD-knockout cell models, growth was specifically impaired under galactose conditions that force reliance on oxidative metabolism. Surprisingly, these cells showed only mild mitochondrial defects but a profound block in the de novo serine synthesis pathway, traced to inhibition of 3-phosphoglycerate dehydrogenase (PHGDH). Patient-derived fibroblasts showed the same metabolic signature. Supplementation with nicotinamide riboside (NR) or inosine improved viability under metabolic stress, acting through distinct mechanisms that partially restored serine-related metabolic activity. These results reveal a key metabolic vulnerability in NAXD deficiency and highlight NR and inosine as promising candidates for mechanism-based therapies in PEBEL disorders.

Journal

Cellular & Molecular Biology Letters