Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction

Summary

Mechanistic paper linking NAD+ depletion to mitophagy failure in the premature-aging disease xeroderma pigmentosum group A (XPA). XPA patient fibroblasts and Xpa-/- mouse tissues accumulate unrepaired DNA damage, which chronically activates PARP-1 and drains cellular NAD+ to roughly half of control levels. The resulting NAD+ deficit suppresses SIRT1 activity, impairing its deacetylation of PGC-1α and downstream mitochondrial quality-control programs — with defective mitophagy and accumulation of damaged mitochondria as the terminal phenotype. Critically, restoring NAD+ by supplementation with NR or NMN — or by PARP-1 inhibition — rescued mitophagy, mitochondrial function, and cellular viability in both patient cells and Xpa-/- mice. The work generalized to other DNA-repair-deficiency progeroid syndromes (Cockayne syndrome, ataxia telangiectasia) in follow-up papers and established the PARP-1 → NAD+ → SIRT1 → mitophagy cascade as a unifying mechanism for segmental progerias. It also provided the strongest mechanistic rationale for NAD+ repletion in neurodegenerative disease where DNA damage accumulates.

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