Nucleotide stress in chronic inflammatory memory: Mitochondrial DNA damage and NAD⁺-dependent PARP1 chromatin...

Chronic sterile inflammation can persist after the initiating stressor has subsided, indicating that resolution failure may involve more than continued cytokine signaling. We propose that nucleotide stress, defined here as disruption of cellular NAD⁺ availability together with altered dNTP/rNTP homeostasis, can couple mitochondrial damage to persistent inflammatory priming. Mitochondrial superoxide (O₂•-) is converted to hydrogen peroxide (H₂O₂), which can support metal-catalyzed formation of hydroxyl radicals (•OH), whereas O₂•- can also react with nitric oxide to form peroxynitrite. These chemistries can produce oxidative base modifications such as 8-oxo-7,8-dihydro-2'-deoxyguanosine, while abasic sites and strand discontinuities represent chemically distinct lesion classes; altered nucleotide ratios can add a separate burden through ribonucleotide incorporation into mtDNA. We emphasize that mtDNA copy number, subcellular localization, and chemical lesion burden are different variables and should not be used interchangeably. Mislocalized mtDNA can engage cGAS-STING and other DNA-sensing pathways, while NLRP3 can respond to mitochondrial damage and oxidized mtDNA in defined contexts. In the nucleus, PARP1 requires NAD⁺ for productive PARylation during the DNA-damage response. We hypothesize that sustained but non-catastrophic NAD⁺ limitation may alter the lifetime of selected DNA-bound PARP1 states and delay post-repair nucleosome restoration. This is a central, unproven kinetic prediction and is not equivalent to pharmacological PARP trapping. We position the NCI framework as a complementary resolution-failure hypothesis rather than a universal model of trained immunity. We outline analytical safeguards, evidence boundaries, and longitudinal withdrawal-rechallenge experiments that can test whether correcting nucleotide stress produces durable chromatin and inflammatory resetting rather than transient suppression.