ER stress-associated IRE1α signalling links impaired QPRT-dependent NAD⁺ biosynthesis to reduced oocyte competence

Oocyte quality is closely linked to metabolic and organelle homeostasis, but the mechanisms underlying naturally occurring differences in oocyte quality remain incompletely understood. Here, we identify a link between endoplasmic reticulum (ER) stress, impaired NAD⁺ biosynthesis and poor oocyte quality. Poor-grade goat oocytes exhibited profound NAD⁺ depletion, accompanied by quinolinic acid accumulation and reduced expression of quinolinate phosphoribosyltransferase (QPRT), suggesting a bottleneck in de novo NAD⁺ biosynthesis. Restoring QPRT expression or bypassing this metabolic step improved meiotic maturation. Further analyses revealed altered ER stress signalling, increased IRE1α-associated activity and reduced QPRT RNA stability. Recombinant IRE1α processed QPRT RNA in vitro, suggesting a possible link between IRE1α activity and QPRT transcript regulation. Supplementation with nicotinamide mononucleotide (NMN) restored NAD⁺ levels and improved several features of poor-quality oocytes, including calcium homeostasis, oxidative stress and mitochondrial membrane potential. NMN treatment also improved early embryonic development, with its beneficial effects involving SIRT6 activity and changes in DNA methylation-associated fluorescence. Importantly, NMN supplementation improved meiotic maturation in poor-grade bovine and porcine oocytes, indicating that this metabolic intervention may have broader relevance across mammals. Analysis of published human oocyte proteomic data further revealed age-associated changes in ER proteostasis and NAD-related proteins. Together, our findings identify ER stress-associated disruption of QPRT-dependent NAD⁺ biosynthesis as a potential contributor to poor oocyte quality and suggest that restoring NAD⁺ metabolism may offer a strategy to improve the functional properties of compromised oocytes.