ER stress-associated IRE1α signalling links impaired QPRT-dependent NAD⁺ biosynthesis to reduced oocyte competence
Year: 2026
Type: preprint
Abstract: 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.
Institution: National Institute of Animal Biotechnology
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225409005