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Peroxiredoxin 4 (Prdx4), a member of the Prdx family, is a vital ER-resident antioxidant in cells. As revealed in our previous study, Prdx4 expression was detected in ovarian granulosa cells and was closely related to ovarian function. This research aimed to explore the effect and underlying molecular mechanism of the protective role of Prdx4 against D-gal-induced ovarian ageing in mice. The D-gal-induced ovarian ageing model has been extensively used to study the mechanisms of premature ovarian failure (POF). In this study, adult Prdx4 -/- and wild-type mice were intraperitoneally injected with D-gal (150 mg/kg/day) daily for 6 weeks. Ovarian function, granulosa cell apoptosis, oxidative damage and ER stress in the ovaries were evaluated in the two groups. Ovarian weight was significantly lower, the HPO axis was more strongly disrupted, and the numbers of atretic follicles and apoptotic granulosa cells were obviously higher in Prdx4 -/- mice. In addition, Prdx4 -/- mice showed increased expression of oxidative damage-related factors and the ovarian senescence-related protein P16. Moreover, the levels of the proapoptotic factors CHOP and activated caspase-12 protein, which are involved in the ER stress pathway, and the level of the apoptosis-related BAX protein were elevated in the ovaries of Prdx4 -/- mice. Thus, D-gal-induced ovarian ageing is accelerated in Prdx4 -/- mice due to granulosa cell apoptosis via oxidative damage and ER stress-related pathways, suggesting that Prdx4 is a protective agent against POF.

Peroxiredoxin 4 (Prdx4) in the endoplasmic reticulum (ER) is the only secretory member of the antioxidant Prdx family. Our previous studies demonstrated that Prdx4 in cumulus cells (CCs) ameliorated the maturation of oocytes in vitro and enhanced oocyte developmental competence by preventing CCs apoptosis caused by oxidative stress (OS) through gap junctions. In this study, we aimed to determine whether Prdx4 released by CCs can repair meiotic defects in mouse oocytes by co-culturing immature (germinal vesicle) oocytes with CCs from mature oocytes in the absence of gap junctions. The OS-induced meiotic defects in mouse oocytes were impeded by co-culture with CCs, as evidenced by the increased first polar body (PB1) extrusion rate and decreased ROS level. CCs increased Prdx4 expression and lowered IRE1α, Bip expression in H 2 O 2 -treated oocytes. After knockdown of Prdx4 expression in CCs, the rate of PB1 extrusion in the oocytes was significantly reduced to the level detected in H 2 O 2 group, and ER stress was not alleviated. CO-IP and immunofluorescence co-localization experiments demonstrated that Prdx4 interacted with PDIA6 in the oocytes and the Pearson's R value was 0.69 calculated using ImageJ. Cumulus cells can promote the maturation of oocytes in vitro by secreting Prdx4 in a paracrine manner and serve as a promising therapeutic antioxidant for improving the quality of oocytes, especially aging oocytes, in clinical in vitro maturation (IVM). • Cumulus cells could secrete Prdx4 in a paracrine manner. • Prdx4 interacts with PDIA6 to ameliorate the release of ROS, rectify misfolded protein. • Prdx4 supplementation might improve the oocyte quality. [ABSTRACT FROM AUTHOR]

Finding an effective regulator to avoid harmful effects caused by excessive reactive oxygen species (ROS) is a bottleneck during oocyte in vitro maturation (IVM). Previously, we found that peroxiredoxin 4 (Prdx4) expression is significantly higher in mature cumulus cell–oocyte complexes (COCs) than in immature COCs. Prdx4 belongs to the antioxidant enzyme family and can catalyze the reduction of H 2 O 2. In this study, we established an oxidative stress model with mouse COCs cultured in vitro. Treatment with H 2 O 2 decreased cumulus expansion indexes and oocyte maturation in a concentration-dependent manner, indicating follicular development dysplasia. Infection with a Prdx4-overexpressing adenovirus significantly attenuated H 2 O 2 -induced changes, exhibiting effects similar to those of the intracellular ROS scavenger tiron (the positive control). Furthermore, the results confirmed that the protective effect of Prdx4 on oocyte maturation may be due to reductions in ROS levels and apoptosis. However, when the gap junctions between cumulus cells (CCs) and oocytes were destroyed, Prdx4 overexpression did not exert antiapoptotic effects. The expression levels of the gap junction marker protein CX43 were significantly recovered in the Prdx4-overexpressing group. These results demonstrate that Prdx4 in CCs may be a new favorable regulator that improves in vitro -matured oocyte quality and enhances oocyte developmental competence by preventing CC apoptosis caused by oxidative stress through gap junctions. The findings expand the body of knowledge regarding follicle development, and the identification of Prdx4 as a new favorable regulator will aid in immature oocyte IVM. • The present study established an oxidative stress model of immature cumulus cells-oocytes cultured in vitro. • Prdx4 in cumulus cells may be a new favorable regulator that improves in vitro oocyte quality by preventing cell apoptosis caused by oxidative stress through gap junctions. • The investigation of Prdx4 as a new regulator will provide us a clue to improve the system of immature oocytes in vitro maturation. [ABSTRACT FROM AUTHOR]