Elevated intracellular pH appears in aged oocytes and causes oocyte aneuploidy associated with the loss of cohesion in mice

Increases in the aneuploidy rate caused by the deterioration of cohesion with increasing maternal age have been well documented. However, the molecular mechanism for the loss of cohesion in aged oocytes remains unknown. In this study, we found that intracellular pH (pH(i)) was elevated in aged oocytes, which might disturb the structure of the cohesin ring to induce aneuploidy. We observed for the first time that full-grown germinal vesicle (GV) oocytes displayed an increase in pH(i) with advancing age in CD1 mice. Furthermore, during the in vitro oocyte maturation process, the pH(i) was maintained at a high level, up to approximate to 7.6, in 12-month-old mice. Normal pH(i) is necessary to maintain protein localization and function. Thus, we put forward a hypothesis that the elevated oocyte pH(i) might be related to the loss of cohesion and the increased aneuploidy in aged mice. Through the in vitro alkalinization treatment of young oocytes, we observed that the increased pH(i) caused an increase in the aneuploidy rate and the sister inter-kinetochore (iKT) distance associated with the strength of cohesion and caused a decline in the cohesin subunit SMC3 protein level. Young oocytes with elevated pH(i) exhibited substantially the increase in chromosome misalignment.