Aneuploidy, the presence of a chromosomal anomaly, is a major cause of spontaneous abortions and recurrent pregnancy loss in humans. However, the underlying molecular mechanisms still remain poorly understood. Here, we report that ARHGAP26, a putative tumor suppressor gene, is a newly identified regulator of oocyte quality to maintain mitochondrial integrity and chromosome euploidy, thus ensuring normal embryonic development and fertility. Taking advantage of knockout mouse model, we revealed that genetic ablation of Arhgap26 caused the oocyte death at GV stage due to the mitochondrial dysfunction-induced ROS accumulation. Lack of Arhgap26 also impaired both in vitro and in vivo maturation of survived oocytes which results in maturation arrest and aneuploidy, and consequently leading to early embryonic development defects and subfertility. These observations were further verified by transcriptome analysis. Mechanistically, we discovered that Arhgap26 interacted with Cofilin1 to maintain the mitochondrial integrity by regulating Drp1 dynamics, and restoration of Arhgap26 protein level recovered the quality of Arhgap26-null oocytes. Importantly, we found an ARHGAP26 mutation in a patient with history of recurrent miscarriage by chromosomal microarray analysis. Altogether, our findings uncover a novel function of ARHGAP26 in the oocyte quality control and prevention of aneuploidy and provide a potential treatment strategy for infertile women caused by ARHGAP26 mutation.

非整倍体，即染色体异常的存在，是人类自然流产和反复妊娠流产的主要原因。然而，潜在的分子机制仍然知之甚少。在此，我们报道 ARHGAP26（一种假定的肿瘤抑制基因）是一种新发现的卵母细胞质量调节因子，可维持线粒体完整性和染色体整倍体，从而确保正常的胚胎发育和生育能力。利用敲除小鼠模型，我们发现Arhgap26的基因消除导致 GV 期卵母细胞死亡，这是由于线粒体功能障碍引起的 ROS 积累。 Arhgap26 的缺乏还会损害存活卵母细胞的体外和体内成熟，导致成熟停滞和非整倍性，从而导致早期胚胎发育缺陷和生育力低下。这些观察结果通过转录组分析得到了进一步验证。从机制上讲，我们发现Arhgap26与Cofilin1相互作用，通过调节Drp1动力学来维持线粒体完整性，并且Arhgap26蛋白水平的恢复恢复了Arhgap26缺失卵母细胞的质量。重要的是，我们通过染色体微阵列分析在一名有反复流产史的患者中发现了ARHGAP26突变。总而言之，我们的研究结果揭示了 ARHGAP26 在卵母细胞质量控制和预防非整倍性方面的新功能，并为ARHGAP26突变引起的不孕女性提供了潜在的治疗策略。