Overweight or obese women seeking pregnancy is becoming increasingly common. Human maternal obesity gives rise to detrimental effects during reproduction. Emerging evidence has shown that these abnormities are likely attributed to oocyte quality. Oxidative stress induces poor oocyte conditions, but whether mitochondrial calcium homeostasis plays a key role in oocyte status remains unresolved. Here, we established a mitochondrial Ca²⁺ overload model in mouse oocytes. Knockdown gatekeepers of the mitochondrial Ca²⁺ uniporters Micu1 and Micu2 as well as the mitochondrial sodium calcium exchanger NCLX in oocytes both increased oocytes mitochondrial Ca²⁺ concentration. The overload of mitochondria Ca²⁺ in oocytes impaired mitochondrial function, leaded to oxidative stress, and changed protein kinase A (PKA) signaling associated gene expression as well as delayed meiotic resumption. Using this model, we aimed to determine the mechanism of delayed meiosis caused by mitochondrial Ca²⁺ overload, and whether oocyte-specific inhibition of mitochondrial Ca²⁺ influx could improve the reproductive abnormalities seen within obesity. Germinal vesicle breakdown stage (GVBD) and extrusion of first polar body (PB1) are two indicators of meiosis maturation. As expected, the percentage of oocytes that successfully progress to the germinal vesicle breakdown stage and extrude the first polar body during in vitro culture was increased significantly, and the expression of PKA signaling genes and mitochondrial function recovered after appropriate mitochondrial Ca²⁺ regulation. Additionally, some indicators of mitochondrial performance-such as adenosine triphosphate (ATP) and reactive oxygen species (ROS) levels and mitochondrial membrane potential-recovered to normal. These results suggest that the regulation of mitochondrial Ca²⁺ uptake in mouse oocytes has a significant role during oocyte maturation as well as PKA signaling and that proper mitochondrial Ca²⁺ reductions in obese oocytes can recover mitochondrial performance and improve obesity-associated oocyte quality.

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