Although the role of oxidative stress in maternal aging and infertility has been suggested, the underlying mechanisms are not fully understood. The present study is designed to determine the relationship between mitochondrial function and spindle stability in metaphase II (MII) oocytes under oxidative stress. MII mouse oocytes were treated with H2O2 in the presence or absence of permeability transition pores (PTPs) blockers cyclosporin A (CsA). In addition, antioxidant N-acetylcysteine (NAC), F0/F1 synthase inhibitor oligomycin A, the mitochondria uncoupler carbonyl cyanide 4-trifluoro-methoxyphenylhydrazone (FCCP) or thapsigargin plus 2.5 mM Ca2+ (Th+2.5 mM Ca2+) were used in mechanistic studies. Morphologic analyses of oocyte spindles and chromosomes were performed and mitochondrial membrane potential (DeltaPsim), cytoplasmic free calcium concentration ([Ca2+]c) and cytoplasmic ATP content within oocytes were also assayed. In a time- and H2O2 dose-dependent manner, disruption of meiotic spindles was found after oocytes were treated with H2O2, which was prevented by pre-treatment with NAC. Administration of H2O2 led to a dissipation of DeltaPsim, an increase in [Ca2+]c and a decrease in cytoplasmic ATP levels. These detrimental responses of oocytes to H2O2 treatment could be blocked by pre-incubation with CsA. Similar to H2O2, both oligomycin A and FCCP dissipated DeltaPsim, decreased cytoplasmic ATP contents and disassembled MII oocyte spindles, while high [Ca2+]c alone had no effects on spindle morphology. In conclusion, the decrease in mitochondria-derived ATP during oxidative stress may cause a disassembly of mouse MII oocyte spindles, presumably due to the opening of the mitochondrial PTPs.

译文

:尽管有人提出了氧化应激在孕产妇衰老和不育中的作用,但其潜在机制尚未完全被理解。本研究旨在确定氧化应激下中期II(MII)卵母细胞线粒体功能与纺锤体稳定性之间的关系。在存在或不存在通透性转换孔(PTP)阻断剂环孢菌素A(CsA)的情况下,用H2O2处理MII小鼠卵母细胞。此外,在机理研究中还使用了抗氧化剂N-乙酰半胱氨酸(NAC),F0 / F1合酶抑制剂寡霉素A,线粒体解偶联剂羰基氰化物4-三氟-甲氧基苯基zone(thaspsigargin)加2.5 mM Ca2(Th 2.5 mM Ca2)。进行了卵母细胞纺锤体和染色体的形态学分析,还测定了卵母细胞中的线粒体膜电位(DeltaPsim),细胞质游离钙浓度([Ca2] c)和细胞质ATP含量。以时间和H2O2剂量依赖性,在用H2O2处理卵母细胞后发现减数分裂纺锤体的破坏,这可以通过用NAC预处理来预防。施用H2O2导致DeltaPsim的耗散,[Ca2] c的增加和细胞质ATP水平的降低。卵母细胞对H2O2处理的有害反应可以通过与CsA预先孵育来阻止。与H2O2相似,寡霉素A和FCCP都消散了DeltaPsim,降低了细胞质ATP含量并分解了MII卵母细胞纺锤体,而单独的高[Ca2] c对纺锤体形态没有影响。总之,氧化应激期间线粒体ATP的减少可能导致小鼠MII卵母细胞纺锤体分解,可能是由于线粒体PTP的开放所致。

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