FSP1 在小鼠卵母细胞成熟过程中调控铁蛋白沉积和线粒体功能

FSP1 regulates ferroptosis and mitochondrial function during mouse oocyte maturation

FSP1 在小鼠卵母细胞成熟过程中调控铁蛋白沉积和线粒体功能

Authors: Hongzhen Ruan, Huifen Xiang, Yajing Liu, Peiwen Wang, Liuliu Dong, Yunxia Cao, Dan Liang, Zhiming Ding

Source: Experimental Cell Research

DOI: 10.1016/j.yexcr.2025.114524

Abstract

Oocyte quality plays a fundamental role in fertilization and embryonic development. Emerging evidence indicates that ferroptosis may impair oocyte quality. Ferroptosis suppressor protein 1 (FSP1), a known ferroptosis inhibitor, has an uncharacterized function in regulating oocyte quality during meiotic maturation. This study identified FSP1 expression across all stages of meiotic maturation with localization to the cytoplasm of mouse oocytes. Aged mice exhibited a marked reduction in FSP1 expression within the ovaries and oocytes. Pharmacological inhibition of FSP1 disrupted germinal vesicle breakdown and polar body emission, leading to spindle defects and chromosome misalignment. Additionally, FSP1 inhibition persistently activated the spindle assembly checkpoint, resulting in meiotic arrest. At the mechanistic level, inhibition of FSP1 led to an increase in intracellular Fe²⁺levels, enhanced dihydroethidium fluorescence, excessive accumulation of reactive oxygen species, and intensified lipid peroxidation. Disruptions in ferroptosis-associated gene expression further indicated that oocytes underwent ferroptosis. Moreover, mitochondrial dysfunction was evident following FSP1 inhibition, as reflected by aberrant mitochondrial distribution, diminished ATP production, and an elevated mitochondrial membrane potential. Collectively, these results establish FSP1 as a key regulator of oocyte meiotic maturation by modulating iron homeostasis and mitochondrial function, while its inhibition triggers ferroptosis-dependent meiotic failure.

Keywords: FSP1; Ferroptosis; Meiosis; Mitochondria; Oocyte.

摘要：

卵母细胞质量在受精和胚胎发育中起着根本性的作用。新的证据表明，铁色素沉着可能会损害卵母细胞的质量。铁变态抑制蛋白1（FSP1）是一种已知的铁变态抑制因子，它在减数分裂成熟过程中调节卵母细胞质量的功能尚未定性。这项研究确定了 FSP1 在小鼠卵母细胞减数分裂成熟各个阶段的表达，并定位在卵母细胞的细胞质中。老龄小鼠卵巢和卵母细胞中的 FSP1 表达明显减少。药理抑制 FSP1 会破坏生殖泡分解和极体发射，导致纺锤体缺陷和染色体错位。此外，抑制 FSP1 会持续激活纺锤体组装检查点，导致减数分裂停滞。在机理层面，抑制 FSP1 会导致细胞内 Fe²⁺ 水平升高、二氢氧荧光增强、活性氧过度积累以及脂质过氧化反应加剧。铁突变相关基因表达的紊乱进一步表明卵母细胞发生了铁突变。此外，FSP1 抑制后线粒体功能障碍明显，线粒体分布异常、ATP 生成减少和线粒体膜电位升高都反映了这一点。总之，这些结果确定了 FSP1 是通过调节铁稳态和线粒体功能来调节卵母细胞减数分裂成熟的关键调节因子，而抑制 FSP1 则会引发依赖于铁突变的减数分裂失败。

关键词： FSP1；铁凋亡；减数分裂；线粒体；卵母细胞