由AARS2催化的乳化会诱导卵泡发育和过早的卵巢衰竭
Zhi-Ling Zhang1, Shu-Ting Ren1,2, Wan-Jie Yang1
1Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Cell death discovery
|April 29, 2025
概括
乳酸和AARS2突变的升高会通过蛋白质乳化导致过早的卵巢缺陷 (POI). 抑制这种乳酸信号可以治疗或预防POI.
科学领域:
- 生物化学 生物化学
- 生殖生物学 生殖生物学
- 代谢学 代谢学 代谢学
背景情况:
- 乳酸是参与各种生理和病理过程的代谢物.
- 蛋白质乳化,由阿兰-tRNA合成酶 (AARS) 催化,是一种翻译后的修饰.
- 过早卵巢衰竭 (POI) 是一种在40岁之前卵巢功能丧失的情况.
研究的目的:
- 调查乳酸和蛋白质乳酸在早产卵巢缺陷 (POI) 病原发生中的作用.
- 探索 mitochondrial alanyl-tRNA合成酶2 (AARS2) 突变在POI中的功能.
- 通过调节乳酸信号来确定POI的潜在治疗点.
主要方法:
- 对POI患者血清乳酸盐水平的分析.
- 突变AARS2的乳酸转移酶活性的表征2.
- 在实验室和体内研究中,使用具有AARS2突变或剥离的小鼠模型.
- 评估蛋白质乳化,卡尼丁棕基转移酶2 (CPT2) 活性和下游信号通路.
- 评估β-氨酸治疗对卵泡发育和POI特征的影响.
主要成果:
- 在POI患者中,血清乳酸水平升高.
- 功能获取的AARS2突变表现出增强的乳酸转移酶活性.
- 通过AARS2介导的乳化使CPT2失活,导致脂肪酸积累和PPARγ激活.
- 通过AARS2对PDHA1的乳化促进了颗粒细胞的增殖和原始毛囊的发育.
- 特定于GC的AARS2过度表达加速了卵泡的枯竭.
- 在小鼠中,AARS2 除或β-氨酸治疗可以防止POI表型.
结论:
- 升高的乳酸和AARS2突变诱导的超乳化促进POI.
- 乳酸信号,通过AARS2-介导的乳化,在毛囊发育和枯竭中发挥着关键作用.
- 抑制乳酸信号传递是预防或治疗POI的潜在治疗策略.
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