The Immp2l Mutation Causes Ovarian Aging Through ROS-Wnt/β-Catenin-Estrogen Pathway: Preventive Effect of Melatonin
The Immp2l Mutation Causes Ovarian Aging Through ROS-Wnt/β-Catenin-Estrogen Pathway: Preventive Effect of Melatonin
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Immp2l突变通过ROS-Wnt/β-Catenin-雌激素途径导致卵巢衰老：褪黑素的预防作用
DOI：
10.1210/endocr/bqaa119
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发表时间：
2020-09-01
期刊：
影响因子：
4.8
通讯作者：
Yang, Yanzhou
中科院分区：
文献类型：
--
作者：
He, Qing;Gu, Lifang;Yang, Yanzhou
线粒体在卵泡发育中起重要作用。线粒体功能障碍，包括线粒体基因缺陷，损害卵巢发育。本研究旨在探讨线粒体内膜基因Immp 2l在卵泡生长发育中的作用及其机制。我们的结果显示，雌性Immp 2l（-/-）小鼠是不育的，而Immp 2l（+/-）小鼠是正常的。雌性Immp 2l（-/）（-）小鼠体重和卵巢重量降低，次级卵泡期卵泡生长发育受阻。虽然有少数卵泡排卵，但由于线粒体功能障碍，卵母细胞未受精。在28日龄的Immp 2l（-/-）小鼠中观察到氧化应激增加、雌激素水平降低以及Wnt/β-连环蛋白和类固醇激素合成途径的基因表达改变。Immp 2 I突变加速了卵巢衰老过程，因为在Imnip 2 I（-/-）小鼠中，到5月龄时没有检测到卵巢卵泡。通过向Immp 2l（-/-）小鼠施用抗氧化剂褪黑激素，Immp 2l（-/）（-）小鼠中的所有上述变化都被逆转。此外，我们使用Immp 2l敲低颗粒细胞的体外研究证实，Immp 2l下调通过增强活性氧（ROS）水平、抑制Wnt 16、增加β-连环蛋白、降低类固醇激素合成基因cyp 19 a1和雌激素水平，伴随颗粒细胞衰老表型的增加，诱导颗粒细胞衰老。褪黑激素治疗延缓颗粒细胞衰老进程。总之，Immp 2l通过ROS-Wnt/β-连环蛋白-雌激素（cyp 19 a1）途径引起卵巢衰老，这可以通过褪黑激素治疗逆转。
Mitochondria play important roles in ovarian follicle development. Mitochondrial dysfunction, including mitochondrial gene deficiency, impairs ovarian development. Here, we explored the role and mechanism of mitochondrial inner membrane gene Immp2l in ovarian follicle growth and development. Our results revealed that female Immp2l(-/-) mice were infertile, whereas Immp2l(+/-) mice were normal. Body and ovarian weights were reduced in the female Immp2l(-/)(-)mice, ovarian follicle growth and development were stunted in the secondary follicle stage. Although a few ovarian follicles were ovulated, the oocytes were not fertilized because of mitochondrial dysfunction. Increased oxidative stress, decreased estrogen levels, and altered genes expression of Wnt/beta-catenin and steroid hormone synthesis pathways were observed in 28-day-old Immp2l(-/-) mice. The Immp2I mutation accelerated ovarian aging process, as no ovarian follicles were detected by age 5 months in Imnip2l(-/-) mice. All the aforementioned changes in the Immp2l(-/)(-) mice were reversed by administration of antioxidant melatonin to the Immp2l(-/-) mice. Furthermore, our in vitro study using Immp2l knockdown granulosa cells confirmed that the Immp2l downregulation induced granulosa cell aging by enhancing reactive oxygen species (ROS) levels, suppressing Wnt16, increasing beta-catenin, and decreasing steroid hormone synthesis gene cyp19a1 and estrogen levels, accompanied by an increase in the aging phenotype of granulosa cells. Melatonin treatment delayed granulosa cell aging progression. Taken together, Immp2l causes ovarian aging through the ROS-Wnt/beta-catenin-estrogen (cyp19a1) pathway, which can be reversed by melatonin treatment.