AbstractPolycystic ovary syndrome (PCOS) is an endocrinopathy characterized by hyperandrogenism, anovulation, and polycystic ovaries, in which hyperandrogenism manifests by excess androgen and other steroid hormone abnormalities. Mitochondrial fusion is essential in steroidogenesis, while the role of mitochondrial fusion in granulosa cells of hyperandrogenic PCOS patients remains unclear. In this study, mRNA expression of mitochondrial fusion genes mitoguardin1, −2 (MIGA 1, −2) was significantly increased in granulosa cells of hyperandrogenic PCOS but not PCOS with normal androgen levels, their mRNA expression positively correlated with testosterone levels. Dihydrotestosterone (DHT) treatment in mice led to high expression of MIGA2 in granulosa cells of ovulating follicles. Testosterone or forskolin/ phorbol 12-myristate 13-acetate treatments increased expression of MIGA2 and the steroidogenic acute regulatory protein (StAR) in KGN cells. MIGA2 interacted with StAR and induced StAR localization on mitochondria. Furthermore, MIGA2 overexpression significantly increased cAMP-activated protein kinase A (PKA) and phosphorylation of AMP-activated protein kinase (pAMPK) at T172 but inhibited StAR protein expression. However, MIGA2 overexpression increased CYP11A1, HSD3B2, and CYP19A1 mRNA expression. As a result, MIGA2 overexpression decreased progesterone but increased estradiol synthesis. Besides the androgen receptor, testosterone or DHT might also regulate MIGA2 and pAMPK (T172) through LH/choriogonadotropin receptor-mediated PKA signaling. Taken together, these findings indicate that testosterone regulates MIGA2 via PKA/AMP-activated protein kinase signaling in ovarian granulosa cells. It is suggested mitochondrial fusion in ovarian granulosa cells is associated with hyperandrogenism and potentially leads to abnormal steroidogenesis in PCOS.

中文翻译：

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Mitoguardin2 与高雄激素血症相关并调节人卵巢颗粒细胞中的类固醇生成


摘要 多囊卵巢综合征（PCOS）是一种以雄激素过多、无排卵和多囊卵巢为特征的内分泌疾病，其中雄激素过多症表现为雄激素过多和其他类固醇激素异常。线粒体融合对于类固醇生成至关重要，但线粒体融合在高雄激素性 PCOS 患者颗粒细胞中的作用仍不清楚。本研究中，线粒体融合基因mitoguardin1,−2（MIGA 1,−2）的mRNA表达在高雄激素PCOS的颗粒细胞中显着增加，但在雄激素水平正常的PCOS中则没有显着增加，其mRNA表达与睾酮水平呈正相关。小鼠双氢睾酮 (DHT) 治疗导致排卵卵泡颗粒细胞中 MIGA2 高表达。睾酮或毛喉素/佛波醇 12-肉豆蔻酸酯 13-乙酸酯治疗可增加 KGN 细胞中 MIGA2 和类固醇生成急性调节蛋白 (StAR) 的表达。 MIGA2 与 StAR 相互作用并诱导 StAR 在线粒体上定位。此外，MIGA2 过表达显着增加 T172 处的 cAMP 激活蛋白激酶 A (PKA) 和 AMP 激活蛋白激酶 (pAMPK) 磷酸化，但抑制 StAR 蛋白表达。然而，MIGA2 过表达增加了 CYP11A1、HSD3B2 和 CYP19A1 mRNA 表达。结果，MIGA2 过表达降低了孕酮，但增加了雌二醇的合成。除了雄激素受体外，睾酮或 DHT 也可能通过 LH/绒毛膜促性腺激素受体介导的 PKA 信号传导调节 MIGA2 和 pAMPK (T172)。综上所述，这些发现表明睾酮通过卵巢颗粒细胞中 PKA/AMP 激活的蛋白激酶信号传导来调节 MIGA2。 有人认为，卵巢颗粒细胞中的线粒体融合与雄激素过多症有关，并可能导致多囊卵巢综合征中类固醇生成异常。