Pituitary P62 deficiency leads to female infertility by impairing luteinizing hormone production.
Pituitary P62 deficiency leads to female infertility by impairing luteinizing hormone production.
复制标题
垂体 P62 缺乏会损害黄体生成素的产生，导致女性不孕
DOI：
10.1038/s12276-021-00661-4
复制
发表时间：
2021-08
影响因子：
12.8
通讯作者：
Long M
中科院分区：
文献类型：
--
作者：
Li X;Zhou L;Peng G;Liao M;Zhang L;Hu H;Long L;Tang X;Qu H;Shao J;Zheng H;Long M
p62的蛋白质适配器缺乏p62的肥胖症。 - ）和特定特异性的P62敲除（p62flox/floxαgsucre）小鼠提出了一种正常的代谢状态，而它们显示出不育症表型（繁殖率减弱，脂肪生成和排卵等），并始终如一地表达了黄质马酮（LH）的表达和生产。测序显示明显的下调线粒体氧化物磷酸化（OXPHOS）的途径oxphos标记，NDUFA2被发现积极调节LH在LβT2细胞中的产生。线粒体oxphos信号传导并导致女性不育症，从而提供了GNRH-P62-OXPHOS（NDUFA2）-CA2+/ATP-LH促性细胞中的ATP-LH途径是研究女性复制功能障碍的新理论基础。
一种有助于维持正常代谢功能的蛋白质还可以调节女性生育能力的产生肥胖和糖尿病，研究人员表明，缺乏这种蛋白质的小鼠在生命后期超重，但在较早的分析中，裸露的排卵率也受损。
P62 is a protein adaptor for various metabolic processes. Mice that lack p62 develop adult-onset obesity. However, investigations on p62 in reproductive dysfunction are rare. In the present study, we explored the effect of p62 on the reproductive system. P62 deficiency-induced reproductive dysfunction occurred at a young age (8 week old). Young systemic p62 knockout (p62-/-) and pituitary-specific p62 knockout (p62flox/flox αGSUcre) mice both presented a normal metabolic state, whereas they displayed infertility phenotypes (attenuated breeding success rates, impaired folliculogenesis and ovulation, etc.) with decreased luteinizing hormone (LH) expression and production. Consistently, in an infertility model of polycystic ovary syndrome (PCOS), pituitary p62 mRNA was positively correlated with LH levels. Mechanistically, p62-/- pituitary RNA sequencing showed a significant downregulation of the mitochondrial oxidative phosphorylation (OXPHOS) pathway. In vitro experiments using the pituitary gonadotroph cell line LβT2 and siRNA/shRNA/plasmid confirmed that p62 modulated LH synthesis and secretion via mitochondrial OXPHOS function, especially Ndufa2, a component molecule of mitochondrial complex I, as verified by Seahorse and rescue tests. After screening OXPHOS markers, Ndufa2 was found to positively regulate LH production in LβT2 cells. Furthermore, the gonadotropin-releasing hormone (GnRH)-stimulating test in p62flox/flox αGSUcre mice and LβT2 cells illustrated that p62 is a modulator of the GnRH-LH axis, which is dependent on intracellular calcium and ATP. These findings demonstrated that p62 deficiency in the pituitary impaired LH production via mitochondrial OXPHOS signaling and led to female infertility, thus providing the GnRH-p62-OXPHOS(Ndufa2)-Ca2+/ATP-LH pathway in gonadotropic cells as a new theoretical basis for investigating female reproductive dysfunction. A protein that helps maintain normal metabolic function also regulates the production of hormones that govern female fertility. Problems with ovulation are the most common cause of infertility, and these are in turn commonly associated with endocrine abnormalities and obesity. Researchers led by Min Long and Hongting Zheng of the Army Medical University in Chongqing, China, have now determined that a protein called P62 links these conditions. P62 is associated with obesity and diabetes, and the researchers showed that mice lacking this protein become overweight late in life but also exhibited impaired ovulation at an early age. Closer analysis revealed that P62 activity in the pituitary gland helps coordinate production of luteinizing hormone, which regulates ova maturation and release. These findings thus offer new insights into the connection between metabolic and reproductive health.
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DOI：
10.1073/pnas.92.11.5219
发表时间：
1995-05-23
影响因子：
11.1
作者：
CHEN, ZP;KRATZMEIER, M;LIGHTMAN, SL
通讯作者：
LIGHTMAN, SL
影响因子：
15.9
作者：
Ahmed, Kashan;LaPierre, Mary P.;Stoffel, Markus
通讯作者：
Stoffel, Markus
DOI：
10.1007/978-981-15-0602-4_21
发表时间：
2019-01-01
期刊：
AUTOPHAGY: BIOLOGY AND DISEASES: BASIC SCIENCE
影响因子：
--
作者：
Gao, Hui;Khawar, Muhammad Babar;Li, Wei
通讯作者：
Li, Wei
miRNA-93抑制GLUT4，并在多囊卵巢综合征患者和具有胰岛素抵抗的女性的脂肪组织中过表达。
影响因子：
7.7
作者：
Chen YH;Heneidi S;Lee JM;Layman LC;Stepp DW;Gamboa GM;Chen BS;Chazenbalk G;Azziz R
通讯作者：
Azziz R
影响因子：
8.8
作者：
Delcour, Clemente;Amazit, Larbi;Beau, Isabelle
通讯作者：
Beau, Isabelle