BNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency.
BNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency.
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BNC1 缺陷通过 NF2-YAP 途径引发铁死亡，诱发原发性卵巢功能不全
DOI：
10.1038/s41467-022-33323-8
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发表时间：
2022-10-05
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
原发性卵巢功能不全（POI）是以原始卵泡过早耗竭为特征的卵巢功能障碍的临床综合征。POI会导致不孕、严重的日常生活干扰和长期的健康风险。然而，其基本机制在很大程度上仍然未知。我们先前从一个中国POI大家系中鉴定了一个Basonuclin 1（Bnc 1）突变，并发现具有靶向Bnc 1突变的小鼠表现出POI的症状。在本研究中，我们发现BNC 1在卵泡发育过程中，在卵巢储备、维持卵母细胞脂质代谢和氧化还原稳态中起关键作用。BNC 1的缺乏导致卵泡过早激活和过度卵泡闭锁。从机制上讲，BNC 1缺陷通过NF 2-雅普途径触发卵母细胞铁凋亡。我们证明，药理学抑制雅普信号或铁凋亡显着rescesBnc 1突变诱导的POI。这些发现揭示了基于BNC 1缺陷的POI的病理机制，并建议雅普和铁凋亡抑制剂作为POI的潜在治疗靶点。
Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by premature exhaustion of primordial follicles. POI causes infertility, severe daily life disturbances and long-term health risks. However, the underlying mechanism remains largely unknown. We previously identified a Basonuclin 1 (BNC1) mutation from a large Chinese POI pedigree and found that mice with targetedBnc1mutation exhibit symptoms of POI. In this study, we found that BNC1 plays key roles in ovarian reserve and maintaining lipid metabolism and redox homeostasis in oocytes during follicle development. Deficiency of BNC1 results in premature follicular activation and excessive follicular atresia. Mechanistically, BNC1 deficiency triggers oocyte ferroptosis via the NF2-YAP pathway. We demonstrated that pharmacologic inhibition of YAP signaling or ferroptosis significantly rescuesBnc1mutation-induced POI. These findings uncover a pathologic mechanism of POI based on BNC1 deficiency and suggest YAP and ferroptosis inhibitors as potential therapeutic targets for POI.
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影响因子：
11.4
作者：
Hayashi S;Nakamura T;Motooka Y;Ito F;Jiang L;Akatsuka S;Iwase A;Kajiyama H;Kikkawa F;Toyokuni S
通讯作者：
Toyokuni S
ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
9
作者：
Lu Y;Yang Q;Su Y;Ji Y;Li G;Yang X;Xu L;Lu Z;Dong J;Wu Y;Bei JX;Pan C;Gu X;Li B
通讯作者：
Li B
影响因子：
5.7
作者：
Pangeni RP;Channathodiyil P;Huen DS;Eagles LW;Johal BK;Pasha D;Hadjistephanou N;Nevell O;Davies CL;Adewumi AI;Khanom H;Samra IS;Buzatto VC;Chandrasekaran P;Shinawi T;Dawson TP;Ashton KM;Davis C;Brodbelt AR;Jenkinson MD;Bièche I;Latif F;Darling JL;Warr TJ;Morris MR
通讯作者：
Morris MR
影响因子：
4
作者：
Luan, Yi;Edmonds, Maxwell E.;Kim, So-Youn
通讯作者：
Kim, So-Youn