PPM1K-regulated impaired catabolism of branched-chain amino acids orchestrates polycystic ovary syndrome
Liangshan Mu, Zhenhong Ye, Junhao Hu, Yurong Zhang, Kai Chen, Haipeng Sun, Rong Li, Weian Mao, Xiaoyu Long, Chunmei Zhang, Yu-Chen Lai, Jun Liu, Yue Zhao, Jie Qiao
Abstract
BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common diseases with the coexistence of reproductive malfunction and metabolic disorders. Previous studies have found increased branched chain amino acid (BCAA) levels in women with PCOS. However, it remains unclear whether BCAA metabolism is causally associated with the risk of PCOS. METHODS: -dependent 1K (PPM1K) was further explored by using Ppm1k-deficient mouse model and PPM1K down-regulated human ovarian granulosa cells. FINDINGS: female mice. Knockdown of PPM1K promoted the conversion of glycolysis to pentose phosphate pathway and inhibited mitochondrial oxidative phosphorylation in human granulosa cells. INTERPRETATION: Ppm1k deficiency-impaired BCAA catabolism causes the occurrence and development of PCOS. PPM1K suppression disturbed energy metabolism homeostasis in the follicular microenvironment, which provided an underlying mechanism of abnormal follicle development. FUNDING: This study was supported by the National Key Research and Development Program of China (2021YFC2700402, 2019YFA0802503), the National Natural Science Foundation of China (81871139, 82001503, 92057107), the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-001), Key Clinical Projects of Peking University Third Hospital (BYSY2022043), the China Postdoctoral Science Foundation (2021T140600), and the Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01).