Xu Chang, Yuan Yexian, Zhang Cha, Zhou Yuchuan, Yang Jinping, Yi Huadong, Gyawali Ishwari, Lu Jingyi, Guo Sile, Ji Yunru, Tan Chengquan, Wang Songbo, Zhang Yongliang, Jiang Qingyan, Shu Gang
Guangdong Laboratory for Lingnan Modern Agriculture, National Engineering Research Center for Breeding Swine Industry and Guangdong Province Key Laboratory of Animal Nutritional Regulation, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.
International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory of Embryo Original Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Life Metab. 2022 Jul 14;1(1):67-80. doi: 10.1093/lifemeta/loac012. eCollection 2022 Aug.
Infertility is a global concern attributed to genetic defects, lifestyle, nutrition, and any other factors that affect the local metabolism and niche microenvironment of the reproductive system. 2-Oxoglutarate receptor 1 (OXGR1) is abundantly expressed in the testis; however, its cellular distribution and biological function of OXGR1 in the male reproductive system remain unclear. In the current study, we demonstrated that OXGR1 is primarily expressed in epididymal smooth muscle cells (SMCs). Aging and heat stress significantly reduced OXGR1 expression in the epididymis. Using OXGR1 global knockout and epididymal-specific OXGR1 knockdown models, we revealed that OXGR1 is essential for epididymal sperm maturation and fluid acid-base balance. Supplementation of α-ketoglutaric acid (AKG), the endogenous ligand of OXGR1, effectively reversed epididymal sperm maturation disorders caused by aging and heat stress. Furthermore, studies showed that AKG markedly stimulated the release of instantaneous intracellular calcium from epididymal SMCs and substantially reduced the pH value in the epididymal SMCs via OXGR1. Mechanistically, we discovered that AKG/OXGR1 considerably increased the expression of Na/HCO cotransporter (NBCe1) mRNA in the epididymal SMCs, mediated by intracellular calcium signaling. The local AKG/OXGR1 system changed the epididymal fluid pH value and HCO concentration, thereby regulating sperm maturation via intracellular calcium signaling and NBCe1 mRNA expression. This study for the first time reveals the crucial role of OXGR1 in male fertility and sheds light on the applicability of metabolic intermediates in the nutritional intervention of reproduction.
不孕症是一个全球性问题，其原因包括基因缺陷、生活方式、营养以及任何影响生殖系统局部代谢和微环境的其他因素。2-氧代戊二酸受体1（OXGR1）在睾丸中大量表达；然而，OXGR1在男性生殖系统中的细胞分布和生物学功能仍不清楚。在本研究中，我们证明OXGR1主要在附睾平滑肌细胞（SMC）中表达。衰老和热应激显著降低了附睾中OXGR1的表达。使用OXGR1全身敲除和附睾特异性OXGR1敲低模型，我们发现OXGR1对附睾精子成熟和液体酸碱平衡至关重要。补充OXGR1的内源性配体α-酮戊二酸（AKG）可有效逆转由衰老和热应激引起的附睾精子成熟障碍。此外，研究表明，AKG通过OXGR1显著刺激附睾SMC中瞬时细胞内钙的释放，并大幅降低附睾SMC中的pH值。从机制上讲，我们发现AKG/OXGR1通过细胞内钙信号传导显著增加了附睾SMC中钠/碳酸氢根共转运体（NBCe1）mRNA的表达。局部AKG/OXGR1系统改变了附睾液的pH值和碳酸氢根浓度，从而通过细胞内钙信号传导和NBCe1 mRNA表达调节精子成熟。本研究首次揭示了OXGR1在男性生育中的关键作用，并为代谢中间体在生殖营养干预中的应用提供了线索。
