Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran.
Sci Rep. 2024 Oct 29;14(1):25965. doi: 10.1038/s41598-024-77875-9.
Numerous variables that regulate the metabolism of Sertoli cells and sperm have been identified, one of which is sex steroid hormones. These hormones play a vital role in maintaining energy homeostasis, influencing the overall metabolic balance of the human body. The proper functioning of the reproductive system is closely linked to energy status, as the reproductive axis responds to metabolic signals. The aim of this study was to investigate the gene expression patterns of metabolite interconversion enzymes in testicular cells (Sertoli cells and spermatogonia) of non-obstructive azoospermia (NOA) patients, as compared to normal controls, to understand the molecular mechanisms contributing to NOA. We used microarray and bioinformatics techniques to analyze 2912 genes encoding metabolite interconversion enzymes, including methyltransferase, monooxygenase, transmembrane reductase, and phosphohydrolase, in both testicular cells and normal samples. In sperm, the upregulation of MOXD1, ACAD10, PCYT1A, ARG1, METTL6, GPLD1, MAOA, and CYP46A1 was observed, while ENTPD2, CPT1C, ADC, and CYB5B were downregulated. Similarly, in the Sertoli cells of three NOA patients, RPIA, PIK3C3, LYPLA2, CA11, MBOAT7, and HDHD2 were upregulated, while NAA25, MAN2A1, CYB561, PNPLA5, RRM2, and other genes were downregulated. Using STRING and Cytoscape, we predicted the functional and molecular interactions of these proteins and identified key hub genes. Pathway enrichment analysis highlighted significant roles for G1/S-specific transcription, pyruvate metabolism, and citric acid metabolism in sperm, and the p53 signaling pathway and folate metabolism in Sertoli cells. Additionally, Weighted Gene Co-expression Network Analysis (WGCNA) and single-cell RNA sequencing (scRNA-seq) were performed to validate these findings, revealing significant alterations in gene expression and cellular distribution in NOA patients. Together, these results provide new insights into the molecular mechanisms underlying NOA and identify potential therapeutic targets.
已经鉴定出许多调节支持细胞和精子代谢的变量，其中之一是性激素。这些激素在维持能量稳态中起着至关重要的作用，影响人体的整体代谢平衡。生殖系统的正常功能与能量状态密切相关，因为生殖轴会对代谢信号做出反应。本研究旨在研究非阻塞性无精子症（NOA）患者睾丸细胞（支持细胞和精原细胞）中代谢物转化酶的基因表达模式，以了解导致 NOA 的分子机制。我们使用微阵列和生物信息学技术分析了睾丸细胞和正常样本中 2912 个编码代谢物转化酶的基因，包括甲基转移酶、单加氧酶、跨膜还原酶和磷酸水解酶。在精子中，观察到 MOXD1、ACAD10、PCYT1A、ARG1、METTL6、GPLD1、MAOA 和 CYP46A1 的上调，而 ENTPD2、CPT1C、ADC 和 CYB5B 则下调。同样，在三名 NOA 患者的支持细胞中，RPIA、PIK3C3、LYPLA2、CA11、MBOAT7 和 HDHD2 上调，而 NAA25、MAN2A1、CYB561、PNPLA5、RRM2 和其他基因下调。使用 STRING 和 Cytoscape，我们预测了这些蛋白质的功能和分子相互作用，并确定了关键的枢纽基因。通路富集分析突出了 G1/S 特异性转录、丙酮酸代谢和柠檬酸代谢在精子中的重要作用，以及 p53 信号通路和叶酸代谢在支持细胞中的重要作用。此外，还进行了加权基因共表达网络分析（WGCNA）和单细胞 RNA 测序（scRNA-seq）来验证这些发现，结果显示 NOA 患者的基因表达和细胞分布发生了显著变化。总之，这些结果为 NOA 的分子机制提供了新的见解，并确定了潜在的治疗靶点。
