Zhao Wenlong, Gu Nihao, Liu Xueyuan, Qing Ningxin, Sheng Jianzhong, Lin Xianhua, Huang Hefeng
The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 310008, China; Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ, USA.
The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 310008, China.
J Adv Res. 2024 Dec 27. doi: 10.1016/j.jare.2024.12.035.
Mammalian sperm within a single ejaculate exhibit significant heterogeneity, with only a subset possessing the molecular characteristics required for successful fertilization. Identifying the defining traits of these high-fertility sperm remains an open question.
To elucidate the molecular markers and mechanisms underlying the fertilization potential of sperm in both mice and humans, with a focus on the role of D-mannose.
Sperm morphology and functionality were analyzed using flow cytometry, biochemical assays, and immunofluorescence. Multi-omics analyses, including proteomics, metabolomics, and lipidomics, were conducted to identify distinct molecular signatures. Pharmacological interventions were employed to validate the role of key pathways, particularly Akt/mTOR signaling.
Sperm with longer flagella demonstrated enhanced motility, mitochondrial activity, and fertilization potential in both mice and humans. Multi-omics analyses revealed distinct molecular profiles in high-fertility sperm, characterized by specific proteins, lipids, and metabolites. Notably, D-mannose supplementation enhanced sperm motility and fertilization capacity, even in asthenozoospermic sperm, by activating the Akt/mTOR pathway. This effect was not replicated by D-glucose or ATP supplementation. Mechanistically, D-mannose bypassed glycolytic rate-limiting steps, increasing ATP production and promoting mitochondrial and acrosomal integrity.
This study identifies key molecular signatures of fertilization-competent sperm and highlights D-mannose as a novel modulator of sperm quality and function. These findings provide valuable insights into sperm biology and propose innovative therapeutic strategies for treating male infertility and optimizing assisted reproduction technologies.
单次射精中的哺乳动物精子表现出显著的异质性，只有一小部分具备成功受精所需的分子特征。确定这些高生育力精子的决定性特征仍是一个悬而未决的问题。
阐明小鼠和人类精子受精潜力的分子标记和潜在机制，重点关注D-甘露糖的作用。
使用流式细胞术、生化分析和免疫荧光分析精子形态和功能。进行多组学分析，包括蛋白质组学、代谢组学和脂质组学，以识别不同的分子特征。采用药理学干预来验证关键通路，特别是Akt/mTOR信号传导的作用。
在小鼠和人类中，鞭毛较长的精子表现出更强的运动能力、线粒体活性和受精潜力。多组学分析揭示了高生育力精子中不同的分子特征，其特点是特定的蛋白质、脂质和代谢物。值得注意的是，补充D-甘露糖可通过激活Akt/mTOR通路增强精子活力和受精能力，即使是弱精子症患者的精子也是如此。补充D-葡萄糖或ATP无法复制这种效果。从机制上讲，D-甘露糖绕过了糖酵解的限速步骤，增加了ATP的产生，并促进了线粒体和顶体的完整性。
本研究确定了具有受精能力的精子的关键分子特征，并强调D-甘露糖是精子质量和功能的新型调节剂。这些发现为精子生物学提供了有价值的见解，并提出了治疗男性不育和优化辅助生殖技术的创新治疗策略。
