Introduction

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.

Objectives

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.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

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D-甘露糖介导的代谢途径维持精子功能和受精的分子特征

 介绍

单个射精中的哺乳动物精子表现出显着的异质性，只有一个子集具有成功受精所需的分子特征。确定这些高生育能力精子的定义特征仍然是一个悬而未决的问题。

 目标

阐明小鼠和人类精子受精潜力的分子标志物和机制，重点是 D-甘露糖的作用。

 方法

使用流式细胞术、生化测定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，以鉴定不同的分子特征。采用药物干预来验证关键通路的作用，尤其是 Akt/mTOR 信号传导。

 结果

具有较长鞭毛的精子在小鼠和人类中均表现出增强的运动性、线粒体活性和受精潜力。多组学分析揭示了高生育能力精子中不同的分子谱，其特征是特定的蛋白质、脂质和代谢物。值得注意的是，D-甘露糖补充剂通过激活 Akt/mTOR 通路增强了精子活力和受精能力，即使在弱精子精子中也是如此。这种效果没有被 D-葡萄糖或 ATP 补充剂复制。从机制上讲，D-甘露糖绕过了糖酵解限速步骤，增加了 ATP 的产生并促进了线粒体和顶体的完整性。

 结论

本研究确定了受精能力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，并为治疗男性不育症和优化辅助生殖技术提出了创新的治疗策略。