Frontiers in endocrinology · 2026
Alterations in the protein lactylation landscape of sperm from patients with varicocele-associated asthenozoospermia.
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Cao Heran, Liu Xiaohua, Nie Hua, Zhu Shenghui, Liu Shujuan, Zhou Yu, Ma Chunjie, Liu Huang, Qin Weibing
Аннотация
BACKGROUNDS: Varicocele is a leading cause of male infertility, primarily manifesting as asthenozoospermia. The underlying molecular mechanisms remain unclear, and the potential role of protein lactylation in this condition is unknown.
METHODS: We performed a comprehensive lactylome analysis using data-independent acquisition (DIA) mass spectrometry on paired sperm samples collected from patients with varicocele-associated asthenozoospermia before and after treatment. Differential lactylation analysis and bioinformatic enrichment analyses were conducted.
RESULTS: Disrupted lactate metabolism was observed in asthenozoospermic sperm, with decreased intracellular L-lactate and elevated seminal plasma L-lactate. This was concomitant with a global reduction in protein lactylation, particularly in the sperm midpiece and tail. Lactylome profiling identified 2,699 lactylation sites on 1,216 proteins. Comparison of pre- and post-treatment samples revealed 133 differentially lactylated proteins, which were significantly enriched in pathways critical for sperm motility, including glycolysis/gluconeogenesis, microtubule-based movement, and flagellar assembly. Notably, lactylation abundance of key proteins (TEKT3, AKAP4, TUBA1A, AKAP3, TUBB4B) were significantly downregulated.
CONCLUSIONS: This study presents an initial characterization of the protein lactylation landscape in human sperm, revealing its alteration in the context of varicocele-associated asthenozoospermia. The findings suggest that dysregulation of the lactate-lactylation axis correlates with impaired sperm motility, potentially through concurrent alterations in energy metabolism and flagellar structure. This correlation underscores specific lactylation events that warrant future mechanistic investigation.
METHODS: We performed a comprehensive lactylome analysis using data-independent acquisition (DIA) mass spectrometry on paired sperm samples collected from patients with varicocele-associated asthenozoospermia before and after treatment. Differential lactylation analysis and bioinformatic enrichment analyses were conducted.
RESULTS: Disrupted lactate metabolism was observed in asthenozoospermic sperm, with decreased intracellular L-lactate and elevated seminal plasma L-lactate. This was concomitant with a global reduction in protein lactylation, particularly in the sperm midpiece and tail. Lactylome profiling identified 2,699 lactylation sites on 1,216 proteins. Comparison of pre- and post-treatment samples revealed 133 differentially lactylated proteins, which were significantly enriched in pathways critical for sperm motility, including glycolysis/gluconeogenesis, microtubule-based movement, and flagellar assembly. Notably, lactylation abundance of key proteins (TEKT3, AKAP4, TUBA1A, AKAP3, TUBB4B) were significantly downregulated.
CONCLUSIONS: This study presents an initial characterization of the protein lactylation landscape in human sperm, revealing its alteration in the context of varicocele-associated asthenozoospermia. The findings suggest that dysregulation of the lactate-lactylation axis correlates with impaired sperm motility, potentially through concurrent alterations in energy metabolism and flagellar structure. This correlation underscores specific lactylation events that warrant future mechanistic investigation.