Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase

• 成果类型: Article
• 署名作者: Violante, Sara; Kyaw, Aye; Kouatli, Lana; Paladugu, Kaushik; Apostolakis, Lauren; Jenks, Macy; Johnson, Amy; Sheldon, Ryan D.; Whitten, Douglas; Schilmiller, Anthony L.; Visconti, Pablo E.; Cross, Justin R.; Levin, Lonny R.; Buck, Jochen; Balbach, Melanie
• 署名单位: Memorial Sloan Kettering Cancer Center; Michigan State University; Van Andel Institute; Michigan State University; University of Massachusetts System; University of Massachusetts Amherst; Cornell University; Weill Cornell Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11204
• DOI: 10.1073/pnas.2506417122
• 发表日期: 2025-09-30
• 关键词: soluble adenylyl-cyclase; pentose-phosphate pathway; lactate-dehydrogenase-c; tyrosine phosphorylation; mouse spermatozoa; capacitation; motility; glycolysis; metabolism; involvement

摘要

Prior to ejaculation, mammalian sperm are stored in the epididymis in a resting metabolic state. Upon ejaculation, sperm must alter their metabolism to generate the energy needed to support the motility and maturation process known as capacitation to reach and fertilize the oocyte. How sperm regulate the capacitation-induced increase in carbon flux is unknown. Here, we use 13C stable isotope labeling in mouse sperm isolated from the cauda epididymis to follow glucose metabolism through central carbon metabolic network before and after sperm activation. As sperm transition from resting to highly activated states, they boost energy yield by increasing flux through glycolysis at the expense of the pentose phosphate pathway. Increased glycolytic activity seems to be achieved via capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the tricarboxylic acid (TCA) cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the flagellum, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase, which also serves to regenerate oxidized nicotinamide adenine dinucleotide (NAD+) ensuring a sufficient supply to support glycolysis. The resultant lactate is at least partially secreted. Finally, we find evidence that there is an as yet unknown endogenous source of energy in sperm, feeding the upregulation of TCA cycle intermediates. These studies provide the most complete picture of the metabolic shift which occurs in capacitating mouse sperm in glucose.