Metabolic pathways fueling human spermatozoa capacitation and hyperactivation: a roadmap for spermatozoa...

Human spermatozoa are highly specialized cells whose function depends on tightly regulated metabolic and signaling networks. Following spermatogenesis and epididymal maturation, ejaculated spermatozoa must undergo capacitation in the female reproductive tract, a complex process characterized by extensive biochemical remodeling and high energy demand that enables hyperactivated motility and fertilizing competence. Human spermatozoa bioenergetics remains a prominent theme in the field of Andrology, whose advances are challenged by inter-species differences and difficulties in extrapolating data from in vitro and animal model studies to human physiology. In this comprehensive review, we discuss the current knowledge of the bioenergetic pathways governing capacitation and hyperactivation in human spermatozoa. While glycolysis remains a primary adenosine triphosphate (ATP) source, supported by sperm-specific glycolytic enzymes that provide a rapid and spatially localized ATP supply directly in the flagellum, accumulating evidence indicates that mitochondrial oxidative phosphorylation (OXPHOS) complements ATP production, assists in the regeneration of reducing equivalents to sustain a high glycolytic flux during capacitation and contributes to capacitation-activating signaling pathways. Besides these core bioenergetic pathways, the great metabolic flexibility of human spermatozoa is evidenced by the mobilization of endogenous energy substrates and engagement of additional metabolic pathways, such as fatty acid β-oxidation, pentose phosphate pathway, ketone body catabolism, and amino acids oxidation to meet the high energetic and redox demands required for capacitation and hyperactivation. Overall, these findings suggest that the metabolic potential of human spermatozoa is considerably broader than previously recognized. A comprehensive understanding of human spermatozoa bioenergetics will assist in the identification of novel biomarkers that may characterize previously male infertility cases identified as idiopathic, as well as identify therapeutic targets to improve medically assisted reproductive procedures.