Sperm Bioenergetic Plasticity and Metabolic Adaptations During the Journey Toward Fertilization

Abstract

Male infertility is a prevalent global health issue, underscoring the critical role of sperm bioenergetics in successful fertilization. This review synthesizes current knowledge on the dynamic metabolic plasticity of spermatozoa throughout their extended lifespan, from primordial germ cell (PGC) development to transit within the female reproductive tract. We systematically delineate how metabolic reprogramming, which involves oscillations between glycolysis and oxidative phosphorylation, is intrinsically coupled to epigenetic remodeling during PGC specification and serves as an active regulator of cell fate decisions during spermatogenesis. Post-testicular maturation in the epididymis equips sperm with metabolic flexibility for diverse substrates, followed by a strategic bioenergetic quiescence for storage. Finally, sperm navigate the female tract by dynamically adapting their energetic strategy to regional microenvironments, shifting from glycolysis in the acidic vagina to a synergistic engagement of both pathways for capacitation and the acrosome reaction. We highlight that this metabolic adaptability is not merely a passive response but a fundamental determinant of fertilization competence. Despite advances, significant controversies remain regarding dominant pathways in specific niches. This review establishes a foundational framework for future research, proposing that elucidating these bioenergetic mechanisms will unlock novel diagnostic biomarkers and therapeutic strategies for male infertility.