All about sperm-specific GAPDH: A key enzyme in sperm energy metabolism and potential biomarker for sperm motility and male fertility

In both animals and human beings, numerous studies have highlighted a rising trend in male infertility, largely driven by a progressive decline in semen quality and motility. However, the underlying causes of this decline remain poorly understood. Hence, the identification of putative diagnostic biomarkers is essential for elucidating the underlying mechanisms responsible for impaired sperm motility and for improving our understanding of the importance of sperm motility-associated molecules in diagnosing male infertility. The primary emphasis of this review article is to consolidate studies on sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHS) and highlight its significance as a promising biomarker of sperm motility. Although oxidative phosphorylation was considered as a major source of energy production in spermatozoa, numerous investigations have substantiated glycolysis as the primary metabolic pathway facilitating sperm motility and hyperactivation. GAPDHS is specially compartmentalized in the principal piece of mammalian spermatozoa to support sperm motility through the continued production of ATP. Knockout models revealed its pivotal role in male fertility. A growing body of research reported that deficits in GAPDHS expression and enzyme activity lead to poor sperm motility and male infertility. Therefore, GAPDHS emerges as a promising biomarker for sperm motility with potential relevance to male infertility diagnosis. Nevertheless, the available evidence is currently insufficient to establish GAPDHS as a clinically validated diagnostic biomarker, and further studies specifically addressing its diagnostic accuracy, sensitivity, specificity, and clinical utility are warranted. GAPDHS may also have broader biological roles beyond spermatozoa, although these aspects are only briefly considered in this review.