Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is required for sperm motility and male fertility

TLDR

Glycolysis is conserved, yet mammalian sperm contain unique isozymes such as GAPDS, a sperm‑specific GAPDH isozyme tightly bound to the flagellar fibrous sheath. The study aimed to determine the importance of sperm glycolysis for in vivo function by disrupting Gapds expression. Gapds was selectively knocked out via gene targeting to block sperm glycolysis. Gapds‑/‑ males were infertile with severely impaired sperm motility, ATP levels fell to 10.4 % of wild‑type, indicating glycolysis supplies most energy for motility and highlighting GAPDS as a potential contraceptive target.

Abstract

Although glycolysis is highly conserved, it is remarkable that several unique isozymes in this central metabolic pathway are found in mammalian sperm. Glyceraldehyde 3-phosphate dehydrogenase-S (GAPDS) is the product of a mouse gene expressed only during spermatogenesis and, like its human ortholog (GAPD2), is the sole GAPDH isozyme in sperm. It is tightly bound to the fibrous sheath, a cytoskeletal structure that extends most of the length of the sperm flagellum. We disrupted Gapds expression by gene targeting to selectively block sperm glycolysis and assess its relative importance for in vivo sperm function. Gapds –/– males were infertile and had profound defects in sperm motility, exhibiting sluggish movement without forward progression. Although mitochondrial oxygen consumption was unchanged, sperm from Gapds –/– mice had ATP levels that were only 10.4% of those in sperm from WT mice. These results imply that most of the energy required for sperm motility is generated by glycolysis rather than oxidative phosphorylation. Furthermore, the critical role of glycolysis in sperm and its dependence on this sperm-specific enzyme suggest that GAPDS is a potential contraceptive target, and that mutations or environmental agents that disrupt its activity could lead to male infertility.