LRRC37A is essential for acrosomal ion homeostasis and male fertility

Mammalian spermatozoa face various challenges during their long march to the destination. As a specialized membrane-bound organelle in the sperm head, the acrosome is particularly sensitive to changes in ionic and osmotic conditions, yet how acrosomal ion homeostasis is maintained remains largely unknown. Here, we show that LRRC37A is required for acrosomal ion homeostasis. Loss of Lrrc37a causes complete male infertility, accompanied by pronounced enlargement and deformation of the acrosome in the sperm head. Acrosome biogenesis was not affected by Lrrc37a knockout during the early stages of spermiogenesis, whereas acrosomal enlargement emerged at later stages and became more pronounced in the epididymis. LRRC37A localized to the outer acrosomal region and interacted with the Na/K-ATPase -subunit isoforms ATP1A1 and ATP1A4. Loss of LRRC37A disrupted the spatial distribution of both isoforms and was accompanied by increased Na within the acrosomal region. In addition, pharmacological perturbation of Na/K-ATPase activity or cellular ion homeostasis induced acrosomal swelling. These findings establish an essential role for LRRC37A in acrosomal ion homeostasis, suggesting that its deficiency may be associated with a distinct form of teratozoospermia characterized by acrosomal enlargement.