FK506 binding protein 12.6-mediated inhibition of sperm-specific calcineurin is essential for FK506-induced male infertility by disturbing the homeostasis of calcium and mitochondria

Impaired sperm motility is a leading cause of male infertility. Studies indicated that FK506, an immunosuppressive drug, resulted in male mouse infertility or an overall decline in the fertilization capacity of male renal transplant recipients. However, the underlying mechanism is not fully elucidated. Here, we reported that the disruption of FK506 binding protein 12.6 (FKBP12.6) significantly alleviated FK506-induced male infertility in mice by restoring sperm motility and mitochondrial functions in immature sperm. Mechanically, we identified that the FK506-FKBP12.6 complex preferentially bound to the sperm-specific calcineurin, which is composed of a catalytic subunit (PPP3CC) and a regulatory subunit (PPP3R2). We revealed that FKBP12.6 deficiency reversed FK506-induced the elevated expression of Down syndrome critical region 1.1 (DSCR1.1, a calcineurin inhibitor) and the reduced expressions of PPP3CC and PPP3R2 in immature sperm. Additionally, we observed that FKBP12.6 deficiency remarkably improved FK506-induced the abnormality of Ca²⁺ release through restoring calcineurin-mediated dephosphorylation at S2808 and S2814 of RyR2, and maintained the mitochondrial homeostasis by suppressing the hyperphosphorylation at S637 of the mitochondrial dynamin-related protein 1 (Drp1) in immature sperm. Furthermore, we demonstrated that FKBP12.6 deficiency reversed FK506-induced the reduction of the acrosome reaction in sperm by retaining the expression of synaptosome-associated protein of 25 kDa (Snap25) in immature sperm, which is essential for the maturation of acrosome exocytosis function. Certainly, our findings should provide an insight in elucidating the mechanism of FK506-induced male infertility, suggesting that FKBP12.6 might be a potential target for male infertility clinically.