Ldha-Dependent Metabolic Programs in Sertoli Cells Regulate Spermiogenesis in Mouse Testis

Simple Summary Infertility affects an estimated 10-15% of couples, and males are responsible for 20-30% of infertility cases worldwide. Male fertility relies on the success of spermatogenesis, which is a complex cellular differentiation process that is coordinated by germ cells and testicular somatic cells. Sertoli cells play a central role in supporting spermatogenesis, and it was proposed that they supply energy substances for the developing germ cells. In the present study, we provide genetic evidence that lactate production in Sertoli cells, which is controlled by the lactate dehydrogenase A (Ldha) gene, is crucial for murine spermatogenesis. Compared to the controls, Ldha deficiency in Sertoli cells greatly reduced the testicular weight, which caused spermatogenic defects and adversely impacted sperm function. The sperm from Ldha conditional knockout animals exhibited low motility, high morphological abnormalities, and an impaired capacity to fertilize oocytes. Metabolic analysis has revealed that limiting lactate production in Sertoli cells changed a large number of metabolites in the sperm from mutant animals. We then identified choline as the key molecule that mediates the function of lactate in sperm, and the supplementation of conditional knockout animals with dietary choline rescued the spermatogenic defects and fertility. This work sheds new light on the functional role of Sertoli cells in regulating spermatogenesis and identifies a candidate molecule that has potential roles in treating male infertility that is caused by metabolic disorders. Sertoli cells play indispensable roles in spermatogenesis by providing the advanced germ cells with structural, nutritional, and regulatory support. Lactate is regarded as an essential Sertoli-cell-derived energy metabolite that nurses various types of spermatogenic cells; however, this assumption has not been tested using genetic approaches. Here, we have reported that the depletion of lactate production in Sertoli cells by conditionally deleting lactate dehydrogenase A (Ldha) greatly affected spermatogenesis. Ldha deletion in Sertoli cells significantly reduced the lactate production and resulted in severe defects in spermatogenesis. Spermatogonia and spermatocytes did not show even mild impairments, but the spermiogenesis of Ldha conditional knockout males was severely disrupted. Further analysis revealed that 2456 metabolites were altered in the sperm of the knockout animals, and specifically, lipid metabolism was dysregulated, including choline, oleic acid, and myristic acid. Surprisingly, choline supplementation completely rescued the spermiogenesis disorder that was caused by the loss of Ldha activities. Collectively, these data have demonstrated that the interruption of Sertoli-cell-derived lactate impacted sperm development through a choline-mediated mechanism. The outcomes of these findings have revealed a novel function of lactate in spermatogenesis and have therapeutic applications in treating human infertility.