Acyl-CoA synthetase 6 enriches seminiferous tubules with the ω-3 fatty acid docosahexaenoic acid and is required for male fertility in the mouse.

Docosahexaenoic acid (DHA) is an ω-3 dietary-derived polyunsaturated fatty acid of marine origin enriched in testes and necessary for normal fertility, yet the mechanisms regulating the enrichment of DHA in the testes remain unclear. Long-chain ACSL6 (acyl-CoA synthetase isoform 6) activates fatty acids for cellular anabolic and catabolic metabolism by ligating a CoA to a fatty acid, is highly expressed in testes, and has high preference for DHA. Here, we investigated the role of ACSL6 for DHA enrichment in the testes and its requirement for male fertility. Acsl6-/- males were severely subfertile with smaller testes, reduced cauda epididymal sperm counts, germ cell loss, and disorganization of the seminiferous epithelium. Total fatty acid profiling of Acsl6-/- testes revealed reduced DHA and increased ω-6 arachidonic acid, a fatty acid profile also reflected in phospholipid composition. Strikingly, lipid imaging demonstrated spatial redistribution of phospholipids in Acsl6-/- testes. Arachidonic acid-containing phospholipids were predominantly interstitial in control testes but diffusely localized across Acsl6-/- testes. In control testes, DHA-containing phospholipids were predominantly within seminiferous tubules, which contain Sertoli cells and spermatogenic cells but relocalized to the interstitium in Acsl6-/- testes. Taken together, these data demonstrate that ACSL6 is an initial driving force for germ cell DHA enrichment and is required for normal spermatogenesis and male fertility.