Abstract
Docosahexaenoic acid (DHA) is one of the essential ω-3 polyunsaturated fatty acids with a wide range of physiological roles important for human health. For example, DHA renders cell membranes more flexible and is therefore important for cellular function, but information on the mechanisms that control DHA levels in membranes is limited. Specifically, it is unclear which factors determine DHA incorporation into cell membranes and how DHA exerts biological effects. We found that lysophosphatidic acid acyltransferase 3 (LPAAT3) is required for producing DHA-containing phospholipids in various tissues, such as the testes and retina. In this study, we report that LPAAT3-KO mice display severe male infertility with abnormal sperm morphology. During germ cell differentiation, the expression of LPAAT3 was induced, and germ cells obtained more DHA-containing phospholipids. Loss of LPAAT3 caused drastic reduction of DHA-containing phospholipids in spermatids that led to excess cytoplasm around its head, which is normally removed by surrounding Sertoli cells via endocytosis at the final stage of spermatogenesis. In vitro liposome filtration assay raised the possibility that DHA in phospholipids promotes membrane deformation that is required for the rapid endocytosis. These data suggest that decreased membrane flexibility in LPAAT3-KO sperm impaired the efficient removal of sperm content through endocytosis. We conclude that LPAAT3-mediated enrichment of cell membranes with DHA-containing phospholipids endows these membranes with physicochemical properties needed for normal cellular processes, as exemplified by spermatogenesis.
Highlights
We previously reported that lysophosphatidic acid acyltransferase 3 (LPAAT3) is an enzyme producing Polyunsaturated fatty acids (PUFAs)-containing phosphatidic acid (PA)
This was consistent with our recent hypothesis that the amount of Docosahexaenoic acid (DHA) in cell membranes is predominantly regulated by LPAATs, enzymes required for cha phospholipid biosynthesis [32]
In LPAAT3-KO mice, DHA-containing phospholipids, but not other PUFA-containing species, in the testes were dramatically decreased, suggesting the amount of DHA in the cell membrane is determined by LPAAT3
Summary
We previously reported that LPAAT3 is an enzyme producing PUFA-containing phosphatidic acid (PA). Stances around the LPAAT3-KO sperm head appear to be plasma membrane of Sertoli cells because nectin-2, a cell adhesion molecule expressed only in the Sertoli cells, was detected in the epididymal sperm of LPAAT3-KO but not HZ or WT mice (Fig. 5B) This suggests sperm–Sertoli cell junctions were not successfully removed when the sperm were released into seminiferous tubules. Coexistence of step 9 and step 16 spermatids (refer to supplemental Fig. S1) in the same stage of seminiferous tubules in LPAAT3-KO testis, which do not coexist normally (Fig. 5C), indicated that detachment of sperm–Sertoli cell junctions were perturbed in LPAAT3-KO mice Taken together, these results suggest that LPAAT3-KO mice failed to release mature sperm competent for normal fertilization. We propose that LPAAT3-mediated production of DHA-enriched flexible membrane is required for the normal spermiation
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