Peroxisomal DBP deficiency causes male infertility through disruption of lipid homeostasis in Drosophila - Cellular and Molecular Life Sciences
Peroxisomes are essential organelles in almost all eukaryotic cells with a variety of functions in cellular metabolism, including β-oxidation of very-long-chain fatty acids (VLCFAs). Impairment in peroxisome biogenesis or single enzyme function often causes human metabolic diseases. Adult male patients with mutations in HSD17B4, which encodes for D-bifunctional protein (DBP), the central enzyme of peroxisomal β-oxidation pathway, present with infertility defects in addition to neurological abnormalities. However, the pathogenic mechanism for DBP deficiency associated male infertility is not known. Here, we employ a Drosophila DBP deficiency model combined with scRNA-seq analysis to examine the pathogenic mechanism of male infertility in DBP deficient animals. We show that loss of Mfe2, the Drosophila ortholog of human HSD17B4, results in male infertility. Further analysis reveals that Drosophila Mfe2 mutant males display several defects in the progression of spermatogenesis, including a delay of cell cycle progression in spermatogonia and spermatocytes as well as defective meiotic cytokinesis. Moreover, aberrant central spindle and contractile ring behaviors are observed in Mfe2 mutant spermatocytes. Lipidomic analysis shows that many lipid derivatives, including phospholipids and sterols, decrease in Mfe2 mutant testes. The levels of phosphatidylinositol 4,5-biphosphate (PI(4,5)P2) and phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3) are both reduced at the cleavage furrow as well as the membrane of Mfe2 mutant spermatocytes. Importantly, diets supplemented with Asolectin, a mixture of polyunsaturated phospholipids, partially rescue the spermatocyte cytokinesis defects in Mfe2 mutants. Together, these results demonstrate the critical roles of Mfe2 during Drosophila spermatogenesis and shed light on our understanding of the pathogenic mechanism of male infertility caused by peroxisomal DBP deficiency.