Sirt1 regulates acrosome biogenesis by modulating autophagic flux during spermiogenesis in mice

Abstract

Sirt1 is a member of the sirtuin family of proteins and has important roles in numerous biological processes. Sirt1 −/− mice display an increased frequency of abnormal spermatozoa, but the mechanism of Sirt1 in spermiogenesis remains largely unknown. Here, we report that Sirt1 might be directly involved in spermiogenesis in germ cells but not in steroidogenic cells. Germ cell-specific Sirt1 knockout mice were almost completely infertile; the early mitotic and meiotic progression of germ cells in spermatogenesis were not obviously affected after Sirt1 depletion, but subsequent spermiogenesis was disrupted by a defect in acrosome biogenesis, which resulted in a phenotype similar to that observed in human globozoospermia. In addition, LC3 and Atg7 deacetylation was disrupted in spermatids after knocking out Sirt1, which affected the redistribution of LC3 from the nucleus to the cytoplasm and the activation of autophagy. Furthermore, Sirt1 depletion resulted in the failure of LC3 to be recruited to Golgi apparatus-derived vesicles and in the failure of GOPC and PICK1 to be recruited to nucleus-associated acrosomal vesicles. Taken together, these findings reveal that Sirt1 has a novel physiological function in acrosome biogenesis.

Comparative proteomic analysis of round and elongated spermatids during spermiogenesis in mice

“…Autophagy is known as an intracellular lysosome‐ or vacuole‐dependent degradation, and recycling process extensively involved in all cellular physiological processes including spermiogenesis (Liu et al, ). Our data show that MAP 2K2, VAMP8, NAGA, CTSC, MAN2B1, ASAH1, PSAP, and GM2A were highly expressed in round spermatids, while ATG4 was specifically expressed in elongated spermatids.…”

PFN4 is required for manchette development and acrosome biogenesis during mouse spermiogenesis

“…SIRT1 ( Liu et al, 2017 ) and ATG7 ( Wang et al, 2014 ) deficient mice show inhibited autophagy, resulting in LC3BI/II and SQSTM1 accumulation and failure of proacrosomal granule formation and fusion. Our study on Pfn3 −/− shows a disturbance in the mTOR/AMPK pathway along with the accumulation of autophagosomes ( Umer et al, 2021 ).…”

Autophagy: A Double-Edged Sword in Male Reproduction

“…Additionally, TBC1D20 regulates the formation of acrosomes via facilitating autophagy flux [ 79 ]. Furthermore, Sirt1 regulates acrosome biogenesis by modulating autophagy flux during spermiogenesis [ 80 ].…”