Pre‐meiotic deletion of PEX5 causes spermatogenesis failure and infertility in mice

Abstract

Peroxisomes are involved in the regulation of various pathological processes. Peroxisomal biogenesis factor 5 (PEX5), which plays an essential role in peroxisomal biogenesis, is critical for reactive oxygen species (ROS) accumulation. However, its underlying functions in spermatogenesis have not yet been identified. Pex5 was deleted by crossing Stra8‐Cre mice with Pex5flox/flox mice before the onset of meiosis. The morphology of testes and epididymides, spermatogenesis function, and fertility in both wild type (WT) and Pex5−/− mice were analysed by haematoxylin and eosin (HE) and immunofluorescent staining. Mechanism of PEX5 affecting peroxisomes and spermatogenesis were validated by Western blot and transmission electron microscopy (TEM). Transcriptome RNA sequencing (RNA‐seq) was used to profile the dysregulated genes in testes from WT and Pex5−/− mice on postnatal day (P) 35. The adult Pex5 knockout male mice were completely sterile with no mature sperm production. Loss of Pex5 in spermatocytes resulted in multinucleated giant cell formation, meiotic arrest, abnormal tubulin expression, and deformed acrosome formation. Furthermore, Pex5 deletion led to delayed DNA double‐strand break repair and improper crossover at the pachytene stage. Impaired peroxisome function in Pex5 knockout mice induced ROS redundancy, which in turn led to an increase in germ cell apoptosis and a decline in autophagy. Pex5 regulates ROS during meiosis and is essential for spermatogenesis and male fertility in mice.

Gss deficiency causes age-related fertility impairment via ROS-triggered ferroptosis in the testes of mice

“…1C ). According to the expression pattern of γH2AX in the testis [ 29 , 30 ], the fluorescence intensity of GSS expression in various germ cells was counted using ImageJ software. In S8/Control male mice, GSS was at a lower level in spermatogonia, leptotene, and zygotene spermatocytes (Fig.…”

The peroxisome: an update on mysteries 3.0

“…Germ cell specific Pex5 deletion leads to impaired spermatocyte meiosis and spermatocyte apoptosis (Liu et al 2023 ) while a lack of Pex13 prevents germ cells from undergoing differentiation into spermatids (Brauns et al 2019 ). Why import-competent peroxisomes are necessary for healthy spermatogenesis is currently unclear, though the ROS accumulation seen in Pex5 -deficient germ cells, and the altered lipid profile observed in Pex13 -deficient testes, may suggest a role for peroxisomal ROS homeostasis and/or lipid metabolism in the process (Brauns et al 2019 ; Liu et al 2023 ). Consistent with the latter, numerous mouse models lacking enzymes involved in peroxisomal lipid metabolism are also infertile (Wang et al 2022a ).…”

“…Peroxisomes were initially suspected to play a role in mammalian spermatogenesis as they undergo significant rearrangements in terms of shape, distribution, and protein composition in the germ cells of mouse testes during the formation of mature spermatozoa (Dastig et al 2011). Several studies have recently confirmed the importance of functional peroxisomes for spermatogenesis in mammals, showing mouse models with testes-specific defects in peroxisomal matrix protein import cannot form mature spermatozoa and are thus infertile (Brauns et al 2019;Liu et al 2023). Germ cell specific Pex5 deletion leads to impaired spermatocyte meiosis and spermatocyte apoptosis (Liu et al 2023) while a lack of Pex13 prevents germ cells from undergoing differentiation into spermatids (Brauns et al 2019).…”

“…Several studies have recently confirmed the importance of functional peroxisomes for spermatogenesis in mammals, showing mouse models with testes-specific defects in peroxisomal matrix protein import cannot form mature spermatozoa and are thus infertile (Brauns et al 2019;Liu et al 2023). Germ cell specific Pex5 deletion leads to impaired spermatocyte meiosis and spermatocyte apoptosis (Liu et al 2023) while a lack of Pex13 prevents germ cells from undergoing differentiation into spermatids (Brauns et al 2019). Why import-competent peroxisomes are necessary for healthy spermatogenesis is currently unclear, though the ROS accumulation seen in Pex5-deficient germ cells, and the altered lipid profile observed in Pex13-deficient testes, may suggest a role for peroxisomal ROS homeostasis and/or lipid metabolism in the process (Brauns et al 2019;Liu et al 2023).…”

The peroxisome protein translocation machinery is developmentally regulated in the fungus Podospora anserina

“…In keeping with their functional versatility, peroxisomes are required for multiple developmental processes. Among them, many key aspects of the developmental processes that conduct sexual reproduction rely on peroxisomes ( 22 – 28 ). One such process is meiosis, the reductional division that allows for the alternation of the haploid/diploid phases of the sexual cycle and that promotes genetic recombination.…”